An Open Label, International, Multicenter, Dose Escalating Phase I/II Trial Investigating the Safety of Daratumumab in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed or Relapsed and Refractory Multiple Myeloma
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: Janssen Research & Development, LLC

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Status: Approved, Date: 29 September 2016
Janssen Research & Development*
Clinical Protocol
An Open label, International, Multicenter, Dose Escalating Phase 1/2 Trial Investigating 
the Safety of Daratumumab in Combination with Lenalidomide and Dexamethasone in 
Patients with Relapsed or Relapsed and Refractory Multiple Myeloma
Protocol GEN503; Phase 1/2
AMENDMENT 8
(Short Title: Daratumumab in Combination with Lenalidomide and Dexamethasone in Relapsed 
and in Relapsed-Refractory Multiple Myeloma)
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*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information
page that accompanies the protocol.
EudraCT NUMBER: 2011-005709-62
Status:
Approved  
Date:
29 September 2016
Prepared by:
Janssen Research & Development, LLC 
EDMS No:
EDMS-ERI-69461791
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT01615029

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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 6
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 28
ABBREVIATIONS ...................................................................................................................................... 42
1.
INTRODUCTION................................................................................................................................ 44
1.1.
Background .................................................................................................................................... 44
1.1.1.
Multiple Myeloma........................................................................................................................ 44
1.1.2.
Current Treatment of Multiple Myeloma ..................................................................................... 44
1.1.3.
Preclinical Pharmacology and Pharmacokinetics....................................................................... 45
1.1.4.
Preclinical Safety ........................................................................................................................ 46
1.1.5.
Clinical Experience ..................................................................................................................... 46
1.2.
Combination Therapy of Daratumumab, Lenalidomide, and Dexamethasone.............................. 46
1.3.
Overall Rationale for the Study...................................................................................................... 50
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 50
2.1.
Objectives ...................................................................................................................................... 50
2.2.
Hypothesis ..................................................................................................................................... 50
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 50
3.1.
Overview of Study Design.............................................................................................................. 50
3.2.
Rationale for Study......................................................................................................................... 52
3.2.1.
Rationale for Subject Population ................................................................................................ 52
3.2.2.
Rationale for Study Design......................................................................................................... 52
3.2.3.
Dose Rationale ........................................................................................................................... 53
3.2.3.1.
Phase 1 Dose Escalation ........................................................................................................ 53
3.2.3.2.
Daratumumab RP2D Rationale............................................................................................... 54
4.
STUDY POPULATION ...................................................................................................................... 54
4.1.
General Considerations ................................................................................................................. 54
4.2.
Inclusion Criteria ............................................................................................................................ 55
4.3.
Exclusion Criteria ........................................................................................................................... 56
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 59
5.1.
Subject Allocation Procedures ....................................................................................................... 59
5.2.
Blinding .......................................................................................................................................... 59
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 59
6.1.
Daratumumab ................................................................................................................................ 59
6.1.1.
Premedication............................................................................................................................. 61
6.2.
Lenalidomide.................................................................................................................................. 61
6.2.1.
Dose Adjustments of Lenalidomide............................................................................................ 61
6.2.1.1.
Deep Vein Thrombosis and Pulmonary Embolism.................................................................. 61
6.2.1.2.
Thrombocytopenia................................................................................................................... 62
6.2.1.3.
Neutropenia ............................................................................................................................. 62
6.2.1.4.
Renal Impairment .................................................................................................................... 62
6.2.1.5.
Other Grade 3 or 4 Adverse Events ........................................................................................ 63
6.3.
Dexamethasone............................................................................................................................. 63
6.3.1.
Dose adjustments of Dexamethasone........................................................................................ 63

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6.4.
Delaying or Skipping Treatment..................................................................................................... 63
6.5.
Dose-limiting Toxicities .................................................................................................................. 64
6.6.
Management of Infusion-related Reactions ................................................................................... 65
6.6.1.
Infusion-related Reactions of Grade 1 or 2................................................................................. 66
6.6.2.
Infusion-related Reactions of Grade 3 or Higher........................................................................ 66
7.
TREATMENT COMPLIANCE............................................................................................................ 66
8.
CONCOMITANT THERAPY.............................................................................................................. 67
8.1.
Recommended Concomitant Medications ..................................................................................... 67
8.2.
Prohibited Medications................................................................................................................... 67
9.
STUDY EVALUATIONS .................................................................................................................... 68
9.1.
Study Procedures by Visit.............................................................................................................. 68
9.1.1.
Overview..................................................................................................................................... 68
9.1.2.
Screening Period ........................................................................................................................ 68
9.1.3.
Treatment Period (Cycle X Visit X)............................................................................................. 68
9.1.3.1.
Treatment Follow-up as per Amendment 8............................................................................. 70
9.1.4.
Safety Follow-up Period.............................................................................................................. 70
9.2.
Assessments Following the Final Analysis .................................................................................... 70
9.2.1.
Clinical Assessments.................................................................................................................. 70
9.2.1.1.
Demographics.......................................................................................................................... 70
9.2.1.2.
Medical History ........................................................................................................................ 70
9.2.1.3.
Physical Examination .............................................................................................................. 71
9.2.1.4.
Electrocardiogram ................................................................................................................... 71
9.2.1.5.
Vital Sign Measurements......................................................................................................... 71
9.2.1.6.
Eastern Cooperative Oncology Group Performance Status ................................................... 72
9.2.1.7.
Concomitant Therapy .............................................................................................................. 72
9.2.1.8.
Adverse Events ....................................................................................................................... 72
9.2.1.9.
Skeletal Survey........................................................................................................................ 72
9.2.2.
Clinical Laboratory Assessments ............................................................................................... 72
9.2.2.1.
Biochemistry ............................................................................................................................ 73
9.2.2.2.
Hematology.............................................................................................................................. 73
9.2.2.3.
Serology for HIV, Hepatitis B, Hepatitis C, and Cytomegalovirus........................................... 74
9.2.2.4.
Pregnancy Test ....................................................................................................................... 74
9.2.3.
Myeloma-related Laboratory Efficacy Assessments .................................................................. 74
9.2.3.1.
Bone Marrow Assessments..................................................................................................... 75
9.2.3.2.
Serum Immunoglobulin A, M, and G (M-component).............................................................. 75
9.2.3.3.
Urinalysis for M-component..................................................................................................... 75
9.2.3.4.
Serum Free Light Chain Ratio................................................................................................. 75
9.2.3.5.
Prognostic Factors- Phase 1 only............................................................................................ 75
9.2.4.
Pharmacokinetics and Immunogenicity Assessments ............................................................... 76
9.2.5.
Analytical Procedures................................................................................................................. 78
9.2.6.
Pharmacokinetic Parameters ..................................................................................................... 78
9.2.6.1.
Immunogenicity Assessments................................................................................................. 78
9.2.6.2.
Biomarker Assessments.......................................................................................................... 79
9.2.6.2.1.
Phase 1 Biomarker Analyses............................................................................................... 79
9.2.6.2.1.1.
Levels of Soluble CD38 .................................................................................................... 79
9.2.6.2.1.2.
Complement...................................................................................................................... 79
9.2.6.2.1.3.
Levels of Circulating NK Cells, B, and T Cells (Flow Cytometry) ..................................... 79
9.2.6.2.2.
Phase 2 Biomarker Analyses............................................................................................... 79
9.2.6.2.3.
Phase 2 Pharmacogenomics ............................................................................................... 80
9.3.
Endpoints ....................................................................................................................................... 81
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 81
10.1.
Discontinuation of Study Treatment............................................................................................... 81
10.2.
Withdrawal ..................................................................................................................................... 81

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11.
STATISTICAL METHODS................................................................................................................. 83
11.1.
Subject Information ........................................................................................................................ 83
11.2.
Sample Size Determination ........................................................................................................... 83
11.3.
Analysis Sets.................................................................................................................................. 83
11.4.
Efficacy Analyses ........................................................................................................................... 84
11.5.
Pharmacokinetic Analyses............................................................................................................. 84
11.6.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 85
11.7.
Subgroup and by Center Analyses ................................................................................................ 85
11.8.
Exploratory Modeling ..................................................................................................................... 85
11.9.
Immunogenicity Analyses .............................................................................................................. 85
11.10.
Biomarker and Pharmacogenomic Analyses................................................................................. 85
11.11.
Safety Analyses ............................................................................................................................. 86
11.12.
Interim Analysis.............................................................................................................................. 86
11.13.
Data Monitoring Committee ........................................................................................................... 86
12.
ADVERSE EVENT REPORTING ...................................................................................................... 88
12.1.
Study Disease ................................................................................................................................ 88
12.2.
Pre-existing Conditions .................................................................................................................. 88
12.3.
Diagnostic and Therapeutic Noninvasive and Invasive Procedures.............................................. 88
12.4.
Definitions ...................................................................................................................................... 88
12.4.1.
Adverse Event Definitions and Classifications ........................................................................... 88
12.4.2.
Attribution Definitions.................................................................................................................. 89
12.4.3.
Severity Criteria .......................................................................................................................... 90
12.5.
Special Reporting Situations.......................................................................................................... 90
12.6.
Procedures..................................................................................................................................... 91
12.6.1.
All Adverse Events...................................................................................................................... 91
12.6.2.
Serious Adverse Events ............................................................................................................. 92
12.6.3.
Pregnancy................................................................................................................................... 93
12.6.3.1.
Pregnancy Reporting............................................................................................................... 93
12.7.
Contacting Sponsor Regarding Safety........................................................................................... 94
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 94
13.1.
Procedures..................................................................................................................................... 94
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 95
14.
STUDY DRUG INFORMATION......................................................................................................... 95
14.1.
Physical Description of Study Drug(s) ........................................................................................... 95
14.2.
Packaging ...................................................................................................................................... 95
14.3.
Labeling.......................................................................................................................................... 95
14.4.
Preparation, Handling, and Storage............................................................................................... 95
14.5.
Drug Accountability ........................................................................................................................ 96
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 96
16.
ETHICAL ASPECTS ......................................................................................................................... 96
16.1.
Study-Specific Design Considerations........................................................................................... 96
16.2.
Regulatory Ethics Compliance....................................................................................................... 97
16.2.1.
Investigator Responsibilities ....................................................................................................... 97
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 97
16.2.3.
Informed Consent ....................................................................................................................... 98
16.2.4.
Privacy of Personal Data ............................................................................................................ 99
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 100
16.2.6.
Country Selection ..................................................................................................................... 100
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 100
17.1.
Protocol Amendments.................................................................................................................. 100
17.2.
Regulatory Documentation .......................................................................................................... 101
17.2.1.
Regulatory Approval/Notification .............................................................................................. 101
17.2.2.
Required Prestudy Documentation........................................................................................... 101

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17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 102
17.4.
Source Documentation................................................................................................................. 102
17.5.
Case Report Form Completion .................................................................................................... 102
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 103
17.7.
Record Retention ......................................................................................................................... 103
17.8.
Monitoring .................................................................................................................................... 104
17.9.
Close-out of Extended Safety Follow-up...................................................................................... 104
17.10.
On-Site Audits .............................................................................................................................. 105
17.11.
Use of Information and Publication.............................................................................................. 105
REFERENCES.......................................................................................................................................... 107
INVESTIGATOR AGREEMENT ............................................................................................................... 119
LAST PAGE.............................................................................................................................................. 119

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LIST OF ATTACHMENTS
Attachment 1: Eastern Cooperative Oncology Group Performance Status.............................................. 109
Attachment 2: Prior Cancer Therapy for Multiple Myeloma...................................................................... 110
Attachment 3: New York Heart Association Criteria for Functional Classification.................................... 111
Attachment 4: Conversion Table for Glucocorticoid Dose........................................................................ 112
Attachment 5: International Myeloma Working Group Uniform Response Criteria .................................. 113
Attachment 6: Model of Worst Toxicity ..................................................................................................... 115
Attachment 7: Calculated Creatinine Clearance....................................................................................... 116
Attachment 8: Limited Schedule of Events for Subjects Continuing Daratumumab as of 
Amendment 7 ........................................................................................................... 117
Attachment 9: Limited Schedule of Events for Subjects Continuing Daratumumab as of 
Amendment 8 ........................................................................................................... 118
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Phase 1 Time and Events Schedule......................................................................................... 33
Table 2:
Phase 2 Time and Events Schedule......................................................................................... 36
Table 3:
Time and Events Schedule as of Amendment 7 (see also Attachment 8) ............................... 40
Table 4:
Time and Events Schedule as of Amendment 8 (see also Attachment 9) ............................... 41
Table 5:
Phase 1 Infusion Rate Recommendations ............................................................................... 60
Table 6:
Phase 2 Infusion Rate Recommendations ............................................................................... 60
Table 7:
Lenalidomide Dose Adjustment for Thrombocytopenia............................................................ 62
Table 8:
Lenalidomide Dose Adjustment for Neutropenia ...................................................................... 62
Table 9:
Lenalidomide Dose Adjustment for Renal Impairment ............................................................. 63
Table 10:
Phase 1 Sample Collection Times for Determination of Daratumumab Concentration 
in Serum.................................................................................................................................... 77
FIGURES
Figure 1:
Improvement of Daratumumab-induced Antibody-dependent Cell-mediated 
Cytotoxicity by Lenalidomide in Bone Marrow Mononuclear Cells from Patients with 
Multiple Myeloma...................................................................................................................... 48
Figure 2:
Addition of Daratumumab to Lenalidomide Significantly Increases the Lysis of Multiple 
Myeloma Cells in Bone Marrow Mononuclear Cells of Patients with Lenalidomide-
refractory Multiple Myeloma...................................................................................................... 49

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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
16 December 2011
Amendment 1
03 February 2012
Amendment 2
23 February 2012
Amendment 3
06 July 2012
Amendment 4
25 February 2013
Amendment 5
26 February 2014
Amendment 6
12 January 2015
Amendment 7
06 October 2015
Amendment 8
29 September 2016
Amendments are listed beginning with the most recent amendment.
Amendment 8 (29 September 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European. Deleted text will be indicated by a 
strikethrough.
The overall reason for the amendment: The final analysis of this study has been achieved (all subjects in Phase 1 
or 2 have either received more than 24 months of study drug or discontinued), therefore the study is being amended 
to allow ongoing subjects to continue receiving study drug and limiting data collection to safety follow-up only 
(serious adverse events [SAEs] and second primary malignancies [SPMs]). Daratumumab will be provided until it is 
approved in combination with lenalidomide and dexamethasone and commercially available to patients with 
relapsed/ refractory multiple myeloma in the participating countries.
Applicable Section(s)
Description of Change(s)
Rationale: A description of the circumstances under which commercial supplies of daratumumab will be provided 
to study subjects was added.
Synopsis. Overview 
of Study Design
Added the following text: Daratumumab will be provided until it is approved for use in 
combination with lenalidomide and dexamethasone and is commercially available for 
patients with relapsed/refractory multiple myeloma in the countries where subjects are still 
receiving combination treatment. Subjects still receiving treatment will be transitioned 
from study drug to commercial product once commercial product is available in their 
region (or when daratumumab can be accessed from another source). In these 
circumstances, the Sponsor and investigator will support transition of the subject to ensure 
that treatment continues and remains uninterrupted. Subjects who are unable to switch to 
commercial supplies will continue to remain on study. All subjects will be followed for 3 
years after the last dose of lenalidomide, to enable collection of secondary primary 
malignancy (SPM). 
Table 4. Time and Events Schedule as of Amendment 8 and Attachment 9 Limited 
Schedule of Events for Subjects Continuing Daratumumab as of Amendment 8 were
added. 

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Applicable Section(s)
Description of Change(s)
Rationale: A description of the data collection methods to be used and the duration of data collection following the 
switch to commercial supply of daratumumab were added. 
Synopsis. Statistical 
Methods
Added the following text: NOTE: As of Amendment 8, the final analysis will have been 
achieved. All subjects in the study have either received at least 24 months of study drug or 
have discontinued study drug. Ongoing subjects may continue treatment with study drug. 
Disease assessments/response evaluations will be performed per local institutional 
practice. Safety information will be limited to collection of data regarding SAEs and 
SPMs. All subjects will be followed for 3 years after the last dose of lenalidomide, to 
enable collection of SPMs.
The study will end when daratumumab is approved for use in combination with 
lenalidomide and dexamethasone and is commercially available. Subjects still receiving 
treatment will be transitioned from study drug to commercial product once commercial 
product is available in their region (or when daratumumab can be accessed from another
source) and will be withdrawn from this study at that time. In these circumstances, the 
sponsor and investigator will support transition of the subject to ensure that treatment 
continues uninterrupted. All subjects will be followed for 3 years after the last dose of 
lenalidomide, to enable collection of SPMs.
Rationale: Description of the data cutoffs was added. 
3.1. Overview of 
Study Design
Added the following text: The study will have 3 data cutoff time points:

The first data cutoff will be for the interim safety analysis, which is estimated to 
be performed approximately 6 months after the last subject in the study receives 
the first dose of daratumumab. All available data at the time of this data cutoff 
will be included in the abbreviated Clinical Study Report (CSR). 

The second data cutoff will be for the primary safety analysis, which is estimated 
to be performed approximately 12 months after the last subject in the study 
received the first dose of daratumumab. All available data at the time of this data 
cutoff will be included in the abbreviated CSR.
As of Amendment 8, the following data cutoff is yet to be completed.

The third and final data cutoff will be for the updated safety analysis, which is 
estimated to be performed approximately 24 months after the last subject in the 
study receives the first dose of daratumumab. All available data at the time of this 
data cutoff will be included in a final CSR addendum.
Rationale: The allowed and prohibited medications and therapies were revised. 
8. Concomitant 
Medications
Deleted the following text: During the Follow up Period and at the End of Trial (EOT) 
Visit, only therapies that are or may be active against multiple myeloma, erythropoietin, 
and medications for skeletal disease must be recorded.
The sponsor must be notified in advance (or as soon as possible thereafter) of any 
instances in which prohibited therapies are administered.
8.2. Prohibited 
Medication
Revised the following text: Local radiotherapy for bone pain may beis allowed. after 
completion of Cycle 2 upon approval by the sponsor’s medical officer.

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Applicable Section(s)
Description of Change(s)
Rationale: Evaluations were revised to indicate the procedures relevant to the use of commercial daratumumab.
9.1.3.1. Treatment 
Follow-up as per 
Amendment 8
Added the following text: As per Amendment 8, subjects will continue to be dosed as per 
Amendment 8 schedule (1 cycle is 28 days) and Table 4. 
Data collection will be limited to SAEs and SPMs, see details in Section 12 and 
Attachment 9. 
Daratumumab will be provided by the sponsor until it is approved for use in combination 
with lenalidomide and dexamethasone for patients with relapsed refractory multiple 
myeloma and is commercially available or can be accessed from another source. Subjects 
receiving treatment will be transitioned from study drug to commercial product once 
commercial product is available in their region (or when daratumumab can be accessed 
from another source). In these circumstances, the sponsor and investigator will support 
transition of the subject to ensure that treatment continues and remains uninterrupted. 
Subjects who are unable to switch to commercial supplies will continue to remain in the 
study. Limited data will be collected for 3 years after the last dose of lenalidomide, to 
enable collection of SPMs.
Deleted the following sections: Follow-up Period and End of Trial Visit
9.1.4. Safety Follow-
up Period
Deleted the following text: After their last dose of lenalidomide, subjects will be followed 
for 3 years (at 6 month intervals) to assess survival, occurrence of new cancers, and new 
antimyeloma treatment. Investigators will be asked to contact the subjects every 3-6 
months to collect this information.
Deleted Unscheduled Visits
9.2. Assessments 
Following the Final 
Analysis
Added the following text: Data collection will only include SAEs and SPMs; see details in 
Section 12 and Attachment 9.
Deleted all text regarding collection of any other adverse event data. 
9.2.4. 
Pharmacokinetics and 
Immunogenicity
Added the following text: As of Amendment 8, blood sample collection will stop and not 
be performed after the last dose of daratumumab. One final sample should be taken before 
the start of the last infusion per Amendment 7.
Deleted all text regarding collection of blood samples as per Amendment 7.
Rationale: The descriptions of subject and study completion were updated to reflect the changes necessitated by use 
of the commercial source of daratumumab.
10. Subject 
Completion/ 
Withdrawal
Deleted the following text: A subject will be considered as having completed the study if 
he or she has completed all visits through the EOT Visit and the posttreatment Week 8 
immunogenicity sampling. Subjects who are withdrawn from the study for any reason 
before completion of this visit will not be considered to have completed.
Added the following text: Subjects will be considered as having completed the study if 
he/she has consented to Amendment 8.
10.1 Discontinuation 
of Study Treatment
Deleted the following text: If a subject's study treatment must be discontinued before the 
end of the treatment regimen, this will not result in automatic withdrawal of the subject 
from the study. 
10.2 Withdrawal
Added the following bullet and text: 

Treatment is delayed for more than 3 weeks and no approval to continue is given by 
the sponsor
If a subject discontinues study treatment or is transferred to commercial supplies, as per 
Amendment 8, follow-up for the occurrence of SPMs will continue for up to 3 years after 
the last dose of lenalidomide.
Deleted all text describing procedures for withdrawal from the study prior to 
Amendment 8.

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Applicable Section(s)
Description of Change(s)
Rationale: The reporting situations and procedures were revised to indicate changes necessitated by limits to the 
data collection.
12.5. Special 
Reporting Situations
Occurrence of SPM was added.
12.6. Procedures
Added the following text: As per Amendment 8, only SAEs and SPMs will be collected 
(see Table 4 and Attachment 9). The SAE and SPM data should be entered in the subject 
file/notes. 
Any SPM that occurs during a subject’s participation in the study or for 3 years after the 
last dose of lenalidomide is considered an immediately reportable event. It must be 
reported to the sponsor within 24 hours after the investigator has gained knowledge of it by 
using the SPM form attached to the regular SAE form. 
Rationale: The handling and storage of daratumumab were revised.
14.4. Preparation, 
Handling, and Storage
Preparation of infusion bags should be done on the day of the planned infusion, and the 
time of the dilution should be written on the infusion bag. After preparation, the infusion 
should be kept at room temperature. If the study drug must be stored for longer than 
3 hours after it has been diluted in 0.9% NaCl before initiation of the infusion, it must be 
kept at 2C to 8C. The prepared infusion bags should be kept at room temperature for 
approximately 1 hour before infusion. The infusion should be completed no later than 
24 hours after preparation. Daratumumab must be administered as an IV infusion. The 
infusion should be given through a well-functioning IV catheter by using an infusion 
pump. The study drug must be filtered by using an inline filter (0.2 m) during the 
infusion.
Rationale: The reporting situations and procedures were revised to indicate changes necessitated by limits to the 
data collection
17.8. Monitoring
Added the following text: As per Amendment 8, on site vVisits are usually made at 
intervals of at least 4 to 1224 weeks. A phone call will be done in between (at 12 weeks). 
At these visits, the monitor will monitor the adequate reporting and follow-up of SAEs, 
SPMs, drug receipt/dispensing/return records and ensure subjects who showed progressive 
disease stopped the study treatment. 
Deleted all text regarding data collection as per study protocol prior to Amendment 8. 
17.9. Close-out of 
Extended Safety 
Follow-up
Added the following text: The extended safety follow-up will be completed 3 years after 
the last subject took the last lenalidomide dose and completed follow-up for the occurrence 
of SPMs. 
Deleted Study Completion: Per the study design, the study is considered completed after 
the last subject participating in the study is administered study drug per schedule 
withdraws consent, dies, is lost to follow up, completes safety follow up, or the study is 
terminated by the sponsor.
Rationale: Minor errors were noted and updates provided
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.  The following 
abbreviations were added CSR, RBC, SPM.
15 Study Specific 
Materials
The following items were deleted as they were no longer necessary: Access to the eCRFs
(usernames, passwords, and training for personnel designated to perform data entry); 
Clinical laboratory supplies; Laboratory manual; eDC Manual, and Investigator Brochure.

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Amendment 7 (06 October 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union
The overall reason for the amendment: The primary analysis of this study has been achieved (all subjects in 
Phase 1 or 2 have either received more than 12 months of study drug or discontinued), therefore the study is being 
amended to allow ongoing subjects to continue receiving study drug with a limited schedule of assessments.
Applicable Section(s)
Description of Change(s)
Rationale: Following the primary analysis, ongoing subjects will follow a limited schedule of assessments. 
Synopsis Added a 
note following the 
Statistical Methods
section;
9.2. Assessments 
Following the
Primary Analysis
Added the following text: 
NOTE: As of Study 54767414GEN503 Protocol Amendment 7, the primary analysis will 
be achieved. All subjects in the study have either received at least 12 months of study drug 
or have discontinued. Ongoing subjects may continue treatment with study drug with a 
limited schedule of assessments. Disease assessments/response evaluations will be 
performed per local institutional practice. Safety information will be limited to study drug 
administration, serious adverse events (SAEs, including secondary malignancies), 
concomitant medications associated with SAEs, and pregnancy testing. No additional PK 
blood sampling will be performed, samples will be collected only for immunogenicity and 
the same samples will be used for determination of the associated daratumumab serum 
concentrations. Follow up will include collection of survival information, best response 
and new antimyeloma therapies, and secondary malignancies every 6 months for 3 years 
after the last dose of study drug or termination of the study by the sponsor, whichever 
occurs first. 
Revised the heading for Section 9.2
Attachment 8 and 
Table 3
Attachment 8 was added, which includes details for the limited assessment schedule as of 
this amendment. Table 3 provides the modified Time and Events Schedule. 
9.1.1 Overview; 
Added text regarding changes with Amendment 7.
9.2.2 Clinical 
Laboratory 
Assessments; 9.2.2.4 
Pregnancy Test; 9.2.3 
Myeloma-related 
Laboratory Efficacy 
Assessments
Modification with this amendment that clinical laboratory assessments (efficacy and 
safety) will now be performed by local laboratories with timing based on local institutional 
practice. Pregnancy tests will continue as scheduled and analyzed by local laboratories.
9.2.4 
Pharmacokinetics and 
Immunogenicity 
Assessments; Table 3; 
Attachment 8
As of Amendment 7, immunogenicity samples will be taken at Weeks 4 and 8 after the last 
dose of study. The same sample will be used to determine the associated daratumumab 
concentration.
Revised heading 9.2.4 and removed heading 9.2.4.1
12.6.1 All Adverse 
Events
As of Amendment 7, only SAEs will be collected and the SAEs should be reported in the 
subject file/source notes.
Rationale: Error noted in Section 6.1 stating that daratumumab treatment would be limited to 18 cycles maximum. 
Treatment with daratumumab can continue until unacceptable toxicity or disease progression, whichever occurs 
first. 
6.1 Daratumumab
Removed “for 18 cycles or”

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Applicable Section(s)
Description of Change(s)
Rationale: Additional information provided about daratumumab interference with indirect antiglobulin test. 
9.2.2.2 Hemoglobin
Additional information provided regarding daratumumab interference with indirect 
antiglobulin test including possible methods for blood banks to provide safe red blood 
cells for subjects receiving daratumumab.
Rationale: Modified the subject completion statement to include the immunogenicity sample (8 weeks after last 
dose of study drug)
10.1 Subject 
Completion
Revised the text: A subject will be considered as having completed the study if he or she 
has completed all visits through the EOT Visit and the posttreatment Week 8 
immunogenicity sampling.
Rationale: As of Amendment 7, there is no longer a Follow-up Period before the EOT visit. Ongoing subjects were 
unlikely to discontinue daratumumab and continue another 2 cycles with lenalidomide/dexamethasone alone 
10.3 Withdrawal from 
the Study
Before Amendment 7 if the subject was withdrawn or discontinued treatment before 
disease progression, the subjects entered a Follow-up Period until disease progression. 
With Amendment 7, there is no longer a Follow-up Period before the EOT visit. 
Removed the following: A subject may be withdrawn from daratumumab and continue 
treatment with Len/Dex alone for a maximum of 2 additional cycles and then enter the 
Follow-up Period. If a subject must discontinue lenalidomide treatment for any reason, he 
or she will be withdrawn from the Treatment Period and will enter the Follow-up Period.
Rationale: The IDMC will no longer evaluate safety after the primary analysis.
11.13 Data Monitoring 
Committee
Added the following statement: The IDMC will no longer be evaluating safety data after 
the primary analysis.
Rationale: The IDMC is no longer evaluating safety after the primary analysis, therefore the definition of study 
completion is no longer applicable. 
17.9.1 Study 
Completion
New definition of study completion: Per the study design, the study is considered
completed after the last subject participating in the study is administered study drug per 
schedule, withdraws consent, dies, is lost to follow up, completes safety follow up, or the 
study is terminated by the sponsor.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.

JNJ-54767414 daratumumab
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Amendment 6 (12 January 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to remove the Phase 1 Time and 
Events Schedule, and to modify the requirements for bone marrow sample collection to allow for differences across 
countries in local clinical practice.
Applicable Section(s)
Description of Change(s)
Rationale: Subjects enrolled in Phase 1 have met all the predefined assessments of Phase 1, have been on study 
treatment for more than 12 months, and are no longer required to follow the Phase 1 schedule of safety and 
pharmacokinetic (PK) assessments, given the data currently available regarding use of the dara/len/dex combination.
Synopsis, Statistical Methods;
Table 1 (Phase 1 Time and Events 
Schedule); 9.2 Assessments; 
Table 8
Text added to explain that subjects enrolled in Phase 1 will now follow the 
Phase 2 Time and Event Schedule.
9.2.4.1. Daratumumab 
Concentration in Serum
Text revised to explain that subjects in Phase 1 will now follow the Phase 2 
Time and Event Schedule for timings of PK assessments.
Rationale: To provide specific details regarding why the blood type is needed and how it should be executed.
9.2.2.2. Hematology
Added text regarding the reason for the blood type testing.
Text was deleted: Direct and indirect Coombs tests will be performed at all
daratumumab infusion visits (before infusion and 2 hours after the end of 
infusion) and all follow up visits until no antibodies are detected. In addition, 
these tests will be performed at the EOT Visit for all subjects, including those 
who withdraw from the study. 
Rationale: To provide more specific detail regarding recalculation of the daratumumab dose based on weight 
change.
Table 2 (Phase 2 Time and Events 
Schedule); 6.1. Daratumumab
Added a statement that the dose of daratumumab does not need to be
recalculated for weight changes <10% from baseline.
Footnote “q” added to T&E table.
Rationale: Infusion of daratumumab via syringe pump is not permitted.
14.4. Preparation, Handling, and 
Storage
Modified text in to indicate that infusion of daratumumab via syringe pump 
is not permitted. 
Rationale: For safety reasons and for consistency across daratumumab studies.
6.4. Delaying or Skipping 
Treatment
Added text that specifies that ONLY if any of the criteria in this section are 
met and the event cannot be ascribed to lenalidomide, the daratumumab 
infusion must be held to allow for recovery from toxicity. 
Modified the criteria for a dose delay to include febrile neutropenia of any 
grade, and to include neutropenia with infection of any grade.
Rationale: To allow for the use of alternate methods of calculation for creatinine clearance.
6.2.1.4. Renal Impairment 
(Table 7); References; 
Attachment 7
Revised text to state that in addition to the Cockcroft-Gault formula, the 
Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formulas may also be used for 
creatinine clearance calculation. 

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Rationale: To address questions from investigative sites.
6.6. Management of Infusion-
related Reactions 
Clarified the definition of subjects with a higher risk of respiratory 
complications as subjects with COPD who have an FEV1<80%, or subjects 
with mild asthma. 
Rationale: Lenalidomide does not need to be taken at the same time as the premedications. The recommendation 
for timing of daratumumab infusion in relation to lenalidomide is no longer applicable.
6.2. Lenalidomide
Modified the text to say that lenalidomide may be administered prior to or
at the same time (preferred) as the premedications. 
Removed the statement that the daratumumab infusion should begin 
approximately 1 hour after the lenalidomide administration. 
Rationale: Lenalidomide is commonly associated with tiredness.
6.2. Lenalidomide
Specified that for days on which daratumumab is not administered,
lenalidomide may be taken in the evening. 
Rationale: To add more detail about prohibited medications.
8.2. Prohibited Medications
Added text to specify that in addition to concomitant administration of 
medications for any other anti-neoplastic therapy for the intention of treating 
multiple myeloma, medications that target CD38 are prohibited, as well as 
medications for other indications that have antimyeloma properties (eg, 
interferon and clarithromycin). 
Rationale: For consistency and alignment across daratumumab protocols with respect to analyses on serum 
samples.
9.2.4.1. Daratumumab Concentration in Serum
Text deleted: Samples collected for determining serum 
concentrations of daratumumab in this study may be retained to 
address questions about drug characteristics that may arise at a 
later time point. Genetic analyses will not be performed on these 
samples, and subject confidentiality will be maintained.
9.2.5. Analytic Procedures 
Text added: Adjustments to bioanalysis timing may be made if it 
is later determined that the timing for data needed to facilitate 
crucial decision-making differs from these two planned efforts. 
However, data from each round of bioanalysis will be considered 
final and samples will not be reanalyzed in any subsequent 
efforts.
11.5. Pharmacokinetic Analyses
Text added: If sufficient data are available, population PK 
analysis of serum concentration-time data of daratumumab may 
be performed and the analysis may include data from other 
studies. If the population PK analysis is conducted, details will 
be specified in a population PK analysis plan, and the results of 
the analysis will be presented in a separate report.
11.6 Pharmacokinetic/Pharmacodynamic 
Analyses
Section 11.6 added: If sufficient data are available, 
pharmacokinetic/pharmacodynamic modeling may be 
performed, including exploring the relationship between serum 
concentrations of daratumumab and endpoints of clinical 
efficacy. If performed, details and results of the analysis will be 
presented in a separate report.

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Rationale: Placement of text regarding efficacy assessments during the follow-up period was placed in the incorrect 
section of protocol. Follow-up period applies to all Cycles, not just Cycles 1-6.
9.1.4. Follow-up Period; 
9.1.6. Safety Follow-Up Period
Text regarding follow-up procedures for efficacy assessments (If a subject 
completes or discontinues treatment without progression, the subject will be 
assessed at 8 week intervals till disease progression or until he or she starts 
new antimyeloma treatment) was moved from Section 9.1.6 (Safety Follow-
up Period) to Section 9.1.4 (Follow-up Period) where it correctly belongs.
Text deleted from Section 9.1.4 header: (Cycles 1-6).
Rationale: Subjects can continue in study until progressive disease or new antimyeloma treatment.
Table 2 (Phase 2 Time and Event 
Schedule);
9.1.4. Follow-up Period;
9.1.6. Safety Follow-up Period
Footnote “r” added to clarify that these assessments are performed on 
subjects without disease progression.
Additional rows added to Table 2 to account for assessment of survival and 
new antimyeloma treatment during the Safety Follow-up Period.
Text regarding follow-up assessments was revised to specify that subjects 
will be assessed at 8 week intervals until death or lost to follow up.
Text revised to clarify that survival and new antimyeloma treatment use will 
be assessed during Safety Follow-up Period.
Rationale: Change made based on a health authority request that annual IEC/IRB approval is not applicable in all 
countries.
Section 16.2.2. Independent Ethics 
Committee or Institutional Review 
Board
Replaced the statement that the IEC/IRB must review and reapprove the 
study at least once a year with a statement indicating that where required, 
progress reports/written summaries of the study status will be submitted to 
the IEC/IRB annually, or more frequently if requested.
Rationale: Clarification regarding start of study cycle.
Synopsis Dosage and 
Administration; 6. Dosage and 
Administration
Provided definition of start of study cycle.
Rationale: Clarification that bone marrow assessment can include aspirate or biopsy.
Table 2 (Phase 2 Time and Event 
Schedule);
9.2.3.1. Bone Marrow Assessment
Text added: Bone marrow aspirate/bone marrow biopsy.
Text revised to specify bone marrow biopsy and/ or aspirate
Rationale: A lack of sufficient baseline samples are available to perform posttreatment minimal residual disease 
(MRD) assessment.
Synopsis Biomarker Evaluations; 
Table 2 (Phase 2 Time and Event 
Schedule); 9.2.3.1. Bone Marrow 
Assessments; 9.2.6.2.2 Phase 2 
Biomarker Analyses; 9.2.6.2.3. 
Phase 2 Pharmacogenomics
Text deleted about MRD assessment.
Text deleted in footnote “g” about MRD assessment.
Rationale: Recent data suggest that treatment with Len/Dex should continue until progressive disease or 
unacceptable toxicity rather than at a fixed timepoint.
Table 2 (Phase 2 Time and Events 
Schedule) 
Column for “Daratumumab continuation only” assessment deleted. Footnote 
“p” associated with this column deletion.
Rationale: Clarification regarding PK assessment.
Table 2 (Phase 2 Time and Event 
Schedule)
Text added to footnote “l”  to clarify one sample is collected before the 
daratumumab infusion and another sample after the end of the daratumumab 
infusion.

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Rationale: For consistency throughout the protocol.
6.3. Dexamethasone
Text added: Dexamethasone will be administered until the subject 
experiences disease progression or unacceptable toxicity, whichever comes 
first.
Rationale: Electrocardiograms will no longer be sent to the central laboratory; local ECG tracing collection is now 
acceptable based on data collected to date.
9.2.1.4. Electrocardiogram
Text deleted: Digital ECGs will be transmitted from the sites electronically to 
a central laboratory (eResearch Technology, Inc) for a treatment-blinded 
measurement of the cardiac rhythm and assessment of morphology by a 
central cardiologist.
Rationale: Alignment with other daratumumab protocols.
12.6.1. All Adverse Events
Text revised to state that adverse events will be collected within 30 days of 
the last dose of any component of the treatment regimen.
Rationale: Subjects may continue daratumumab treatment beyond 24 cycles.
Table 2 (Phase 2 Time and Event 
Schedule)
Changed range of Study visits column header from “7-24” to “7+”.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 5 (26 February 2014)  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: This amendment included defining the change in sponsor to Janssen
Research & Development (JRD) and converting to the JRD protocol template. Additionally 10 of the approximately 
30 subjects enrolled on Phase 2 will have shortened infusion times for the first daratumumab infusion to evaluate the 
safety and incidence of infusion related reactions when infusion time is shortened. Eligibility criteria have also been 
modified to remove the cap placed on prior lines of therapy to allow a broader population to be studied in Phase 2.
Applicable Section(s)
Description of Change(s)
Rationale: JRD has taken over responsibility of this study from Genmab A/S in a partnership effort to develop 
daratumumab.
Global
Changed sponsor name from Genmab A/S to Janssen Research & 
Development
Rationale: The Time and Event Schedules were revised to reflect the changes made in the assessments for the study
and to provide more detail and clarity by adding separate tables for assessment in Phase 1 and Phase 2. 
Table 1 and Table 2 Time and 
Event Schedules
Revised Table 1 (Time and Event Schedule) to reflect changes in the 
protocol. Added Table 2 (Time and Event Schedule for Phase 2 which 
includes pharmacokinetic/immunogenicity and exploratory biomarker 
assessments) for clarity
Rationale: A secondary objective was added to evaluate immunogenicity using JRD analysis methods.
Synopsis, Section 2.1 Objectives
Added secondary objective for immunogenicity.
Synopsis, T&E
HAHA immunogenicity was removed from Phase 1, as all immunogenicity 
samples will now be analyzed using the JRD methods.

JNJ-54767414 daratumumab
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Sections 9.2.4 Pharmacokinetics 
and Immunogenicity Assessments, 
Sections 9.2.5 Analytical 
Procedures, 9.2.6.1 
Immunogenicity Assessments, 11.8
Immunogenicity Analyses
Immunogenicity assessments clarified for Phase 1 and Phase 2. Additional 
details for sample collection, handling, and storage were added. Details of 
analysis procedures were added. 
Rationale: Preclinical and clinical text shortened and link added to Investigator’s Brochure (IB).
Sections 1.1.3 Preclinical
Pharmacology and 
Pharmacokinetics; 1.1.4 Preclinical 
Safety; 1.1.5 Clinical Experience
Text was removed and link to IB added.
Section 1.2 Combination Therapy 
of Daratumumab, Lenalidomide, 
and Dexamethasone
Text regarding the most commonly reported AEs in GEN 501 was removed as 
it is no longer relevant.
Rationale: The study hypothesis was added to clarify no formal statistical hypothesis will be tested and to conform 
to the JRD template.
Synopsis, Section 2.2 Hypothesis
Added hypothesis
Rationale: The number of subjects to be enrolled into Phase 2 was revised to approximately 30 subjects and 
clarified 3+3 rules for dose escalation.
Synopsis, Sections 3.1 Overview of 
Study Design, 3.2.2 Rationale for 
Study Design, 11.2 Sample Size 
Determination;
Added text “the standard “3 + 3” rules for dose escalation will be applied, 
However, if the study sites have identified 4 eligible subjects to start a new 
dose level, all 4 subjects may be enrolled.”
Revised the number of subjects to be enrolled in Phase 2 to approximately 
30 subjects; updated the sample size determination with the revised number 
of subjects and revised the rationale for the sample size to reflect the 
historical overall response rate and the estimated power of the study. 
Synopsis, Sections 4.1 General 
Considerations, 11.2 Sample Size 
Determinations
The total number of subjects and screen failure rate has been updated. The 
number of subjects for Phase 2 was changed from 32 to approximately 30
subjects.
Rationale: Subjects may continue daratumumab treatment beyond 24 cycles.
Synopsis, Sections 3.1 Overview of 
Study Design, 9.1.3 Treatment 
Period (Cycle X Visit X), 17.9.1
Study Completion
“Up to 24 cycles” has been removed throughout the document as treatment 
may continue until the subjects’ experiences disease progression or 
unacceptable toxicity. In addition, daratumumab may continue until 
investigator’s or sponsor’s recommendation of discontinuation, subject’s 
decision to discontinue, or disease progression
Rationale: In Phase 2, the 2 separate cohorts were removed to form 1 cohort.
Sections 3.2.1 Rationale for Subject 
Population, 3.2.2 Rationale for 
Study Design, 5.1 Subject 
Allocation Procedures
Text regarding 2 cohorts and prior therapies was removed. Subject 
population also clarified.
Rationale:  Based upon emerging safety data and further understanding of the occurrence of infusion related 
reaction, the pre-dose infusion is no longer required. Pre and post medications and dose interruptions of 
daratumumab in ongoing single agent and combination studies have provided adequate intervention.
Sections 3.1 Overview of Study 
Design, 3.2.3 Dose Rationale, 6.1
Daratumumab
Phase 2 pre-dose was removed

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Rationale:  Serum samples will be analyzed for PK for both Phase 1 and Phase 2 of this protocol. In addition, 
GEN501 PK data presented also was analyzed in serum not plasma. 
Synopsis, Sections 3.2.3.1 Phase 1 
Dose Escalation; 9.3 Endpoints
Plasma was removed due to typographical error and replaced with serum 
throughout the protocol.
Rationale:  Daratumumab RP2D Rationale Section added
Section 3.2.3.2 Daratumumab 
RP2D Rationale
Section added based on new data from Study GEN501 and MMY2002
Rationale: The inclusion and exclusion criteria were revised to better define the patient population and the JRD 
template. In addition, eligibility criteria have also been modified to remove the cap placed on prior lines of therapy 
to ensure a broader relapsed/refractory population is study in Phase 2.
Sections 4.2 Phase 2 Inclusion 
Criterion
Revised: Phase 2 inclusion #1 to include:
-
Subjects must have received at least 1 prior line of therapy for multiple 
myeloma (refer to Attachment 2).
-
Subject must have achieved a response (PR or better) to at least one prior 
regimen.
-
Subject must have documented evidence of progressive disease (PD) as 
defined by the IMWG criteria on or after their last regimen.
Attachment 2 added.
Section 4.3 Exclusion Criteria #3,
#4 (removed), #6 (removed) #5 
(modified),  #12, #14, #18, #20
(renumbered)
#3: Antimyeloma treatment changed to within 2 weeks instead of 3 weeks
#5: modified to #4: “Have discontinued lenalidomide due to any treatment-
related adverse event or be refractory to any dose of lenalidomide. 
Refractory to lenalidomide is defined as either:
-
Subjects whose disease progresses within 60 days of lenalidomide, or
-
Subjects whose disease is nonresponsive while on any dose of 
lenalidomide. Nonresponsive disease is defined as either failure to achieve at 
least an MR or development of PD while on lenalidomide.”
#12: Persistent asthma added
#14:  Clarified/added HIV, Hepatitis B and C text 
#18: Added “or have known allergies, hypersensitivity, or intolerance to 
monoclonal antibodies or human proteins, or their excipients (refer to 
Investigator Brochure 2013), or have known sensitivity to mammalian-
derived products.”  For clarity
#20: added “or other anti-CD38 therapies”
Rationale: Dosage and administration for Phase 1 and Phase 2 was clarified.
Section 6.1 Daratumumab
Dosage and administration for Phase 2 was added
Rationale:  Based on the infusion rate data from the Phase 2 daratumumab single agent, Study 501, demonstrated 
safe and well tolerated infusion at median duration of 4 hours.
Section 6.1 Daratumumab
The infusion rates for Phase 2 have been adjusted. New Table 4 for Phase 2 is 
added.
Rationale: Dexamethasone modifications were added to ensure that appropriate dosing of dexamethasone is 
addressed for smaller patients as well as the elderly, both of whom would not require as large a dose of 
dexamethasone.
Section 6.3 Dexamethasone
Dexamethasone dose adjustment for elderly or underweight subjects added
Section 6.3.1 Dose adjustments of 
Dexamethasone
Section added

JNJ-54767414 daratumumab
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Rationale: Text added regarding delaying or skipping treatment.
Section 6.4 Delaying or Skipping 
Treatment
Section added
Rationale: DLT text needed regarding hemolysis, neutropenic fever, and transfusion of platelets based on GEN501 
study. 
Section 6.5 Dose-Limiting 
Toxicities
DLT section moved based on JRD template. 
Rationale:  Management of infusion-related reactions for patients with respiratory complications needed.
Section 6.6 Management of 
Infusion-Related Reactions
Former Section 6.1.2 moved here. New text was added for the management of 
infusion-related reactions for patients at a higher risk of respiratory 
complications. 
Section 6.6.1 Infusion-related 
Reactions of Grade 1 or 2
Section 6.6.2 Infusion-related 
Reactions of Grade 3 or Higher
Sections headers and text added for clarity on infusion reactions of Grade 1 
and 2 and Grade 3 and higher.
Rationale:  Text clarified regarding use of bisphosphonates
Section 8.1 Recommended 
Concomitant Medications
Zoledrolic acid removed and dose removed
Rationale: Changes and clarifications for study evaluations/assessments needed.
Section 9.1.2 Screening Period
Rescreening text removed and Phase 2 screening assessments added
Section 9.1.3 Treatment Period
(Cycle X Visit X)
Clarified dosing in Treatment Periods for Phase 1 and Phase 2
Section 9.1.6 Safety Follow-up 
Period
Safety Follow-up period clarified assessments every 8 weeks
Section 9.2.1.4 Electrocardiogram
Clarified electrocardiograms assessment times for Phase 1 and Phase 2; 
removed “at least 10 minutes apart”
Section 9.2.2.2 Hematology
Clarified assessment times for Coomb’s tests in Phase 1 and Phase 2
Section 9.2.2.3 Serology for HIV, 
Hepatitis B and Cytomegalovirus 
Serology
Clarified that these assessments are for Phase 1 only.

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Rationale: At the sponsor’s request, sections were added and revised as needed to include and clarify biomarker and 
pharmacogenomic assessments and analysis.
Synopsis, Sections 9.2.3 Myeloma-
related laboratory efficacy 
assessments, 9.2.3.1 Bone Marrow 
Assessments, 9.2.3.2 Serum 
Immunoglobulin A,M, and G,
9.2.3.4 Serum Free Light Chain 
Ratio, 9.2.6.2.2 Complement, 
9.2.6.2.2.1 Leveling of Circulating 
NK Cells, B, and T Cells (Flow 
Cytometry), 9.2.6.2 Biomarker 
Assessments, 9.2.6.2.3 
Pharmacogenomics, 9.2.6.2.2
Phase 2 Biomarker Analyses added; 
11.9 Biomarker and 
Pharmacogenomic Analyses

Added the rationale for evaluating biomarkers during Phase 2

Added an introduction to the biomarker evaluations and sections for 
evaluation of FcgR polymorphisms, antibody-dependent cell-mediated 
cytotoxicity, infusion reaction biomarkers, MRD, and circulating 
multiple myeloma cells; revised the section on serum biomarkers for 
Phase 1 and Phase 2 

Added a section to describe the analyses to be performed on biomarker 
data

Added a section on pharmacogenomic samples, research, and storage.
Rationale: The section describing pharmacokinetic and immunogenicity assessments was revised to clarify 
procedures and to reflect the sponsor’s requests.
Sections 9.2.4 Pharmacokinetics 
and Immunogenicity Assessments, 
9.2.5 Analytical Procedures, 9.2.6 
Pharmacokinetic Parameters, 
9.2.6.1 Immunogenicity 
Assessments, 11.5 Pharmacokinetic
Analyses
Revised the pharmacokinetic and immunogenicity assessments to be 
performed and clarified the timing of sample collection and analysis
Rationale: The section termed “variables” was changed to “endpoints” and updated to reflect changes in the study
design.
Section 9.3 Endpoints
Moved section to conform to JRD template.
Rationale: The reasons for discontinuation of treatment and withdrawal from the study were revised to reflect the 
sponsor’s requests and JRD template.
Sections 10.2 Discontinuation of 
Treatment and 10.3 Withdrawal
Revised for discontinuation of treatment.
Rationale:  Statistical methods clarified for Phase 1 and Phase 2
Sections 11.1 Subject Information 
(added), 11.2 Sample Size
Determination, 11.3 Analysis sets, 
11.5 Pharmacokinetic Analyses,  
11.8 Immunogenicity Analyses, 
11.9 Biomarker and 
Pharmacogenomic Analyses.11.10
Safety Analyses, 11.12 Data 
Monitoring Committee 

“No formal statistical hypothesis” deleted

Statistical methods for Phase 1 and Phase 2 separated for clarity. New 
statistical methods added for Phase 2, including change of number of 
subjects to 20. Removed Figure 5.

Clarified Phase 1 and Phase 2 analysis set

PK analyses clarified

JRD template text added

IDMC text clarified
Rationale: The procedures and contact information for reporting of serious adverse events were revised to reflect 
the changes made because of the change in sponsors.
Section 12.6.2. Serious Adverse 
Events, 12.6.3 Pregnancy 
Revised procedures for reporting serious adverse events and pregnancy and 
changed contact from Chiltern International, Ltd to sponsor.
Rationale: The drug accountability section was revised to reflect the sponsor’s procedures.
Section 14.5 Drug Accountability
Revised to reflect sponsor’s procedures and conform to the JRD template

JNJ-54767414 daratumumab
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Rationale: Sections were added, deleted, revised, or reordered to reflect JRD standard procedures and to match the 
JRD protocol template better.
Title page
Approval page, Sponsor Contact 
page, Investigator Agreement 
page
Section 10.2 Discontinuation of 
Study Treatment, 10.3 
Withdrawal
Section 11.1 Subject Information
Throughout the protocol and 
Section 11.10 Safety Analyses
Section 12 Adverse Event 
Reporting, Section 13 Product 
Quality Complaint Handling, 
Section 15 Study-Specific 
Materials, Section 16 Ethical 
Aspects, 16.1. Study-specific 
Design Considerations, 16.2.4
Privacy of Personal Data, 
Section 16.2.6 Country 
Selection, Section 17
Administrative Requirements, 
Sections 17.1 Protocol 
Modifications, Section 17.2.1 
Regulatory 
Approval/Notification, Section 
17.2.2 Required Prestudy 
Documentation, 17.3 Subject 
Identification, Enrollment, and 
Screening Logs, 17.4 Source 
Documentation, 17.5 Case 
Report Form Completion, 17.6 
Data Quality Assurance/Quality 
Control, 17.7 Record Retention, 
17.8 Monitoring, 17.9.1 Study 
Completion, 17.9.2 Termination, 
17.11 Use of Information and 
Publication 
Reformatted and revised to conform to the JRD template
Removed INC Research and Genmab approval page and sponsor contact 
information because these pages are not required in the JRD template
Reformatted and revised the synopsis to reflect the changes in the protocol 
and to conform to the JRD template
Changed references to the Safety Committee to sponsor
Revised to match JRD procedures and template
Added/Revised or updated to match JRD procedures and template
Section 15.5.2 and 15.5.3 of 
Genmab template has been 
deleted
Rationale: Minor grammatical, formatting, and spelling changes were made. 
Throughout the protocol
“Trial” changed to “Study”. Part 1 and Part 2 changed to Phase 1 and Phase 
2. “Visit 0”changed to “before the first infusion”.

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Amendment 4 (25 February 2013)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: This amendment includes the change of sponsor from Genmab A/S to 
Janssen Research & Development; update of contract research organization (CRO) personnel approving the 
protocol; addition of more flexible choice of dose for Phase 2, premedication and dosing guidelines, and infusion 
rates; change in dexamethasone administration; clarification of screening assessments and an exclusion criterion; 
change in trial drug preparation and storage; removal of glucocorticoid administration after infusion; and minor 
editorial changes.
Applicable Section(s)
Description of Change(s)
Rationale: Change of sponsor from Genmab A/S to Janssen Research & Development
Title page, Signature Page, 
Investigator Agreement, Synopsis, 
Section 1.4, Section 12.6, 
Section 13, Section 14.3, and 
Section 15.10
Genmab will be undertaking the conduct of the GEN503 trial of 
daratumumab with Janssen Research & Development as sponsor. Therefore, 
the protocol was updated to reflect this collaboration by including Janssen on 
the title page, adding an approval signatory from Janssen, and clarifying that 
Genmab and/or Janssen (as “sponsor”) would have responsibility for certain 
aspects of the trial.
Rationale: Update of CRO personnel approving the protocol
Signature Page
The approving medical monitor and biostatistician were updated to reflect 
personnel changes at the CRO.
Rationale: Addition of more flexible choice of dose for Phase 2
Synopsis, Section 1.4.2, Section 3, 
Figure 4, Section 11.7, Section 13, 
and List of Abbreviations
To provide the sponsor with more flexibility in the choice of Phase 2 dose, 
the maximum tolerated dose originally planned to be determined during 
Phase 1 was changed to a recommended Phase II dose (RP2D), which could 
be the MTD or any dose evaluated in the range of 4 to 16 mg/kg of 
daratumumab. It was noted that the RP2D could be selected before escalation 
to or completion of the 16 mg/kg cohort.
Rationale: Addition of more flexible premedication and dosing guidelines
Section 6.1
In the event that data from the ongoing GEN501 trial provides information 
that might necessitate a change, wording was added to indicate that the 
sponsor or Independent Data Monitoring Committee (IDMC) may modify 
predose infusions, infusion rates, or premedications.
Rationale: Addition of more flexible infusion rates
Table 2
Table 2 was revised to indicate that infusions after the first full-dose infusion 
may be started and continued at a higher infusion rate at the discretion of the 
investigator if the subject experienced no infusion reactions during the last 
full-dose infusion.
Rationale: Change in dexamethasone administration
Synopsis, Section 6.3, and 
Section 8.1.3
The administration of dexamethasone was changed from 2 doses of 20 mg 
each on the day of infusion (20 mg intravenously [IV] before infusion and 
20 mg orally [PO] after the end of infusion) to 1 dose of 20 mg IV before 
infusion and 20 mg PO the day after the infusion.

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Rationale: Clarification of screening assessments
Synopsis and Section 8.1.2
Text was added to the description of the screening period assessment to 
clarify that vital sign and electrocardiogram (ECG) measurements were to be 
performed during the Screening Visit and should be done within 21 days 
before trial entry (Cycle 1 Visit 1).
Rationale: Clarification of an exclusion criterion
Synopsis and Section 4.3
Exclusion criterion #3 was clarified to include radiotherapy within 3 weeks 
before the first infusion as an excluded treatment. This exclusion was added 
based on an adverse event seen in the ongoing GEN501 trial where a subject 
had received radiotherapy within 3 weeks before the first infusion of 
daratumumab and then experienced an allergic reaction including severe 
throat edema and breathing difficulties.
Rationale: Change in trial drug preparation and storage
Section 12.4
Preparation of the trial drug was revised to indicate that the infusion should 
be kept at room temperature after preparation, unless it was to be stored 
longer than 3 hours after dilution and before initiation of the infusion in 
which case it was to be stored at 2C to 8C.
Rationale: Removal of glucocorticoid administration after infusion
Section 6.1.2
The administration of methylprednisolone on the first and second days after 
all full-dose infusion was removed because the dose of dexamethasone on the 
day after full-dose infusions is believed to cover the subjects adequately.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.

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Amendment 3 (06 July 2012)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: This amendment includes the addition of long-term monitoring for new 
onset of cancer and more extensive pregnancy testing, as well as clarifications of the screening process, inclusion 
and exclusion criteria, recommended concomitant medications, timing of the Coomb’s tests, urinalysis assessments 
for M-component, planned flow cytometry testing, and timing of the bone marrow biopsies.
Applicable Section(s)
Description of Change(s)
Rationale: Addition of long-term monitoring for new onset of cancer
Synopsis, Table 1,
Section 8.1.6, Section 9.3.2, 
Section 9.3.3, and Section 13
The French Competent Authorities (Agence nationale de sécurité du 
médicament et des
produits de santé) requested that the sponsor collect information regarding all 
cases of cancer that might occur in all participants of this trial for 3 years 
after the last dose of lenalidomide. In response to this request, the sponsor is 
amending the protocol to include a Safety Follow-up Period during which 
investigators will contact subjects every 6 months after their last dose of 
lenalidomide to collect information on any new cancers. This information 
will be entered on a questionnaire provided by the sponsor for this purpose. 
Data from these questionnaires will be entered into the Clinical Drug Safety 
database. In addition, the agency requested that any cases of new cancer be 
reported as unexpected serious adverse events (SAEs) (Sections 9.3.2 and 
9.3.3) and that the Independent Data Monitoring Committee (IDMC) make 
recommendations at least every 6 months regarding whether the trial should 
continue based on the occurrence of new cancers and the reported benefits of 
daratumumab treatment (Section 13).
Rationale: Addition of more extensive pregnancy testing
Table 1 and Section 8.2.2.4)
The French Competent Authority requested that more extensive pregnancy 
testing be added to the protocol to bring it more into accordance with the 
Summary of Product Characteristics (warnings and precaution for use) for 
lenalidomide. In addition to pregnancy testing at the Screening and End of 
Treatment (EOT) Visits, testing will be done every 4 weeks during the 
treatment and follow-up periods. Serum samples will be tested by the central 
laboratory.
Rationale: Clarification of screening process
Synopsis and Section 8.1.2)
To respond to inquiries from investigators, the sponsor clarified the screening 
process by stating that subjects may be rescreened after failing to meet the 
inclusion and exclusion criteria if their condition changes. Rescreening is 
allowed only after discussion with and approval by the sponsor.
Rationale: Inclusion Criterion #1 for Phase 2
Synopsis and Section 4.2
The requirement for subjects to be naive to lenalidomide treatment has been 
removed because it conflicted with statements made elsewhere in the 
protocol.

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Rationale: Exclusion Criterion #30 and Pregnancy
Synopsis and Section 4.3
The French Competent Authority requested that clarification on the length of 
time subjects must have used adequate contraception before study drug 
administration be added to the protocol to bring it more into accordance with 
the Summary of Product Characteristics (warnings and precaution for use) for 
lenalidomide. Therefore, this criterion has been clarified to include the 
requirement for adequate contraception for 4 weeks before the first infusion 
of daratumumab. The section on pregnancy as an adverse event has also been 
updated to include this requirement.
Section 9.1.6
Rationale: Recommended Concomitant Medications
Section 7.1
Recommended treatment for tumor lysis syndrome has been added to clarify 
that such treatment is allowed and should be performed according to local 
standards.
Rationale: Hematology 
Table 1 and Section 8.2.2.2
To ensure that a final assessment is performed for subjects who withdraw 
from the trial,
additional direct and indirect Coomb’s tests have been added to the EOT 
Visit for all subjects, including those who withdraw from the trial.
Rationale: Urinalysis for M-component
Table 1 and Section 8.2.3.3)
The urinalysis for total protein at the Screening Visit has been clarified to 
include analysis of albumin. In addition, quantitation of total protein 
(including albumin) and creatinine clearance has been added to the urinalysis 
on the first day of each cycle and at all follow-up visits.
Rationale: Levels of Circulating B and T Cells (Flow Cytometry)
Section 8.2.4.4
Analysis of CD3-CD56+ has been added to the blood sample assessment by 
flow cytometry. In addition, a statement that other subgroups may be 
analyzed for exploratory purposes has been added. These additions will allow 
for further characterization of the plasma cells and other cells in the blood.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.

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Amendment 2 (23 February 2012)
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: This amendment includes a correction to the reasons for withdrawal of 
subjects from treatment.
Applicable Section(s)
Description of Change(s)
Rationale: Withdrawal
Section 10.2
During review of the protocol, the Medicines and Healthcare products 
Regulatory Agency noted that subjects must be withdrawn from treatment 
due to pregnancy. Further review of the protocol by the sponsor indicated 
that Section 10.2 stated that subjects may be withdrawn from treatment for 
the reasons listed (including pregnancy). This amendment corrects that 
statement to clarify that subjects will be withdrawn from treatment for any of 
the reasons listed.

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Amendment 1 (03 February 2012)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: This amendment includes clarification of an exclusion criterion, and 
changes to an inclusion criterion, vital sign assessments, the laboratory analyzing electrocardiograms, bone marrow 
assessments, the definition of dose-limiting toxicities, and informed consent. Details of and reasons for the changes 
are presented below.
Applicable Section(s)
Description of Change(s)
Rationale: Inclusion Criterion #2
Synopsis and Section 4.2
Key opinion leaders have advised Genmab to include only patients with 
measurable M-component in blood or urine. Patients who have involved free 
light chain levels but no measurable M-component are difficult to evaluate. It 
is, therefore, the opinion of Genmab and key opinion leaders that including 
this population could distort evaluation of both safety and efficacy 
assessments in this small trial and result in ambiguous conclusions. To avoid 
any unclear and misleading results of GEN503, Genmab has opted to exclude 
these patients from the trial.
Rationale: Exclusion Criterion #16
Synopsis, Table 1, Section 4.3, and 
Section 8.2.2.3
No HIV testing will be performed during the assessment of subject eligibility 
for enrollment in this trial. Subjects with a history of a positive HIV test will 
be excluded.
Rationale: Electrocardiogram
The central laboratory that will analyze the electrocardiograms performed 
during this study was incorrectly referred to as BARC and has been corrected 
to eResearch Technology.
Rationale: Timing of Vital Sign Measurements
Table 1 and Section 8.2.1.5
The timing of the preinfusion measurement of vital signs was changed to just 
before the planned infusion start time to provide more relevant information.
Rationale: Addition of Analyses for Bone Marrow Assessments
Section 8.2.3.1
Three analyses were added to the bone marrow aspirate assessment by flow 
cytometry: CD19, CD28, and CD117. These additions will allow further 
characterization of the plasma cells and other cells in the marrow.
Rationale: Addition to the Informed Consent Process
Section 8.2.3.5
Because of its exploratory nature, subjects will be asked to sign a separate 
informed consent form for the analysis of prognostic factors.
Rationale: Correction of Definition of Dose-limiting Toxicities
Section 8.2.3.1
Three analyses were added to the bone marrow aspirate assessment by flow 
cytometry: CD19, CD28, and CD117. These additions will allow further 
characterization of the plasma cells and other cells in the marrow.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.

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SYNOPSIS
An Open label, International, Multicenter, Dose Escalating Phase 1/2 Trial Investigating the Safety of 
Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or 
Relapsed and Refractory Multiple Myeloma
Description of Compound
Daratumumab is an IgG1human monoclonal antibody that specifically recognizes the CD38 epitope. It 
has demonstrated antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent 
cytotoxicity (CDC) in multiple myeloma cells, efficacy in multiple myeloma patient cells as well as in 
vivo antitumor activity in xenograft models.
OBJECTIVES AND HYPOTHESIS
Primary Objective
To establish the safety profile of daratumumab when given in combination with Len/Dex in subjects with 
relapsed or relapsed and refractory multiple myeloma.
Secondary Objectives

To evaluate the efficacy of daratumumab when given in combination with Len/Dex in subjects with 
relapsed or relapsed and refractory multiple myeloma.

To evaluate the PK profile of daratumumab when given in combination with Len/Dex in subjects 
with relapsed or relapsed and refractory multiple myeloma.

To assess the immunogenicity of daratumumab.
Hypothesis
No formal statistical hypotheses are planned to be tested.
OVERVIEW OF STUDY DESIGN
This is an open-label, dose-escalation, multicenter, Phase 1/2 safety study of daratumumab in 
combination with lenalidomide and dexamethasone (Len/Dex) in the treatment of subjects with relapsed 
or relapsed and refractory multiple myeloma. The dose escalation portion of the study (Phase 1) will be a 
standard 3 + 3 design and will evaluate daratumumab, at doses from 2 mg/kg up to a maximum of 
16 mg/kg, in combination with Len/Dex in 28-day treatment cycles. The maximum tolerated dose (MTD) 
will be defined as the highest dose of the combination regimen at which less than 33% of subject’s 
experience dose-limiting toxicity (DLT). A recommended Phase 2 dose (RP2D) will be determined 
during Phase 1. The MTD or any dose evaluated in the range of 2 to 16 mg/kg of daratumumab may be 
considered as the RP2D based on available safety, pharmacokinetic (PK)/pharmacodynamic, and efficacy 
data from Phase 1. The RP2D could be selected before escalation to or completion of the 16 mg/kg 
cohort. Once the RP2D is determined, the expansion (Phase 2) will open to further explore the safety and 
efficacy of the RP2D in approximately 30 subjects.
For Phase 1 and Phase 2 portions of the study, the first 2 treatment cycles will consist of weekly 
daratumumab infusions, totaling 4 infusions during each 28-day cycle. Cycles 3 through 6 will consist of 
daratumumab infusions administered every other week; Cycle 7 and all subsequent cycles will consist of 
monthly daratumumab infusions. The combination treatment may continue until the subject experiences 
disease progression or unacceptable toxicity, whichever comes first. Daratumumab may be continued 
until investigator’s or sponsor’s recommendation of discontinuation, the subject’s decision to discontinue 
for any reason, or disease progression. In Phase 1 and Phase 2, if the subject must stop one component of 
the combination treatment (either daratumumab, lenalidomide or dexamethasone), the subject may 

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continue the other components until progression or commencing a new regimen for the treatment of 
multiple myeloma. However, subjects will still receive dexamethasone as premedication to daratumumab.
In Phase 1, to minimize the risk of cytokine release syndrome, the first infusion of the first cycle will be 
preceded by a predose infusion the day before the scheduled full-dose infusion. The predose infusion will 
be 10% of the full dose, but will never be more than 10 mg in total dose. Further measures to prevent 
cytokine release syndrome will include premedication with antihistamines, acetaminophen, and 
dexamethasone before each daratumumab infusion (both predose and full dose).
Lenalidomide will be administered at a dose of 25 mg orally (PO) on Days 1 through 21 of each 28-day 
cycle, and dexamethasone will be administered at a total dose of 40 mg weekly. Further details on the 
administration of dexamethasone are provided in the Test Product, Dose and Mode of Administration 
section of this synopsis.
During Phase 1, decisions to escalate the dose of daratumumab for the next cohort will be based on the 
safety data obtained from the 3 (+ 3) subjects in the previous cohort during their first treatment cycle 
(28 days). The Independent Data Monitoring Committee (IDMC) will evaluate all safety data (including 
serious adverse events [SAEs], adverse events [AEs], and laboratory data) after each cohort completes 
Cycle 1. The third subject in the cohort must have received all 4 full doses of daratumumab, and data 
from an observation period of 6 days after the last infusion must be available for the IDMC to review. 
Based on the results presented in these safety profiles, the IDMC will recommend to the sponsor if it 
appears safe to escalate the dose. The recommendation will be discussed and confirmed by the sponsor, 
who will ultimately decide if dose escalation will occur. Subjects who discontinue the study during the 
first cycle for reasons other than a DLT will be replaced.
The RP2D dose selected is 16 mg/kg based upon marked M-protein reduction with an acceptable safety 
profile in doses up to 16 mg/kg, the highest dose of Phase 1. In addition, the following data from Phase 1 
of this combination study and data at 16 mg/kg in ongoing monotherapy studies is supportive of the 
RP2D dose.

Clinical pharmacokinetic data have shown the 16 mg/kg dose to be the lowest dose that results in 
complete target suppression at all time points. This dose and schedule continuously suppressed NK 
cells throughout dosing. 

ORR appeared higher for the 16-mg/kg dose compared with the 8-mg/kg dose, based on early 
preliminary data from Part 2 of Study GEN501 and from Study MMY2002 (both ongoing) as of a 
cutoff date of 24 January 2014.

In Study GEN501, the ORRs (ie, partial response [PR] or greater) were 11% and 40% for the 
8-mg/kg (n=28) and 16-mg/kg (n=15) dose regimens, respectively. 

For the Study MMY2002, the unconfirmed ORRs for the 8-mg/kg and 16-mg/kg dose regimens 
were similar to those observed in GEN501. 

In addition, VGPRs were observed for 7 of 30 subjects treated with the 16-mg/kg dose in those 
2 studies. VGPR was not observed at lower dose levels. These preliminary data support that full 
target saturation at the 16-mg/kg dose is needed to achieve higher and deeper response rates. 

The 16-mg/kg dose and schedule was shown to have an acceptable and manageable safety profile for 
the approximately 30 subjects for whom preliminary data were available in Studies GEN501 and 
MMY2002. In Phase 1 of this study, no additive toxicity was observed when comparing the 
16 mg/kg combination with the lower dose cohorts
Daratumumab will be provided until it is approved for use in combination with lenalidomide and 
dexamethasone and is commercially available for patients with relapsed/refractory multiple myeloma in 
the countries where subjects are still receiving combination treatment. Subjects still receiving treatment
will be transitioned from study drug to commercial product once commercial product is available in their 

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region (or when daratumumab can be accessed from another source). In these circumstances, the Sponsor 
and investigator will support transition of the subject to ensure that treatment continues and remains 
uninterrupted. Subjects who are unable to switch to commercial supplies will continue to remain on study.
All subjects will be followed for 3 years after the last dose of lenalidomide, to enable collection of second 
primary malignancy (SPM).
SUBJECT POPULATION
The study population for Phase 1 will consist of adults who have relapsed/refractory multiple myeloma 
after receiving a minimum of 2 and a maximum of 4 prior lines of therapy and be eligible for treatment 
with Len/Dex. The study population for Phase 2 will consist of approximately 30 adults with a diagnosis 
of multiple myeloma who have received at least 1 prior therapy, are not refractory to lenalidomide, and
meet all other criteria. 
Between 42 and 58 subjects will be enrolled in this study, depending on the number of dose levels 
included during dose escalation in Phase 1. It is estimated that the screen failure rate will be 25% and that 
between 56 and 78 subjects will be screened in order to enroll the expected number.
DOSAGE AND ADMINISTRATION
The start of a cycle is defined as the start of any of the study treatments (ie, daratumumab or Len/Dex). If 
all treatments are held, then it should be reported as a cycle delay.
Daratumumab will be administered by intravenous (IV) infusion in a 28-day cycle, in combination with 
Len/Dex. For the first 2 cycles (8 weeks), administration of daratumumab will be weekly. In Cycles 3 
through 6 (16 weeks), daratumumab will be administered every other week. After Cycle 6, daratumumab 
will be administered monthly (every 4 weeks). In Phase 1 only, a predose infusion will be given on 
Day 0. 
Lenalidomide will be administered on Days 1 through 21 of each 28-day cycle at a dose of 25 mg/day PO. 
Lenalidomide will be administered until the subject experiences disease progression or unacceptable 
toxicity, whichever comes first. All investigators must follow the guidelines of the lenalidomide 
RevAssistprogram in the United States (US) and Pregnancy Prevention Programme in the European 
Union (EU).
Dexamethasone will be administered at a total dose of 40 mg/week (except for the first week of Cycle 1; 
see below). As of Amendment 5, subjects older than 75 years or underweight (body mass index [BMI] 
<18.5), the dexamethasone dose may be administered at a dose of 20 mg weekly. On weeks when 
daratumumab is administered the 20 mg dose should be administered as the premedication per protocol.
During daratumumab infusion weeks, dexamethasone will be administered on the day of daratumumab 
infusion as 20 mg IV before the infusion and 20 mg PO the day after the infusion. During weeks when no 
daratumumab infusion is planned, dexamethasone will be administered at a dose of 40 mg/week PO. 
After the completion of Cycle 6, the administration of dexamethasone may be adjusted at the discretion of 
the investigator; however, dexamethasone should always be administered at a dose of 20 mg IV on 
daratumumab infusion days. Dexamethasone will be administered until the subject experiences disease 
progression or unacceptable toxicity, whichever comes first.
EFFICACY EVALUATIONS/ENDPOINTS
Efficacy endpoints are the rate of response according to the International Uniform Response Criteria, time 
to progression, duration of response, and progression-free survival.

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PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
PK variables are the area under the concentration-time curve (AUC), maximum concentration in serum
(Cmax), minimum (or trough) concentration in serum (Cmin), time to Cmax (Tmax), apparent clearance (CL), 
volume of distribution (V), and elimination half-life (t1/2). 
IMMUNOGENICITY EVALUATIONS
Samples drawn from all subjects will be assessed for the generation of antibodies to daratumumab. 
BIOMARKER EVALUATIONS 
Phase 1: Biomarkers assessments may include evaluation of complement proteins, soluble CD38 levels, 
and levels of circulating NK Cells, B, and T Cells by flow cytometry.
Phase 2: Biomarker assessments may include further understanding the MOA (ADCC/CDC/ADCP) of 
daratumumab in combination with lenalidomide and dexamethasone, immunophenotyping, evaluation of 
complement 
proteins, 
soluble 
CD38, 
and 
multiple 
myeloma 
cell 
profiling 
(including 
CD38/CD46/CD55/CD59 expression). In addition, exploratory proteomics and SNP analysis may be 
performed. Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
may be deferred or not performed if during or at the end of the study it becomes clear that the analysis 
will have no scientific value, or if there are not enough samples or not enough responders to allow for 
adequate biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy, 
completion of biomarker assessments is based on justification and intended utility of the data. 
PHARMACOGENOMIC (DNA) EVALUATIONS
A pharmacogenomic blood sample will be collected to allow for pharmacogenomic research, as necessary 
(where local regulations permit). Subject participation in the pharmacogenomic research is optional.
SAFETY EVALUATIONS
Safety variables are the incidence of AEs, physical examination findings, electrocardiogram results, vital 
sign measurements, ECOG performance status, laboratory test results, and immunogenicity assessments.
Dose-limiting Toxicity:
Dose-limiting toxicities are defined as any of the following events that occur during the first treatment 
cycle (28 days):

Nonhematologic toxicity considered to be a serious adverse event (SAE) of grade 3 or higher and 
related to daratumumab with the exception of:

Any nonhematologic reaction of grade 3 or higher that has an onset after the start of infusion on 
an infusion day, responds to symptomatic therapy, and resolves within 6 hours from onset

Adverse reactions that prevent the infusion from being resumed regardless of the length of the 
reaction

Hematologic toxicity, considered related to daratumumab, defined as

Thrombocytopenia (platelet count < 20,000 cells/L)

Asymptomatic grade 4 neutropenia for more than 3 days

Neutropenic fever (defined as grade 3 or 4 neutropenia and temperature > 38.5C) for more than 
3 days

Inability to receive the Day 1 infusion of Cycle 2 because of any toxicity related to daratumumab

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STATISTICAL METHODS
The 2 phases of this study will be analyzed separately. When appropriate, all subjects who are treated 
with daratumumab may be combined together for comprehensive safety assessment. The latest available 
measurements before study drug administration will serve as baseline values.
Phase 1 follows a standard 3+3 design. For Phase 2, it is assumed that lenalidomide + dexamethasone 
would achieve an ORR of 50% in the targeted population. With a two-sided alpha of 0.10 and assuming 
that the addition of daratumumab improves the ORR to 75%, a sample size of approximately 30 subjects 
would achieve 89% power to detect such a difference. If the addition of daratumumab can improve the 
ORR to 80%, this sample size would achieve 97% power to detect such a difference. The proportion of 
subjects with response to treatment (stringent CR [sCR], CR, very good PR [VGPR], and PR) will be 
estimated. The quality of response (also including subjects who achieve MR) will be summarized. The 
proportions will be presented with corresponding exact 2-sided 95% confidence intervals. Duration of 
response, time to progression, and PFS will be estimated using Kaplan-Meier techniques. 
Subject information variables will be estimated by using descriptive statistics. Continuous variables will 
be summarized by using the number of observations (n), mean, standard deviation, median, minimum, 
and maximum, where n denotes the number of subjects with available data. Categorical variables will be 
summarized by using n and percentages, where the calculation of the percentages will be based on the 
number of subjects in the population (N) and the number of subjects with available data (n). Results will 
be presented by cohort as well as by all subjects combined.
NOTE: As of Amendment 7, the primary analysis will be achieved. All subjects in the study have either 
received at least 12 months of study drug or have discontinued. Ongoing subjects may continue treatment 
with study drug with a limited schedule of assessments. Disease assessments/response evaluations will be 
performed per local institutional practice. Safety information will be limited to study drug administration, 
serious adverse events (SAEs, including secondary malignancies), concomitant medications associated 
with SAEs, and pregnancy testing. No additional PK blood sampling will be performed, samples will be 
collected only for immunogenicity and the same samples will be used for determination of the associated 
daratumumab serum concentrations. Follow up will include collection of survival information, best 
response and new antimyeloma therapies, and secondary malignancies every 6 months for 3 years after 
the last dose of study drug or termination of the study by the sponsor, whichever occurs first.
NOTE: As of Amendment 8, the final analysis will have been achieved. All subjects in the study have 
either received at least 24 months of study drug or have discontinued study drug.  Ongoing subjects may 
continue treatment with study drug. Disease assessments/response evaluations will be performed per local 
institutional practice. Safety information will be limited to collection of data regarding SAEs and SPMs. 
All subjects will be followed for 3 years after the last dose of lenalidomide, to enable collection of SPMs.
The study will end when daratumumab is approved for use in combination with lenalidomide and
dexamethasone and is commercially available. Subjects still receiving treatment will be transitioned from 
study drug to commercial product once commercial product is available in their region (or when
daratumumab can be accessed from another source) and will be withdrawn from this study at that time. In 
these circumstances, the sponsor and investigator will support transition of the subject to ensure that 
treatment continues uninterrupted. All subjects will be followed for 3 years after the last dose of 
lenalidomide, to enable collection of SPMs.

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
33
Approved, Date: 29 September 2016
Table 1:
Phase 1 Time and Events Schedule 
Note: As of Amendment 8, all subjects are to follow the Time and Events Schedule in Table 4 (see Attachment 9 for additional details)
Study Visits
Assessments
Screening
Cycle 1
Cycle 2a
Cycle 3-6a
Cycle 7-24a
FU
EOT
Safety 
FU
Visit Number
0
1
2
3
4
5
1
2
3
4
1
2
1
1-6
—
—
Day/Week/Month
21 days before 
Cycle 1 Visit 1
0d
1d
1w
2w
3w
1d
1w
2w
3w
1d
2w
1d
Monthly
—
—
Visit Window
—
—
—
1d
1d
1d
4d
1d
1d
1d
4d
1d
4d
7d
2d
7d
Clinical Assessments
Informed consent
Xb
Eligibility criteria
X
Demographics
X
Medical historyc
X
Height and body weight
X
X
Physical examination
X
X
X
Vital sign measurementsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiograme
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X-ray or CT scan
Xf
Xg
Xg
Xg
X
ECOG performance status
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Administration of daratumumab 
(predose)
X
Administration of daratumumab
X
X
X
X
X
X
X
X
X
X
X
Administration of lenalidomide
X (Days 1-21)
X (Days 1-21)
X (Days 1-21)
X (Days 1-21)
Administration of dexamethasone
X
X
X
X
X
X
X
X
X
X (4 weekly)
X (4 weekly)
Laboratory Assessmentsh
Biochemistryi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Flow cytometry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testk
X
X
X
X
X
X
X
Immunogenicity
X
X
X
X
X
X
Hepatitis B, cytomegalovirus
X
Complement (CH50)l
X
X
X
X
X
Serum daratumumab levelm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood type assessment
X
Direct & indirect Coombs testsn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
34
Approved, Date: 29 September 2016
Table 1:
Phase 1 Time and Events Schedule 
Note: As of Amendment 8, all subjects are to follow the Time and Events Schedule in Table 4 (see Attachment 9 for additional details)
Study Visits
Assessments
Screening
Cycle 1
Cycle 2a
Cycle 3-6a
Cycle 7-24a
FU
EOT
Safety 
FU
Visit Number
0
1
2
3
4
5
1
2
3
4
1
2
1
1-6
—
—
Day/Week/Month
21 days before 
Cycle 1 Visit 1
0d
1d
1w
2w
3w
1d
1w
2w
3w
1d
2w
1d
Monthly
—
—
Visit Window
—
—
—
1d
1d
1d
4d
1d
1d
1d
4d
1d
4d
7d
2d
7d
Prognostic factors
X
Soluble CD38
X
X
X
Response Assessments
Bone marrow
Xf
Xg
Xg
Xg
IgA, IgM, IgG (M-component 
serum)
X
X
X
X
X
X
X
X
M-component (24-hour urine 
sample)o
X
X
X
X
X
X
X
X
Free light chain kappa, lambda, 
and ratio (serum)
X
X
X
X
X
X
X
X
New cancer assessmentp
X
Key:
CT = computed tomography; d = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End of Trial; FU = Follow-up;
Ig = immunoglobulin; w = week
a
All cycles are 28-day cycles: the first visit of a cycle should be 4 weeks after the start of the previous cycle.
b
Informed consent may be obtained outside of the Screening Visit window, ie, before the Screening Visit date.
c
Signs and symptoms (nonserious adverse events) occurring between the Screening Visit (before the first infusion) and the first study drug treatment at Cycle 1 Visit 1 should 
be recorded as medical history.
d
Vital signs, defined as blood pressure, pulse, and temperature will be measured at the following time points on days when daratumumab infusions are given: just before the 
planned infusion start time; at 15-minute intervals during the first 2 hours of the infusion; at 60-minute intervals after the first 2 hours during the infusion; at the end of the 
infusion; and after the infusion at 10 minutes, 30 minutes, 1 hour, and 2 hours.
e
Electrocardiograms (ECGs) will be performed at the Screening Visit (before the first infusion), before and after each daratumumab infusion, and at the EOT Visit. Three 
baseline ECGs should be performed before the first infusion of study drug. Before the ECGs are recorded, the subjects must be resting in a horizontal position for at least 
20 minutes.
f
The computed tomography scan and bone marrow biopsy/aspirate may have been performed within 6 weeks before Cycle 1 Visit 1.
g
To be completed as indicated to confirm response at the subsequent bone marrow biopsy visit or to investigate new symptoms, and at physician discretion.
h
Unless otherwise stated, all blood and urine samples must be taken before administration of daratumumab.
i
Blood samples drawn for biochemistry assessments will be analyzed for the following: sodium, potassium, blood urea nitrogen, creatine, aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase, bone-specific alkaline phosphatase, albumin, calcium, glucose, total creatinine kinase, total bilirubin, lactic dehydrogenase, uric acid, 
2-microglobulin, and C-reactive protein.
j
Blood samples drawn for hematology assessments will be analyzed for the following: red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, white blood cell count with differential, platelet count, and reticulocyte count.

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
35
Approved, Date: 29 September 2016
Table 1:
Phase 1 Time and Events Schedule 
Note: As of Amendment 8, all subjects are to follow the Time and Events Schedule in Table 4 (see Attachment 9 for additional details)
k
Blood samples for serum pregnancy tests will be collected at the Screening Visit (before the first infusion), every 4 weeks during the treatment and follow-up periods, and at 
the EOT Visit.
l
Blood samples for analysis of complement (CH50) must be drawn 2 hours after the end of infusions.
m
Blood samples will be collected for pharmacokinetic assessments at the following time points: before infusion and at the end of infusion on all daratumumab infusion days; at 
2, 5, and 12 hours after the end of infusion at Cycle 1 Visit 2 (first full-dose daratumumab infusion); at 2 hours after the end of infusion at Cycle 2 Visit 4; at each Follow-up 
Visit; and at the EOT Visit.
n
Direct and indirect Coombs tests will be performed at all daratumumab infusion visits (before infusion and 2 hours after the end of infusion) and all follow-up visits until no 
antibodies are detected. These tests will also be performed at the EOT Visit for all subjects, including those who withdraw from the study.
o
In addition to quantitation of M-component, urinalysis for total protein (including albumin) and creatinine clearance will be performed.
p
Subjects will be contacted and asked about the occurrence of new cancers every 6 months for 3 years after their last dose of lenalidomide.

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
36
Approved, Date: 29 September 2016
Table 2:
Phase 2 Time and Events Schedule 
Note: As of Amendment 8, all subjects are to follow the Time and Events Schedule in Table 4 (see Attachment 9 for additional details)
Study Visits
Assessments
Screening
Cycle 1
Cycle 2a
Cycle 3-6a
Cycle 7+
FUr
EOT
Safety 
FU
Visit Number
0
1
2
3
4
5
1
2
3
4
1
2
1
—
—
Day/Week/Month
21 days 
before 
Cycle 1 
Visit 1
0d 
Phase 1 
only
1d
1w
2w
3w
1d
1w
2w
3w
1d
2w
1d
Q8w
—
—
Visit Window
—
—
—
1d 1d 1d 4d 1d 1d 1d
4d
1d
4d
7d
2d
7d
Clinical Assessments
Informed consent
Xb
Eligibility criteria
X
Demographics
X
Medical historyc
X
Height and body weight
X
X
Physical examination
X
X
Vital sign measurementsd
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiograme
X
X
X
X
X
X
X-ray or CT scan
Xf,g
Xg
Xg
Xg
X
X
ECOG performance status
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
      Administration of 
daratumumabq
X
X
X
X
X
X
X
X
X
X
X
Administration of 
lenalidomide
X (Days 1-21)
X (Days 1-21)
X (Days 1-21)
X (Days 
1-21)
Administration of 
dexamethasone
X
X
X
X
X
X
X
X
X (4 weekly)
X (4 
weekly)
Laboratory Assessmentsh
Biochemistryi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testk
X
X
X
X
X
X
X

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
37
Approved, Date: 29 September 2016
Table 2:
Phase 2 Time and Events Schedule 
Note: As of Amendment 8, all subjects are to follow the Time and Events Schedule in Table 4 (see Attachment 9 for additional details)
Study Visits
Assessments
Screening
Cycle 1
Cycle 2a
Cycle 3-6a
Cycle 7+
FUr
EOT
Safety 
FU
Visit Number
0
1
2
3
4
5
1
2
3
4
1
2
1
—
—
Day/Week/Month
21 days 
before 
Cycle 1 
Visit 1
0d 
Phase 1 
only
1d
1w
2w
3w
1d
1w
2w
3w
1d
2w
1d
Q8w
—
—
Visit Window
—
—
—
1d 1d 1d 4d 1d 1d 1d
4d
1d
4d
7d
2d
7d
Hepatitis B, C, HIV, and 
cytomegalovirus
X
      Serum daratumumab levell
X
  Cycles 
3 and 6 
only 
C12 only
Weeks 4 
and 8 
after last 
dose
       Immunogenicityp
No additional sample required; taken from PK sample (see Section 9.2.4)
X
Week 4 
and 8 
after last 
dose
Blood type assessment
X
      Direct & indirect Coombs 
tests
X
Flow cytometry
X
X
X
X
X
X
X
X
X
X
X
X
       CDC and other serum-
based markers
X
X
X
X
X
ADCC
X
X
X
       Biomarkers: Whole blood 
draw (PBMC and plasma 
for CD38)
X
C3 only
X
      Pharmacogenomics
X

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
38
Approved, Date: 29 September 2016
Table 2:
Phase 2 Time and Events Schedule 
Note: As of Amendment 8, all subjects are to follow the Time and Events Schedule in Table 4 (see Attachment 9 for additional details)
Study Visits
Assessments
Screening
Cycle 1
Cycle 2a
Cycle 3-6a
Cycle 7+
FUr
EOT
Safety 
FU
Visit Number
0
1
2
3
4
5
1
2
3
4
1
2
1
—
—
Day/Week/Month
21 days 
before 
Cycle 1 
Visit 1
0d 
Phase 1 
only
1d
1w
2w
3w
1d
1w
2w
3w
1d
2w
1d
Q8w
—
—
Visit Window
—
—
—
1d 1d 1d 4d 1d 1d 1d
4d
1d
4d
7d
2d
7d
Response Assessments
X
X
X
X
X
Bone marrow aspirate/bone 
marrow biopsyf
Xg
Xg
Xg
IgA, IgM, IgG (M-
component serum)
Xo
Xo
Xo
Xo
Xo
X
Xo
Xo
M-component (24-hour 
urine sample)m
X
X
X
X
X
X
X
Free light chain kappa, 
lambda, and ratio (serum)
X
X
X
X
X
X
X
X
New cancer assessmentn
X
New antimyeloma 
treatmentn
X
Survivaln
X
Key:
ADCC = antibody-dependent cell-mediated cytotoxicity; CDC = complement-dependent cytotoxicity; CT = computed tomography; d = day; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EOT = End of Trial; FU = Follow-up; Ig = immunoglobulin; w = week
a
All cycles are 28-day cycles: the first visit of a cycle should be 4 weeks after the start of the previous cycle.
b
Informed consent may be obtained outside of the Screening Visit window, ie, before the Screening Visit date.
c
Signs and symptoms (nonserious adverse events) occurring between the Screening Visit (before the first infusion) and the first study drug treatment at Cycle 1 Visit 1 should be 
recorded as medical history.
d
Vital signs are to be measured on days when daratumumab infusions are administered: before the start of the daratumumab infusion and at the end of the infusion.
e
Electrocardiograms (ECGs) will be performed at the Screening Visit (before the first infusion), before and after daratumumab infusion on Day 1 of each cycle, and at the EOT 
Visit. Three baseline ECGs should be performed before the first infusion of study drug. Before the ECGs are recorded, the subjects must be resting in a horizontal position for at
least 20 minutes.
f
The computed tomography scan and bone marrow biopsy/aspirate may have been performed within 6 weeks before Cycle 1 Visit 1.
g
To be completed at Screening for clinical staging, at Cycle 3 Day 1, and to confirm sCR, CR, or relapse from CR. May also be performed to investigate new symptoms or at the 
physician discretion. A portion of the bone marrow aspirate or biopsy will be utilized for biomarker analyses. 
h
Unless otherwise stated, all blood and urine samples must be taken before administration of daratumumab. Samples must be sent to the central laboratory.
i
Blood samples drawn for biochemistry assessments will be analyzed for the following: sodium, potassium, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase, bone-specific alkaline phosphatase, albumin, calcium, glucose, total creatine kinase, total bilirubin, lactic dehydrogenase, uric acid, 
2-microglobulin, and C-reactive protein.

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
39
Approved, Date: 29 September 2016
Table 2:
Phase 2 Time and Events Schedule 
Note: As of Amendment 8, all subjects are to follow the Time and Events Schedule in Table 4 (see Attachment 9 for additional details)
j
Blood samples drawn for hematology assessments will be analyzed for the following: red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, white blood cell count with differential, platelet count, and reticulocyte count.
k
Blood samples for serum pregnancy tests will be collected at the Screening Visit (before the first infusion), every 4 weeks during the treatment and follow-up period, and at the 
EOT Visit.
l
If on a daratumumab dosing day, one sample to be collected before (up to 2 hours before but not after the start of infusion) and one sample immediately after (up to 2 hours after but 
not before the end of infusion) daratumumab administration. For additional information refer to Section 9.2.4.
m
In addition to quantitation of M-component, urinalysis for total protein (including albumin) and creatinine clearance will be performed.
n
Subjects will be contacted and asked about the occurrence of new cancers every 3 months for 3 years after their last dose of lenalidomide. Survival data will also be collected.
o
Serum sample will be split into 2 aliquots, with 1 reserved for potential follow-on testing if daratumumab interference with IFE is suspected.
p
In addition, any time an infusion-related reaction is observed during the study, an unscheduled blood sample should be drawn as soon as possible after the reaction for potential 
immune response analysis.
q
The daratumumab dose does not need to be recalculated for weight changes that are <10% from baseline.
r
For subjects without disease progression.

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
40
Approved, Date: 29 September 2016
Table 3:
Time and Events Schedule as of Amendment 7 (see also Attachment 8) 
Treatment Phase
End-of-Treatment
Follow-up
Start of First Cycle with 
Amendment 7a
Every Cycle Until Treatment 
Discontinuation
(±4 days)
EOT Visit
(3 to 5 weeks after the last 
dose of study drug)
Every 6 months for 3 years 
after last dose of study drug g
(±7 days)
Study Procedures
Informed consent
X
Administration of 
Daratumumab
X (Day 1)
X (Day 1)
Administration of 
Lenalidomide
X (Days 1-21)
X (Days 1-21)
Administration of 
Dexamethasoneb
X (4 weekly)
X (4 weekly)
Disease assessmentsc
X
X
X
SAEsd
X
X
X
Pregnancy testinge
X (every 4 cycles)
X
Best response and new 
antimyeloma therapyf
X
X
New cancer assessmentf
X
X
Survivaf
X
X
Immunogenicity and associated 
serum daratumumab levelg
Weeks 4 and 8 (±1 week) after last dose of study drugh
EOT=End-of-Trial; SAE=serious adverse event
a
This will be the first cycle after the subject completes a cycle and all scheduled assessments under protocol Amendment INT-6 (there should not be a restarting of the cycle 
number). All cycles are 28-day cycles: the first visit of a cycle should be 4 weeks after the start of the previous cycle.
b
The administration of dexamethasone may be adjusted at the discretion of the investigator, however, dexamethasone should always be administered at a dose of 20 mg IV on
daratumumab infusion days. 
c
Disease assessments/response evaluations are to be performed per local institutional practice. 
d
Includes secondary malignancies. Concomitant medication information associated with SAEs will also be collected (See Attachment 8 for more details).
e
Samples will be analyzed by a local laboratory. 
f
Subjects will be contacted and asked about the occurrence of new cancers, best response, new antimyeloma treatment, and information on survival every 6 months for 3 years 
after the last dose of study drug or until termination of the study by the sponsor, whichever occurs first. 
g
Subjects will have blood samples taken only for immunogenicity, the associated daratumumab concentration will be determined from the same sample. In addition, any time 
an infusion-related reaction is observed during the study, an unscheduled blood sample should be drawn as soon as possible after the reaction for potential immune response 
analysis.
h
The Week 4 sample will be collected at the EOT visit.

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
41
Approved, Date: 29 September 2016
Table 4:
Time and Events Schedule as of Amendment 8 (see also Attachment 9)
Study Procedure
Start of First Dosing with Amendment 8a
Informed Consent Amendment 8 
X
Administration of Daratumumab
X (Day 1)
Administration of Lenalidomide
X (Day 1-21)
Administration of Dexamethasoneb
X (4 weekly)
Disease assessmentsc
X
SAEs
X
Secondary Primary Malignancyd
X
Immunogenicity Samplee
1x before start of the last dose under study Amendment 7
a.
This will be the first dosing once Amendment 8 is fully approved at the site, and after the subject completes a final cycle and all 
scheduled assessments under protocol Amendment 7.
b.
The administration of dexamethasone may be adjusted at the discretion of the investigator; however, dexamethasone should always 
be administered at a dose of 20 mg intravenously on daratumumab infusion days. See Section 6.3 for further detail.
c.
Disease assessments/response evaluations are to be performed per local institutional practice.
d.
Subjects will be contacted regarding the occurrence of new SPMs every 3 months by phone (month 3, month 9, etc..) or in a site visit 
(month 6, month 12, etc…). In cases where subjects become aware of the occurrence of a new SPM, they will instructed to report it as 
soon as possible to their study investigator.
e.
As of Amendment 8, blood sample collection will stop and will not be performed after the last dose of daratumumab. One final sample 
should be collected before the last infusion of daratumumab per Amendment 7 and sent to the central laboratory. Sample will also be 
assessed for serum daratumumab concentration to ensure proper interpretation of immunogenicity data.

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
42
Approved, Date: 29 September 2016
ABBREVIATIONS
Abbreviation
Definition
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
ALT
alanine aminotransferase
anti-HBc
antibodies to hepatitis B core antigen
anti-HBs
antibodies to hepatitis B surface antigen
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
auto-SCT
autologous stem cell transplantation
CDC
complement-dependent cytotoxicity
CL
total systemic clearance of drug after IV administration
Cmax
maximum concentration in serum
Cmin
minimum or trough concentration in serum
CR
complete response
CrCl
creatinine clearance
CRO
contract research organization
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events, version 4.0
DCF
Data Clarification Form
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DVT
deep vein thrombosis
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
End of Trial
EU
European Union
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
IAT
indirect antiglobulin test
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
immunoglobulin
IL
interleukin
IMiD
immunomodulatory drugs
IRB
Institutional Review Board
ITT
Intent-to-Treat
IV
intravenous
Len/Dex
lenalidomide and dexamethasone
mAb
monoclonal antibody
MR
minimal response
MTD
maximum tolerated dose
NaCl
sodium chloride
NK
natural killer
ORR
overall response rate
PD
progressive disease
PE
pulmonary embolism
PFS
progression-free survival

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
43
Approved, Date: 29 September 2016
PK
pharmacokinetic(s)
PO
orally
PP
Per-Protocol
PQC
product quality complaint
PR
partial response
RBC
red blood cell
RhD
Rh blood group, D antigen
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SPM
second primary malignancy
t1/2
elimination half-life
Tmax
time to maximum concentration in serum
ULN
upper limit of normal
US
United States
V
volume of distribution
Vcen
central volume of distribution
VGPR
very good partial response

JNJ-54767414 daratumumab
Clinical Protocol GEN503 Amendment 8
44
Approved, Date: 29 September 2016
1.
INTRODUCTION
The investigational medicinal product, daratumumab, is an IgG1human monoclonal antibody 
(mAb) that specifically recognizes the CD38 epitope. It is produced in a recombinant Chinese 
Hamster Ovary cell line. Standard mammalian cell culture and purification techniques are 
employed in the manufacture of daratumumab.
For the most comprehensive nonclinical and clinical information regarding daratumumab, refer 
to the latest version of the Investigator's Brochure for 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
1.1.1.
Multiple Myeloma
Multiple myeloma is a plasma cell disorder, characterized by uncontrolled, malignant 
proliferation and accumulation of plasma cells. In the majority of patients, the malignant plasma 
cells produce a monoclonal protein (M protein or paraprotein). The majority of M proteins are 
immunoglobulin (Ig) G (~ 50%) and IgA (~ 20%). The proliferation of myeloma cells causes 
displacement of the normal bone marrow. Myeloma cells are highly dependent upon external 
factors, ie, the microenvironment in bone marrow, including stromal cells and cytokines 
(eg, interleukin [IL]-6) (Klein 1989, Vidriales 1996).9,30 In multiple myeloma, the major clinical 
findings include anemia, monoclonal Ig (M protein) in serum and/or urine, abnormal bone 
radiographs (bone resorption seen as diffuse osteoporosis or characteristic lytic lesions), 
hypercalcemia, renal insufficiency or failure, and neurologic complications.
Multiple myeloma accounts for approximately 1% of all malignancies and 10% of all 
hematologic malignancies, with a higher frequency in African Americans where it accounts for 
20% of all hematologic malignancies (Howe 2001).8 In the United States (US), approximately 
11,000 deaths each year are related to multiple myeloma, and the estimated number of new cases 
has risen from 15,270 in 2004 to 20,180 in 2010.1 At present, there is no cure available.
1.1.2.
Current Treatment of Multiple Myeloma
Treatments include combination chemotherapy, proteasome inhibition, immunomodulatory 
drugs (IMiDs), high-dose chemotherapy, and autologous stem cell transplantation (auto-SCT). 
Allogenic transplantation is performed only in a minority of younger patients, and its role as a 
treatment modality is not determined.
Current first-line treatment regimens have often included the use of an alkylating agent. 
Melphalan, combined with prednisone, has been the standard of care for many years and results 
in response rates of 50% to 60%. However, few patients achieve a complete response (CR) by 
using this approach. More recently, combinational strategies involving new agents have been 
added to the standard of care. The use of these agents, including IMiDs (eg, thalidomide and 
lenalidomide) and proteasome inhibitors (eg, bortezomib), has increased response rates and rates 

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of CR in particular (Palumbo 2006, Rajkumar 2008, Lacy 2007, San Miguel 2008).20,23,13,25 In 
younger, healthier patients, auto-SCT has been performed after induction therapy and has 
resulted in CR rates of 20% to 40% (Attal 2007).2
For relapsed multiple myeloma, treatment with bortezomib as a single agent results in a response 
rate of approximately 38% and a CR rate of 6% (Richardson 2005).24 However, a combination of 
bortezomib and dexamethasone gives higher response rates, up to approximately 70% (Kropff 
2005).11 This combination has become standard of care when using bortezomib in patients with 
relapsed multiple myeloma (NCCN 2011).19 Because of the side-effect profile of bortezomib, 
which includes peripheral neuropathy, reduced dose regimens (once weekly) have been 
investigated and have demonstrated similar efficacy but improved safety (Bringhen 2010).3
Treatment with dexamethasone has been associated with side effects of gastrointestinal 
problems, headache, dizziness, insomnia, restlessness, anxiety, acne, bruising, swelling of face 
and legs, and vision problems.
Combinations of thalidomide or lenalidomide and dexamethasone are approved by the US Food 
and Drug Administration (FDA) and the European Medicines Agency and are also considered as 
standard of care for relapsed multiple myeloma. Clinical trials included high-dose 
dexamethasone and demonstrated response rates of approximately 60% with CR rates of 15.9%
(Dimopoulos 2007).6 High-dose dexamethasone, however, is associated with significant toxicity. 
More recently, lenalidomide combined with a lower dose of dexamethasone (40 mg weekly) has 
demonstrated significantly reduced toxicity and increased overall survival when compared with 
lenalidomide and high-dose dexamethasone (Rajkumar 2010).22 Low-dose dexamethasone is 
now widely used when combined with lenalidomide in the treatment of relapsed multiple 
myeloma.
Lenalidomide (Revlimid) is approved in the US and the European Union (EU) for the second-
line treatment in combination with dexamethasone (Revlimid SmPC).
As previously described, targeting multiple myeloma cells with combination therapy has 
demonstrated superior clinical responses as compared with single-agent therapy. Using an IMiD 
with a monoclonal antibody (mAb) combines both indirect and direct antitumor mechanisms, 
and such a combination has previously indicated efficacy in the treatment of multiple myeloma
(Moreau 2011).18
1.1.3.
Preclinical Pharmacology and Pharmacokinetics
Potential mechanisms of action have been investigated in both in vitro and in vivo 
pharmacodynamic studies. Results from these studies suggest that complement-dependent 
cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) may be the 
major mechanisms of action for daratumumab, and that these mechanisms are of crucial 
importance in the treatment of malignancies expressing CD38. Half-maximal killing of myeloma 
cells in vitro by CDC and ADCC occurred at antibody levels of approximately 0.1 g/mL and 
0.03 g/mL, respectively. Studies in the xenograft lymphoma model in severe combined 
immunodeficiency mice have shown that daratumumab potently inhibits the in vivo growth of 

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CD38-expressing tumor cells at concentrations from 0.5 mg/kg. Thus far, it is uncertain if the 
inhibition of the enzyme activity of CD38 by daratumumab contributes to its therapeutic effect.
Daratumumab does not induce the production of IL-6 or interferon by human mononuclear 
cells cultured in vitro. Thus, no stimulatory effects of daratumumab have been demonstrated in 
vitro.
For further information, refer to the Investigator’s Brochure.
1.1.4.
Preclinical Safety
The safety and toxicity of daratumumab was studied in chimpanzees because daratumumab does 
not bind to CD38 in other nonhuman primate species.
Overall, the safety study with daratumumab in chimpanzees revealed 2 potential safety issues: 
cytokine release syndrome and platelet depletion. Administration of a predose infusion of 
daratumumab before the first full-dose infusion prevented or minimized the clinical signs of 
cytokine release syndrome in chimpanzees. Therefore, a predose infusion has been incorporated 
into the Phase 1 dosing regimen of this clinical study. During the first-in-human clinical study 
(Protocol No. GEN501; ClinicalTrial.gov NCT00574288), no major changes in platelet counts 
over time have been observed in doses up to and including 4 mg/kg.
Based upon emerging safety data and further understanding of the occurrence of infusion related 
reaction, the pre-dose infusion is no longer required and will not be utilized in Phase 2. Pre and 
post medications and dose interruptions of daratumumab in ongoing single agent and 
combination studies have provided adequate intervention.
Daratumumab binding was investigated by immunohistochemistry in a human tissue 
cross-reactivity study. As shown by staining, daratumumab binds to lymphoid cells in the spleen, 
tonsil, lymph nodes, and thymus; capillaries of the pituitary gland; vascular endothelial cells; 
epithelial cells of the fallopian tubes and prostate; lymphocytes in the ileum serosa; and 
parathyroid, kidney, testis, and thyroid interstitial cells. Chimpanzee and human CD38 proteins 
are highly similar, and the interaction of daratumumab with these proteins is comparable 
regarding in vitro binding.
For further information, refer to the Investigator’s Brochure.
1.1.5.
Clinical Experience
Daratumumab is currently under investigation in multiple ongoing singe agent and combination 
studies. Safety information and limited efficacy data from daratumumab clinical studies may be 
referenced in the Investigator’s Brochure.
1.2.
Combination Therapy of Daratumumab, Lenalidomide, and 
Dexamethasone
To date, targeting multiple myeloma cells by a combination therapy approach has demonstrated 
superior clinical response as compared with that of single agents. In theory, targeting both the 

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tumor cells and the surrounding stromal compartment, upon which the tumor is dependent, 
should lead to higher efficacy. The combination of an IMiD and an mAb utilizes indirect and 
direct antitumor mechanisms and has previously been shown to be effective (Lonial 2010).16
Based on preclinical data, combining daratumumab and lenalidomide is not expected to induce 
unacceptable aggravation of the toxicology profile, and the mechanisms of action elucidated by 
preclinical studies indicate a potential for additive clinical efficacy.
Daratumumab directly targets the tumor cells by selectively binding to CD38 receptors, which 
are present at high levels on malignant plasma cells in multiple myeloma. Daratumumab has 
multiple mechanisms of action, including ADCC and CDC (de Weers 2011).5
Importantly, 
daratumumab-induced ADCC and CDC does not appear to be affected by the presence of bone 
marrow stromal cells, indicating that daratumumab can effectively kill multiple myeloma tumor 
cells in a tumor-preserving bone marrow microenvironment. In vivo studies have shown that 
daratumumab is highly active and interrupts xenograft tumor growth at low doses (de Weers 
2011).5
Lenalidomide is an immunomodulatory agent that is thought to mediate antimyeloma activity by 
3 main mechanisms: 1) direct antitumor effect; 2) inhibition of the microenvironment support for 
tumor cells; and 3) an immunomodulatory role (Vallet 2008).28 The direct tumor effect is 
described both as growth inhibition of myeloma cell lines and induction of apoptosis. The 
microenvironment support is affected by down regulation of cell adhesion molecules 
(eg, intercellular adhesion molecule 1), thus inhibiting stromal cell interaction with tumor cells, 
and inhibition of growth factors (eg, insulin growth factor 1 and vascular endothelial growth 
factor) induced by myeloma cell adhesion. Furthermore, lenalidomide has been demonstrated to 
possess antiangiogenic and antiosteoclastogenic effects. Finally, lenalidomide exhibits 
immunomodulatory activity including inhibition of proinflammatory signaling molecules 
(cytokines) such as tumor necrosis factor , IL-1, and IL-6, the latter of which is a known 
growth factor for myeloma cells (Vallet 2008).28
Importantly, it has also been shown that lenalidomide causes upregulation of natural killer (NK) 
cells in myeloma (Kotla 2009)10 and enhances ADCC of multiple myeloma cells, (Tai 2008, Tai 
2005) 26,27 which is a mechanism shown in preclinical studies to be involved in the efficacy of 
daratumumab.
In a preclinical study that used bone marrow mononuclear cells from patients with multiple 
myeloma, increased killing of tumor cells was demonstrated when daratumumab was combined 
with lenalidomide as compared with that of either agent alone as shown in Figure 1A (van der 
Veer 2011).29 Notably, daratumumab and lenalidomide acted in a synergistic fashion to generate 
an extra effect of 20% as compared with the expected additive effects of the agents (Figure 1B). 
This increased activity was retained even in patients whose multiple myeloma was clinically 
refractory to lenalidomide (Figure 2).

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Figure 1:
Improvement of Daratumumab-induced Antibody-dependent Cell-mediated Cytotoxicity by 
Lenalidomide in Bone Marrow Mononuclear Cells from Patients with Multiple Myeloma
Key:   DARA = daratumumab; LEN = lenalidomide; MM = multiple myeloma.
Note: (A) Bone marrow mononuclear cells of 14 patients with MM were incubated for 47 hours with the control 
antibody, with lenalidomide (3 M), and/or daratumumab (0.1 g/mL). Surviving MM cells were enumerated by 
Fluorescence-activated Cell Sorting analysis of CD138+ cells. The percentages of lysis of MM cells treated with 
lenalidomide, daratumumab, and lenalidomide + daratumumab were calculated by the Tukey’s post hoc analysis of 
repeated measures analysis of variance.
(B) The observed effect (% lysis) of the combination treatment was compared with the expected additive effect 
(proportional) of the combined treatments. Mixed model analysis supported the conclusion that the combination 
treatment was synergistic.

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Figure 2:
Addition of Daratumumab to Lenalidomide Significantly Increases the Lysis of Multiple 
Myeloma Cells in Bone Marrow Mononuclear Cells of Patients with Lenalidomide-refractory 
Multiple Myeloma
Key:
DARA = daratumumab; LEN = lenalidomide; MM = multiple myeloma.
Note:
Bone marrow mononuclear cells from 4 patients with lenalidomide-refractory MM were incubated lenalidomide (3 M), 
daratumumab (10 g/mL), or in combination for 48 hours. Surviving MM cells were enumerated by Fluorescence-activated 
Cell Sorting analysis of CD138+ cells. The percentages of lysis of MM cells treated with lenalidomide, daratumumab, or 
lenalidomide + daratumumab were calculated as compared with the survival of MM cells treated with the control keyhole 
limpet hemocyanin antibody alone.
Finally, it was demonstrated that peripheral blood mononuclear cells isolated from patients 
during or just after lenalidomide treatment showed a significantly increased capacity to mediate 
daratumumab-dependent ADCC against multiple myeloma cells alone (van der Veer 2011).29
Thus, in this ex vivo clinical setting, daratumumab-mediated multiple myeloma tumor cell 
killing was demonstrated to be significantly augmented by stimulating effector cells. In 
conclusion, preclinical data, both from the literature and the sponsor’s own ex vivo studies, 
support the combination of daratumumab with an IMiD in the treatment of multiple myeloma.
Based on the current safety data from the ongoing GEN501 study (Section 1.1.5) and the safety 
information in the label for lenalidomide, the expected safety profile of daratumumab in this 
combination therapy study is considered manageable. 
No major changes in thrombocyte counts over time have been observed during treatment with 
daratumumab in doses up to 4 mg/kg. Thrombocytopenia was an expected finding based on the 
data from preclinical studies. Because lenalidomide may cause thrombocytopenia, an additive 
effect cannot be excluded. Therefore, thrombocytopenia must be closely monitored, and dose 
adjustments in accordance with the label for lenalidomide must be followed during this study of 
the combination of daratumumab and lenalidomide. Lenalidomide also increases the risk of DVT 
and pulmonary embolism (PE). No thromboembolic events have been observed with 
daratumumab; however, a thrombocyte-sensitizing effect of daratumumab cannot be excluded. 
Therefore, aspirin should be administered to all subjects, and low-molecular weight heparin 
should be given to subjects who are at increased risk of thromboembolic events. Intense safety 

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monitoring by the sponsor and an Independent Data Monitoring Committee (IDMC) will be 
performed.
No additive adverse effects are expected when combining dexamethasone with daratumumab 
based on results of the analysis of daratumumab safety data in the GEN501 study.
1.3.
Overall Rationale for the Study
The sponsor is evaluating daratumumab as a treatment for subjects with relapsed or relapsed and 
refractory multiple myeloma.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective is to establish the safety profile of daratumumab when given in 
combination with Len/Dex in subjects with relapsed or relapsed and refractory multiple 
myeloma.
Secondary Objectives
The secondary objectives are: 

To evaluate the efficacy of daratumumab when given in combination with Len/Dex in 
subjects with relapsed or relapsed and refractory multiple myeloma.

To evaluate the pharmacokinetic (PK) profile of daratumumab when given in combination 
with Len/Dex in subjects with relapsed or relapsed and refractory multiple myeloma.

To assess the immunogenicity of daratumumab.
2.2.
Hypothesis
No formal statistical hypotheses are planned to be tested.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is an open-label, multicenter Phase 1/2 safety study of daratumumab in combination with 
Len/Dex in the treatment of subjects with relapsed or relapsed and refractory multiple myeloma. 
The dose escalation portion of the study (Phase 1) will be a standard 3 + 3 design and will 
evaluate daratumumab, at doses from 2 mg/kg up to a maximum of 16 mg/kg, in combination 
with Len/Dex in 28-day treatment cycles. The standard “3 + 3” rules for dose escalation will be 
applied, However, if the study sites have identified 4 eligible subjects to start a new dose level, 
all 4 subjects may be enrolled. The MTD will be defined as the highest dose of the combination 
regimen at which less than 33% of subject’s experience DLT. A recommended Phase 2 dose 
(RP2D) will be determined during Phase 1. The MTD or any dose evaluated in the range of 2 to 
16 mg/kg of daratumumab may be considered as the RP2D based on available safety, 

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PK/pharmacodynamic, and efficacy data from Phase 1. The RP2D could be selected before 
escalation to or completion of the 16 mg/kg cohort. Once the RP2D is determined, the expansion 
(Phase 2) will open to further explore the safety and efficacy of the RP2D in approximately 
30 subjects.
For Phase 1 and Phase 2 of the study there will be a Screening Period followed by the first 
2 treatment cycles and will consist of weekly daratumumab infusions, totaling 4 infusions during 
each 28-day cycle. Cycles 3 through 6 will consist of daratumumab infusions administered every 
other week; Cycle 7 and all subsequent cycles will consist of monthly daratumumab infusions. 
The combination treatment may continue until the subject experiences disease progression or 
unacceptable toxicity, whichever comes first. For Phase 1 only, to minimize the risk of cytokine 
release syndrome, the first infusion of the first cycle will be preceded by a predose infusion the 
day before the scheduled full-dose infusion. The predose infusion will be 10% of the full dose, 
but will never be more than 10 mg in total dose. Further measures to prevent cytokine release 
syndrome will include premedication with antihistamines, acetaminophen, and dexamethasone 
before each daratumumab infusion (both predose and full dose).
For Phase 1 and Phase 2, lenalidomide will be administered at a dose of 25 mg orally (PO) on 
Days 1 through 21 of each 28-day cycle, and dexamethasone will be administered at a total dose 
of 40 mg weekly. As of Amendment 5, subjects older than 75 years or underweight (body mass 
index [BMI] <18.5), the dexamethasone dose may be administered at a dose of 20 mg weekly. 
On weeks when daratumumab is administered the 20 mg dose should be administered as the 
premedication per protocol. Details on the dosing regimens for Len/Dex are provided in
Section 6.2 and Section 6.3, respectively.
During Phase 1, decisions to escalate the dose of daratumumab for the next cohort will be based 
on the safety data obtained from the 3 (+ 3) subjects in the previous cohort during their first 
treatment cycle (28 days). The IDMC will evaluate all safety data (including SAEs, AEs, and 
laboratory data) after each cohort completes Cycle 1. The third subject in the cohort must have 
received all 4 full doses of daratumumab, and data from an observation period of 6 days after the 
last infusion must be available for the IDMC to review. Based on the results presented in these 
safety profiles, the IDMC will recommend to the sponsor if it appears safe to escalate the dose. 
The recommendation will be discussed and confirmed by the sponsor, who will ultimately decide 
if dose escalation will occur. Subjects who discontinue the study during the first cycle for 
reasons other than a DLT will be replaced.
The IDMC and sponsor may decide to implement intermediate doses to ensure subject safety and 
better define the RP2D. The RP2D, as defined by the IDMC and sponsor, or the maximum dose 
tested will be the dose level at which subjects will be treated in Phase 2 of the study.
In both phases of the study, investigational product will be administered per schedule up to 
disease progression, intolerability, withdrawal, death, or unless otherwise indicated by IDMC. 
Daratumumab may be continued until investigator’s or sponsor’s recommendation of 
discontinuation, the subject’s decision to discontinue for any reason, or disease progression.

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The study will have 3 data cutoff time points:

The first data cutoff will be for the interim safety analysis, which is estimated to be 
performed approximately 6 months after the last subject in the study receives the first dose 
of daratumumab. All available data at the time of this data cutoff will be included in the 
abbreviated Clinical Study Report (CSR). 

The second data cutoff will be for the primary safety analysis, which is estimated to be 
performed approximately 12 months after the last subject in the study received the first dose 
of daratumumab. All available data at the time of this data cutoff will be included in the 
abbreviated CSR.
As of Amendment 8, the following data cutoff is yet to be completed.

The third and final data cutoff will be for the updated safety analysis, which is estimated to 
be performed approximately 24 months after the last subject in the study receives the first 
dose of daratumumab. All available data at the time of this data cutoff will be included in a
final CSR addendum. 
3.2.
Rationale for Study
3.2.1.
Rationale for Subject Population
Despite great strides in treatment, multiple myeloma remains an incurable condition that claims 
some 11,000 lives a year in the US and an equal number in the EU. There is currently no cure
available, and clearly, there is a need for novel therapies, particularly for those patients who are 
not candidates for auto-SCT.
In Phase 1 (dose escalation), the subject population will include patients with relapsed multiple 
myeloma after receiving a minimum of 2 and a maximum of 4 prior lines of therapy.
In Phase 2 (cohort expansion), the subject population will include patients with relapsed or 
refractory multiple myeloma that have received at least 1 prior line of therapy, and are not 
refractory to lenalidomide.
3.2.2.
Rationale for Study Design
In this Phase 1/2 safety study of daratumumab in combination with lenalidomide and low-dose 
dexamethasone (Len/Dex), a standard Phase 1 “3 + 3” design is appropriate to adequately 
observe DLTs associated with the regimen while not exposing an undue number of subjects to 
doses that may be subtherapeutic. The dose escalation phase of the study (Phase 1) will be 
followed by Phase 2, upon identification of recommended Phase 2 dose (RP2D). Approximately
30 subjects will be enrolled in Phase 2, which will allow for a greater degree of experience with 
the combination therapy at what is expected to be a therapeutic dose of daratumumab and 
Len/Dex.

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3.2.3.
Dose Rationale
3.2.3.1.
Phase 1 Dose Escalation
Safety and PK data on daratumumab as a single-agent therapy are currently being obtained and 
evaluated in the ongoing Phase 1, dose-escalation, clinical study (GEN501). Doses of 
0.005 mg/kg up to and including 4 mg/kg have been judged safe, and dose escalation is ongoing.
Preliminary PK analysis of subject data from the GEN501 dose-escalation study has shown low 
serum recovery of daratumumab in the 0.1 mg/kg cohort. In the 1, 2, and 4 mg/kg cohorts, the 
maximum concentration in serum (Cmax) corresponds to a Vcen of 54, 54, and 25 mL/kg, 
respectively, which is consistent with initial distribution into the serum compartment as expected 
for an antibody. The considerably larger Vcen observed in the 0.1 and 0.5 mg/kg cohorts is likely 
due to target binding.
Plots comparing the observed daratumumab concentrations with concentrations expected in 
serum from a general IgG PK model show that the observed daratumumab clearance is faster 
than expected for IgG, which indicates that the PK of daratumumab in humans is affected by a 
“sink.” It is speculated that, in patients with multiple myeloma, tumor load has a large 
contribution to the “sink”, which may explain the observed intersubject variability.
In vitro studies showed that daratumumab may exert antitumor effects at low concentrations, but 
that maximum efficacy of all potential mechanisms of action requires saturation of the target, 
which occurs at concentrations greater than approximately 2 g/mL. Because concentrations of 
daratumumab in serum of subjects in the 1.0 mg/kg cohort of the GEN501 study were only 
above this level for a limited time, it was concluded that doses of 1 mg/kg and below would add 
suboptimal therapeutic support to patients with relapsed multiple myeloma. In addition, it should 
be noted that concentrations of daratumumab around tumor cells are likely to be below those in 
serum. Consistent with the existence of a “sink”, the increase in the area under the concentration-
time curve (AUC) was more than dose-proportional when the dose level was increased from 0.5 
to 4 mg/kg. In the 4 mg/kg cohort, the importance of the “sink” seems to become smaller 
compared with that of the preceding cohorts. One subject in this cohort had trough levels of 
daratumumab above 10 g/mL throughout an observation period of more than 5 weeks.
By using a PK model based on the available data, in which the “sink” is represented by a 
nonlinear route of clearance and assuming that the “sink” remains unchanged during therapy, 
predictions were made for alternative dosing schedules. For weekly infusions at a dose level of 
8 mg/kg, it is expected that the effect of the “sink” will become relatively small, the Cmax of 
daratumumab will be in the range of 200 to 300 g/mL, trough concentrations will be around 
100 g/mL, and no major accumulation will occur. Furthermore, at the proposed dose schedule 
(where the dose interval after Week 8 is extended to 2 weeks), no accumulation of daratumumab 
is expected, even if the “sink” diminishes during therapy.
The starting dose of the daratumumab component in this combinational study will be 2 mg/kg. 
This dose corresponds to ¼ of the dose currently being investigated (8 mg/kg) and ½ of the 

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highest dose that has been approved by the external IDMC (4 mg/kg) in the ongoing GEN501 
monotherapy study.
To prevent cytokine release syndrome, a predose infusion will be administered the day before the
first full-dose infusion of daratumumab. The predose infusion will be 10% of the full dose, but 
never more than 10 mg in total. In Phase 2, the predose will not be administered. Further 
measures to prevent cytokine release syndrome will include premedication with antihistamines, 
acetaminophen, and dexamethasone before each infusion (both predose and full dose).
3.2.3.2.
Daratumumab RP2D Rationale
The RP2D has been selected based on marked M-protein reduction with an acceptable safety 
profile in doses up to16 mg/kg, the highest dose of Phase 1. MTD was not reached in Phase 1.
The IDMC reviewed the safety data of 2, 4, 8 and 16 mg/kg cohorts and concluded that an 
acceptable benefit/risk profile was observed in doses up to 16 mg/kg. The majority of the Grade 
3 adverse
events were
neutropenia, which was
attributed to lenalidomide.
The 
daratumumab/Len/Dex combination PK-profile was similar to daratumumab alone suggesting
Len/Dex does not affect the pharmacokinetic profile of daratumumab. 
The rationale of PR2D is also supported by the ongoing single agent daratumumab studies. 
Clinical pharmacokinetic data have shown the 16 mg/kg dose to be the lowest dose that results in 
complete target suppression at all time points. This dose and schedule continuously suppressed 
NK cells throughout dosing. Additionally, the overall response rate (ORR) appeared higher for 
the 16-mg/kg dose compared with the 8-mg/kg dose, based on early preliminary data from Part 2 
of Study GEN501 and from Study MMY2002 (both ongoing) as of a cutoff date of 24 January 
2014. In Study GEN501, the ORRs (ie, partial response [PR] or greater) were 11% and 40% for 
the 8-mg/kg (n=28) and 16-mg/kg (n=15) dose regimens, respectively. For the Study MMY2002, 
the unconfirmed ORRs for the 8-mg/kg and 16-mg/kg dose regimens were similar to those 
observed in GEN501. In addition, VGPRs were observed for 7 of 30 subjects treated with the 
16-mg/kg dose in those 2 studies. VGPR had not been observed at lower dose levels. These 
preliminary data support that full target saturation at the 16-mg/kg dose is needed to achieve 
higher and deeper response rates. In addition, the 16-mg/kg dose and schedule was shown to 
have an acceptable and manageable safety profile for the approximately 30 subjects for whom 
preliminary data were available in Studies GEN501 and MMY2002, and no additive toxicity has 
been observed in the Phase 1 dose escalation when comparing the safety from 16 mg/kg dose 
cohort with lower dose cohorts.
4.
STUDY POPULATION
4.1.
General Considerations
Between 42 and 58 subjects will be enrolled in this study, depending on the number of dose 
levels included during dose escalation in Phase 1. It is estimated that the screen failure rate will 
be 25% and that between 56 and 78 subjects will be screened in order to enroll the expected 
number.

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4.2.
Inclusion Criteria
Before entering Phase 1 of the study, subjects must: 
1.
Have relapsed multiple myeloma after receiving a minimum of 2 and a maximum of 
4 prior lines of therapy and be eligible for treatment with Len/Dex.
2.
Have measurable levels of M-component, defined as serum M-component 1.0 g/dL 
and/or urine M-component 200 mg/24-hour sample.
3.
Be 18 years of age.
4.
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 
(Attachment 1).
5.
Have a life expectancy of 3 months.
6.
Provide signed informed consent after receipt of oral and written information about the 
study and before any study-related activity is performed.
Before entering Phase 2 of the study, subjects must:
1.

Have received at least 1 prior line of therapy for multiple myeloma (refer to 
Attachment 2).

Have achieved a response (PR or better) to at least one prior regimen.

Have documented evidence of progressive disease (PD) as defined by the IMWG 
criteria on or after their last regimen.
2.
Have measurable levels of M-component, defined as serum M-component 1.0 g/dL 
and/or urine M-component 200 mg/24-hour sample.
3.
Be 18 years of age.
4.
Have an ECOG performance status score of 0, 1, or 2 (Attachment 1).
5.
Have a life expectancy of 3 months.
6.
Provide signed informed consent after receipt of oral and written information about the 
study and before any study-related activity is performed.

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4.3.
Exclusion Criteria
Before entering the study, subjects must not:
1.
Have previously received an allogenic stem cell transplant.
2.
Have received auto-SCT within 12 weeks before the first infusion.
3.
Have received antimyeloma treatment, radiotherapy, or any experimental drug or 
therapy within 2 weeks before the first infusion.
4.
Have discontinued lenalidomide due to any treatment-related adverse event or be
refractory to any dose of lenalidomide. 
Refractory to lenalidomide is defined as either:
-
Subjects whose disease progresses within 60 days of lenalidomide, or
-
Subjects whose disease is nonresponsive while on any dose of lenalidomide. 
Nonresponsive disease is defined as either failure to achieve at least an MR or 
development of PD while on lenalidomide.
5.
Have experienced prior DVT of Grade 3 according to the National Cancer 
Institute’s Common Terminology Criteria for Adverse Events, version 4.0 
(CTCAE).
6. 
Have experienced prior PE.
7. 
Have had past or current malignancy, except for:

cervical carcinoma of Stage 1B or less;

noninvasive basal cell or squamous cell skin carcinoma;

malignant melanoma with a CR of > 10 years duration;

prostate cancer with a current prostate-specific antigen level < 0.1 ng/mL;

any curable cancer with a CR of > 5 years duration.
8. 
Have any current serious infectious disease requiring systemic treatment.
9. 
Have clinically significant cardiac disease, including:

unstable angina;

acute myocardial infarction within 6 months of the Screening Visit (before the 
first infusion);

congestive heart failure (Class III or IV as classified by the New York Heart 
Association; Attachment 3);

a known decreased cardiac ejection fraction of < 50%;

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
a screening 12-lead electrocardiogram (ECG) reading showing a baseline QT 
interval as corrected by Fridericia’s formula (QTcF) > 470 msec for females or 
> 450 msec for males or a complete left bundle branch block (defined as a QRS 
interval 120 msec in left bundle branch block form).
10. 
Have a significant, concurrent, uncontrolled medical condition including, but not 
limited to, renal (except as related to multiple myeloma), hepatic, hematologic 
(except as related to multiple myeloma), gastrointestinal, endocrine, pulmonary, 
neurologic, cerebral, or psychiatric disease.
11. 
Be exhibiting clinical signs of meningeal involvement of multiple myeloma.
12. 
Have known severe chronic obstructive pulmonary disease or asthma (defined as a 
forced expiratory volume in 1 second [FEV1] <60% of predicted normal) or 
persistent asthma.
13. 
Have a history of significant cerebrovascular disease.
14. 
Have known to be seropositive for human immunodeficiency virus (HIV) or have 
active hepatitis B or hepatitis C. 
15. 
Have screening laboratory test results as the following:

absolute neutrophil count 1.5 109/L;

hemoglobin level 80 g/L (5 mmol/L);

platelet count < 75 109/L

alanine aminotransferase (ALT) 2.5 times the upper limit of normal (ULN);

alkaline phosphatase level 2.5 ULN;

direct bilirubin level 2 ULN;

creatinine clearance (CrCl) 60 mL/min within 7 days before the Screening 
Visit (before the first infusion);

potassium level < 3.0 mEq/L.
16. 
Have 
received 
granulocyte-colony 
stimulating 
factor 
(G-CSF) 
or 
granulocyte/macrophage-colony stimulating factor support for < 1 week or 
pegylated G-CSF for < 2 weeks before the Screening Visit or before the first 
infusion.
17. 
Have received a cumulative dose of corticosteroid 200 mg (dexamethasone, or 
equivalent doses of prednisone) within 2 weeks before the first infusion.

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18. 
Have a known hypersensitivity to components of the study drug or combination 
therapy, or have known allergies, hypersensitivity, or intolerance to monoclonal 
antibodies or human proteins, or their excipients (refer to Investigator Brochure 
2013), or have known sensitivity to mammalian-derived products.
19. 
Have plasma cell leukemia or Waldenström’s macroglobulinemia.
20. 
Have previously received daratumumab, or other anti-CD38 therapies.
21. 
Be known to have any contraindications to receiving lenalidomide (as specified in 
the lenalidomide label).
22. 
Have received treatment with any nonmarketed drug substance within 4 weeks 
before the first infusion. 
23. 
Be currently participating in any other interventional clinical study.
24. 
Be known or suspected of not being able to comply with the study protocol 
(eg, because of alcoholism, drug dependency, or psychological disorder).
25. 
Be breastfeeding female.
26. 
Have a positive pregnancy test at the Screening Visit or before the first infusion.
27. 
Be unwilling to use adequate contraception for 4 weeks before the first infusion of 
daratumumab, during the study, and for 6 months after the last infusion of 
daratumumab if a female of childbearing potential. Adequate contraception is 
defined as hormonal birth control or an intrauterine device. For subjects in the US, 
the use of a double-barrier method during interruption periods and for at least 
4 weeks after the end of treatment is also considered adequate. Subjects in the EU 
must follow the Pregnancy Prevention Programme.
28. 
Be males unwilling to use a latex condom during any sexual contact with females of 
childbearing potential during and for 6 months after the last infusion of 
daratumumab, even after having undergone a successful vasectomy.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's status changes (including laboratory results or receipt of additional medical records) 
after screening but before the first dose of study drug is given such that he or she no longer meets
all eligibility criteria, then the subject should be excluded from participation in the study. 
Section 17.4, Source Documentation, describes the required documentation to support meeting 
the enrollment criteria.

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5.
TREATMENT ALLOCATION AND BLINDING
5.1.
Subject Allocation Procedures
In Phase 1, subjects will be allocated to the dose escalation cohorts in a standard 3 + 3 study
design. In Phase 2, subjects will be enrolled to an expansion cohort. Allocation of subjects in 
both Phases 1 and 2 will be controlled by the contract research organization (CRO).
When a potential subject is identified at a site, the site personnel must contact the CRO regarding 
the subject. If there is an opening in the currently enrolling cohort, the site will be given approval 
to start the screening process.
If there is no opening in the currently enrolling cohort, the CRO will place the subject on a list of 
potential subjects. If another subject fails the screening process, the CRO will alert the site that 
has the next subject on the waiting list. If the subject is still eligible, the site will be given 
approval to start the screening process.
5.2.
Blinding
As this is an open study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
The start of a cycle is defined as the start of any of the study treatments (ie, daratumumab or 
Len/Dex). If all treatments are held, then it should be reported as a cycle delay.
6.1.
Daratumumab
Daratumumab will be administered as an IV infusion. Each subject’s dose will be calculated 
based on the subject’s weight rounded to the nearest kilogram, ie, assigned cohort dose in 
mg/kg body weight in kg. The dose does not need to be recalculated for weight changes that 
are <10% from baseline. The weight will be used to determine the number of vials required for 
dosing. The pharmacist will then calculate the required volume of daratumumab from the 
number of vials needed for each subject. For subjects whose body mass index is greater than 
30 kg/m2, the investigator should use a weight that, based on the subject’s height, corresponds to 
a maximum body mass index of 30.
For Phase 1, daratumumab will be given as follows:

Cycle 1: Day 0 (predose infusion), Day 1 (first full-dose infusion), and Days 8, 15, and 22 of 
a 28-day cycle

Cycle 2: Days 1, 8, 15, and 22 of a 28-day cycle

Cycles 3-6: Days 1 and 15 of a 28-day cycle for 4 cycles or until the subject experiences 
unacceptable toxicity or disease progression, whichever comes first

Cycles 7+: Day 1 of a 28-day cycle until the subject experiences unacceptable toxicity or 
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For Phase 2, daratumumab will be given as follows:

Cycle 1: Day 1 (first full-dose infusion), and Days 8, 15, and 22 of a 28-day cycle

Cycle 2: Days 1, 8, 15, and 22 of a 28-day cycle 

Cycles 3-6: Days 1 and 15 of a 28-day cycle for 4 cycles or until the subject experiences 
unacceptable toxicity or disease progression, whichever comes first

Cycles 7+: Day 1 of a 28-day cycle until the subject experiences unacceptable toxicity or 
disease progression, whichever comes first Table 5 and Table 6 provide recommendations 
for the rate of infusion.
Table 5:
Phase 1 Infusion Rate Recommendations
Predose Infusions
First Full-dose Infusiona
Subsequent Full-dose Infusionsa
Time (minutes)
Rate (mL/hour)
Time 
(minutes)
Rate (mL/hour)
Time (minutes)
Rate (mL/hour)
0 - 240
12.5
0 – 60
50
0 - 60
50c
61 – 180
100
61 - 120
100
181 -
150b
121 - 180
150
181 -
200
Total volume
50 mL
Total volume
1000 mL
Total volume
1000 mL
a
Additional details for administration times and rates for the full-dose infusions will be provided in the 
administration guidelines.
b
If the infusion is uneventful after 2 hours at a rate of 150 mL/hour, the investigator may increase the infusion 
rate to 200 mL/hour.
c
If no infusion reactions occurred during the last full-dose infusion, the infusion rate may start at 100 mL/hour at 
the investigator’s discretion.
Table 6:
Phase 2 Infusion Rate Recommendations
First Full-dose Infusion for 
Approximately 20 Subjectsa
First Full-dose Infusion for
Approximately 10 Subjectsa
Subsequent Full-dose Infusion for 
all subjectsa
Time (minutes)
Rate (mL/hour)
Time 
(minutes)
Rate (mL/hour)
Time (minutes)
Rate (mL/hour)
0 - 60
50
0 – 60
50c
0 - 60
50c
61 - 180
100
61 – 120
100
61 - 120
100
181 -
150b
121 – 180
150
121 - 180
150
181 -
200
181 -
200
Total volume
1000 mL
Total volume
500 mL
Total volume
500 mL
a
Additional details for administration times and rates for the full-dose infusions will be provided in the 
administration guidelines.
b
If the infusion is uneventful after 2 hours at a rate of 150 mL/hour, the investigator may increase the infusion 
rate to 200 mL/hour.
c
If no infusion reactions occurred during the last full-dose infusion, the infusion rate may start at 100 mL/hour at 
the investigator’s discretion.
The sponsor or IDMC may modify the predose infusion, infusion rates, or premedications, 
prospectively based upon the information collected to date from this and other studies. 
Additional details for administration times and rates, as well as premedications, will be provided 
in the administration guidelines.

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6.1.1.
Premedication
Subjects will receive the following premedications before all infusions with daratumumab:

Dexamethasone (or equivalent in accordance with local standards) will be administered as 
described in Section 6.3.

Paracetamol (acetaminophen) will be administered at a dose of 1 g PO 30 minutes to 2 hours 
before infusion.

An antihistamine (clemastine 1 mg IV, cetirizine 10 mg PO, or equivalent) will be 
administered 30 minutes to 2 hours before infusion.
6.2.
Lenalidomide
For Phase 1 and Phase 2, lenalidomide will be administered at a dose of 25 mg PO each day on 
Days 1 through 21 of each 28-day cycle. Cycle 1, Day 1 will be the day of the first full dose of 
daratumumab (Cycle 1 Visit 2). Lenalidomide will be administered until the subject experiences 
disease progression or unacceptable toxicity, whichever comes first.
On daratumumab infusion days, lenalidomide may be administered prior to or at the same time 
(preferred) as the premedications. A common side effect of lenalidomide is tiredness. On days 
when daratumumab is not administered, subjects may take their dose of lenalidomide in the 
evening.
6.2.1.
Dose Adjustments of Lenalidomide
Dose adjustments of lenalidomide will follow the approved labeling as follows:

Starting dose - 25 mg

Dose level 1 - 15 mg

Dose level 2 - 10 mg

Dose level 3 - 5 mg
Dose adjustments should be based on the highest grade of toxicity that is ascribed to 
lenalidomide.
6.2.1.1.
Deep Vein Thrombosis and Pulmonary Embolism
Lenalidomide has been associated with DVT and PE. Therefore, all subjects should be 
prophylactically treated with aspirin at a dose of 100 to 150 mg PO daily. Subjects at increased 
risk of thromboembolic events (based on their medical history) should be treated with 
enoxaparin at a dose of 40 mg subcutaneously daily. The injection should be handled according 
to local practice.

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6.2.1.2.
Thrombocytopenia
If the subject’s platelet count decreases, dose adjustments should be made according to the 
recommendations in Table 7.
Table 7:
Lenalidomide Dose Adjustment for Thrombocytopenia
Platelet Count
Recommended Course of Action

When count first falls to < 30 109/L

When count returns to 30 109/L

Interrupt lenalidomide treatment, follow complete 
blood count weekly

Resume lenalidomide at 15 mg

For each subsequent drop in count to < 30 109/L

When count returns to 30 109/L

Interrupt lenalidomide treatment

Resume lenalidomide at the next lower dose level 
(10 mg or 5 mg) once daily. Do not decrease dose 
below 5 mg once daily
6.2.1.3.
Neutropenia
If the subject experiences neutropenia, the investigator should consider the use of growth factors 
in the subject’s management. If the neutrophil count decreases below 1.5 109/L after the 
second cycle, the subject should be treated with G-CSF at a dose of 300 g/day if his or her 
weight is less than 75 kg or 480 g/day if his or her weight is 75 kg or more. G-CSF may be 
given daily or 2 to 3 times a week as appropriate to maintain the subject’s neutrophil count above 
1.0 109/L.
If the subject’s neutrophil count decreases further, dose adjustments should be made according to 
the recommendations in Table 8.
Table 8:
Lenalidomide Dose Adjustment for Neutropenia
Neutrophil Count
Recommended Course of Action

When count first falls to < 1.0 109/L

When count returns to 1.0 109/L and 
neutropenia is the only observed toxicity

Interrupt lenalidomide treatment, start G-CSF 
treatment, follow complete blood count weekly

Resume lenalidomide at 25 mg once daily

When count returns to 1.0 109/L and other 
toxicity is observed

Resume lenalidomide at 15 mg once daily

For each subsequent drop in count to < 1.0 109/L

When count returns to 1.0 109/L

Interrupt lenalidomide treatment

Resume lenalidomide at the next lower dose level 
(15, 10 mg, or 5 mg) once daily. Do not decrease 
dose below 5 mg once daily
6.2.1.4.
Renal Impairment
Because lenalidomide is primarily excreted unchanged by the kidney, adjustments to the dose of 
lenalidomide are recommended to provide appropriate drug exposure in subjects with moderate 
or severe renal impairment. Lenalidomide dose adjustment should be instituted for subjects with 
a CrCl of 60 mL/minute or less. The recommended doses for subjects with multiple myeloma
and renal impairment are shown in Table 9.

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Table 9:
Lenalidomide Dose Adjustment for Renal Impairment
Category
Renal Functiona
Dose
Moderate renal impairment
CrCl 30-60 mL/min
10 mg every 24 hours
Severe renal impairment
CrCl < 30 mL/min (not requiring 
dialysis)
15 mg every 48 hours
End-stage renal disease
CrCl < 30 mL/min (requiring 
dialysis)
5 mg once daily. On dialysis days, 
administer the dose after dialysis
Key:
CrCl = creatinine clearance.
a
Estimated by CrCl as calculated by the Cockcroft-Gault, Diet in Renal Disease (MDRD), or Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) formulas formula (Attachment 7).
6.2.1.5.
Other Grade 3 or 4 Adverse Events
For other Grade 3 or 4 toxicities judged by the investigator to be related to lenalidomide alone, 
treatment with lenalidomide should be interrupted and restarted at the next lower dose level once 
the toxicity has resolved to Grade 2 or less. Treatment with daratumumab and dexamethasone 
may continue.
6.3.
Dexamethasone
For Phase 1 and Phase 2, dexamethasone (or equivalent in accordance with local standards; see 
Attachment 4 for conversion table) will be administered at a total dose of 40 mg weekly. As of 
Amendment 5, subjects older than 75 years or underweight (body mass index [BMI] <18.5), the 
dexamethasone dose may be administered at a dose of 20 mg weekly. On weeks when 
daratumumab is administered the 20 mg dose should be administered as the pre-medication per 
protocol. During weeks when the subject receives an infusion of daratumumab, dexamethasone 
will be administered on infusion days at a dose of 20 mg IV before the infusion and 20 mg PO 
the day after the infusion. During weeks when no daratumumab infusion is administered, 
dexamethasone will be administered at a dose of 40 mg/week PO. Dexamethasone will be 
administered until the subject experiences disease progression or unacceptable toxicity, 
whichever comes first.
After Cycle 6, the dose of dexamethasone may be reduced at the investigator’s discretion. The 
20-mg IV dose of dexamethasone given before the infusion on the day of daratumumab infusions 
must not be decreased. When dexamethasone is reduced to 20 mg/week and is given as 
preinfusion medication, subjects may receive low-dose methylprednisolone (≤20 mg) PO (or 
equivalent in accordance with local standards), for the prevention of delayed infusion-reaction 
reactions as clinically indicated.
6.3.1.
Dose adjustments of Dexamethasone
Investigators should refer to the manufacturer’s full prescribing information for side effects 
associated with dexamethasone. Dexamethasone administration may be held for up to 2 weeks 
until the toxicity resolves to Grade 1 or baseline levels.
6.4.
Delaying or Skipping Treatment
After completion of each cycle, initiation of a new cycle should be delayed for at least 1 week if 
the subject experiences toxicity. A subject whose cycle is delayed should be evaluated weekly 
for resolution or recovery of the toxicity, and a decision regarding further delay or initiation of 

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the next cycle should be made. However, the start of a new cycle after more than a 3-week delay 
(with all study therapy withheld) may occur only if there is clear clinical benefit and only after 
approval by the sponsor.
Refer to Section 6.6.1 for details on management of infusion-related reactions. ONLY if any of 
the following criteria below are met, and the event cannot be ascribed to lenalidomide, the 
daratumumab infusion must be held to allow for recovery from toxicity. The following 
parameters must be met on the first day of a new cycle (after Cycle 1):

Platelet count 50 109/L

Febrile neutropenia of any grade

Neutropenia with infection, of any grade

Hemoglobin 8.0 g/dL (4.96 mmol/L) (prior red blood cell transfusion or recombinant 
human erythropoietin use is allowed)

ANC 0.75 109/L

Nonhematologic toxicity of Grade 3 or higher must have recovered to baseline or Grade 1 or 
less unless otherwise specified
A subject whose cycle is delayed should be evaluated at least weekly for resolution of the 
toxicity. For severe hematologic toxicity (Grade 3 or higher), a complete blood count may be 
repeated more frequently as necessary until the requirements for reinitiating treatment are met.
6.5.
Dose-limiting Toxicities
Overall toxicity occurring during the first treatment cycle of each cohort will be used to assess 
DLTs for the purposes of dose escalation and subsequent dose assignment. Dose-limiting 
toxicities must be reported to the sponsor within 24 hours.
Dose-limiting toxicities are defined as any of the following events that occur during the first 
treatment cycle (28 days):

Nonhematologic toxicity considered to be a serious adverse event (SAE) of grade 3 or 
higher and related to daratumumab with the exception of:

Any nonhematologic reaction of grade 3 or higher that has an onset after the start of 
infusion on an infusion day, responds to symptomatic therapy, and resolves within 
6 hours from onset

Adverse reactions that prevent the infusion from being resumed regardless of the length of 
the reaction

Hematologic toxicity, considered related to daratumumab, defined as

Thrombocytopenia (platelet count < 20,000 cells/L)

Asymptomatic grade 4 neutropenia for more than 3 days

Neutropenic fever (defined as grade 3 or 4 neutropenia and temperature > 38.5C) for 
more than 3 days

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
Inability to receive the Day 1 infusion of Cycle 2 because of any toxicity related to 
daratumumab
If noncompliance with protocol-defined requirements results in toxicities of Grade 3 or higher, 
these toxicities should not qualify as DLTs.
Data from the Study GEN501 have shown the presence of free hemoglobin during daratumumab 
infusions without any clinical impact. Because this study includes escalating doses of 
daratumumab and combination therapy, the sponsor has specified that hemolysis greater than 
Grade 3 will be considered a DLT.
Neutropenic fever (defined as Grade 3 or 4 neutropenia and temperature >38.5C) for more than 
3 days has been specified by the sponsor as a DLT because, if the subject has been treated with 
G-CSF and the neutropenia has not normalized within 3 days, the bone marrow suppression is 
severe and clinically important.
Transfusion of platelets should be initiated at a platelet count of <20,000 cells/L to prevent life-
threatening thrombocytopenia (<10,000 cells/L).
Subjects who experience a DLT but have demonstrated a response to study drug therapy may 
remain in the study at the discretion of the investigator at 1 dose level below that at which the 
DLT occurred.
6.6.
Management of Infusion-related Reactions
Subjects who experienced AEs during the infusion must be treated according to the 
investigator’s judgment and best clinical practice. The infusion may be paused or the infusion 
rate may be decreased, which may cause a longer-than-anticipated infusion time. Overnight stays 
at the hospital because of slow infusions times should not be reported as an SAE.
The study staff at the site should be prepared to intervene in case of the occurrence of any 
infusion reaction, and resuscitation equipment must be available at bedside. Special attention 
should be paid during each subject’s first full-dose infusion.
For patients at higher risk of respiratory complications (eg, patients with COPD who have an 
FEV1 <80%, or subjects with mild asthma), the following post infusion medications should be 
considered:

Antihistamine (clemastine 1 mg IV, cetirizine 10 mg PO, or equivalent) on the first and 
second days after all full-dose infusions

Salbutamol aerosol

Controller medications (eg, inhaled corticosteroids ± long-acting beta agonists for patients 
with asthma; long-acting bronchodilators such as tiotropium or salmeterol ± inhaled 
corticosteroids for patients with chronic obstructive pulmonary disease)
In addition, these at-risk patients may be hospitalized for monitoring for up to 2 nights after an 
infusion. If patients are hospitalized, their FEV1 should be measured before discharge. If these 

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patients are not hospitalized, follow-up telephone calls should be made to monitor their condition 
twice daily on the first and second days after all full-dose infusions.
6.6.1.
Infusion-related Reactions of Grade 1 or 2
If the investigator judges the AE to be related to the infusion, the infusion should be paused. 
When the subject is stable, the infusion may be restarted at the investigator’s discretion. Upon 
restart, the infusion rate should be half of that employed before the interruption.
Subsequently, the infusion rate may be increased at the investigator’s discretion as described in 
Table 5 and Table 6.
If the subject experiences a Grade 2 or higher event of bronchospasm or laryngeal edema, the 
subject must be withdrawn from treatment.
6.6.2.
Infusion-related Reactions of Grade 3 or Higher
For infusion-related AEs that are Grade 3 or higher, the infusion must be stopped and the subject 
must be observed carefully until resolution of the AE.
If the intensity of any other AE remains at Grade 3 or 4 after 2 hours, the subject must be 
withdrawn from treatment.
If the intensity of any other AE decreases to Grade 1 or 2 within 2 hours, the infusion may be 
restarted at the investigator’s discretion. Upon restart, the infusion rate should be half of that 
employed before the interruption. Subsequently, the infusion rate may be increased at the 
investigator’s discretion as described in Table 5 and Table 6.
If the intensity of the AE returns to Grade 3 or 4 after restart of the infusion, the procedure 
described in this section may be repeated at the investigator’s discretion. Should the intensity of 
the AE increase to Grade 3 or 4 for a third time, the subject must be withdrawn from treatment.
7.
TREATMENT COMPLIANCE
Compliance for the administration of daratumumab will be ensured by the recording of the 
following information in the subject’s medical records:

Start and stop dates and times

Amount of daratumumab infused

Reason for any interruption of the infusion or decrease in infusion rate
For dexamethasone given on daratumumab infusion days, compliance will be assessed by 
recording the date, time, and dose of the IV administration before infusion and the PO 
administration after infusion.
Subject compliance with oral lenalidomide, dexamethasone,
and methylprednisolone 
administration will be assessed by pill counts. Subjects will be required to return all unused study
drug at each visit.

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8.
CONCOMITANT THERAPY
Any medication other than daratumumab, lenalidomide, and dexamethasone (or equivalent) is 
considered concomitant therapy and must be recorded in the electronic case report form (eCRF) 
with the following information:

Start and stop dates (or ongoing at study termination)

Route of administration

Dose regimen for glucocorticoid and other multiple myeloma treatment only (units and 
frequency). (Note: initiation of other multiple myeloma treatment is reason to discontinue 
the subject from the study [Section 10.2]; however, if the investigator deems it necessary to 
initiate such treatment, the dose regimen should be recorded)

Indication/reason for use (if administered to treat an AE, the AE number must be recorded)
Premedications given before infusion of daratumumab must be recorded separately in the eCRF 
with the following information:

Start and stop dates and times

Route of administration

Dose
Concomitant medications should be recorded beginning at the Screening Visit or before the first 
infusion and at all subsequent visits. 
8.1.
Recommended Concomitant Medications

Prophylactic antibiotic treatment (eg, amoxicillin, ciprofloxacin) is recommended during 
periods of neutropenia.

Pneumocystic pneumonia prophylaxis (sulfamethoxazole with trimethoprim) should be 
given to subjects who have a CD4 lymphocyte count less than 0.2 109/L.

To reduce the need for blood transfusions, recombinant erythropoietin is recommended at 
dose levels according to international guidelines for the management of anemia in patients 
with multiple myeloma (Ludwig 2011).17

Subjects with osteopenia or osteolytic lesions should be treated with bisphosphonates in 
accordance with international guidelines (Kyle 2007).12

Subjects should be monitored for symptoms of tumor lysis syndrome, including dehydration 
and abnormal laboratory test results such as hyperkalemia, hyperuricemia, and 
hypocalcemia. It is recommended that high-risk subjects be treated prophylactically in 
accordance with local standards (eg, rehydration; diuretics; allopurinol 300 mg daily and 
medication to increase urate excretion).
8.2.
Prohibited Medications
During the study, the following therapies are prohibited:

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
Concomitant administration of any other anti-neoplastic therapy for the intention of treating 
multiple myeloma is prohibited, including medications that target CD38, as well as 
medications used for other indications that have antimyeloma properties (eg, interferon and 
clarithromycin).

Any other investigational or nonmarketed drug substance therapy
Local radiotherapy for bone pain is allowed.
9.
STUDY EVALUATIONS
9.1.
Study Procedures by Visit
9.1.1.
Overview
The following sections give a brief overview of the Screening Period, Treatment Period, 
Follow-up Period, and EOT Visit. The Time and Events Schedule summarizes the frequency and 
timing of safety, efficacy, pharmacokinetic, pharmacodynamic, and other measurements 
applicable to this study. As of Amendment 8, follow the schedule of events outlined in Table 4
and additional details are provided in Attachment 9.
9.1.2.
Screening Period 
Subjects, or their legally acceptable representative, will provide written informed consent before 
any study-specific procedures are performed. Medical history, vital sign and ECG measurements, 
and samples for laboratory analysis (hematology, biochemistry, and urinalysis) will be collected, 
and physical examination, computed tomography (CT) imaging or X-ray, and bone marrow 
biopsy and aspirate will be performed to determine the subject’s baseline disease status and 
eligibility for the study. Collection of medical history, vital sign and ECG measurements, 
laboratory analysis, and physical examination must be performed within 21 days before the start 
of treatment (Cycle 1 Visit 1). The CT imaging or X-ray must be performed within 6 weeks 
before study entry (Cycle 1 Visit 1). If a bone marrow biopsy report documenting a diagnosis of 
multiple myeloma within a maximum of 6 weeks before study entry (Cycle 1 Visit 1) is 
available, a repeat bone marrow aspirate and biopsy is not required. The subject’s blood type will 
be analyzed, and a blood type card will be issued. It is recommended that the subject carry this 
card at all times while enrolled in the study, including the Follow-up Period. For Phase 2, a 
sample for pharmacogenomics will also be collected during the Screening Period. 
9.1.3.
Treatment Period (Cycle X Visit X)
The investigator must evaluate the subject’s eligibility and inform the sponsor. The sponsor must 
approve the enrollment of every subject before the subject receives the first administration of 
study drug.
For Phase 1 and Phase 2 of the study, the first 2 treatment cycles will consist of weekly 
daratumumab infusions, totaling 4 infusions during each 28-day cycle. Cycles 3 through 6 will 
consist of daratumumab infusions administered every other week; Cycle 7 and all subsequent 
cycles will consist of monthly daratumumab infusions. The combination treatment may continue 
until the subject experiences disease progression or unacceptable toxicity, whichever comes first. 

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Daratumumab may be continued until investigator’s or sponsor’s recommendation of 
discontinuation, the subject’s decision to discontinue for any reason, or disease progression. 
To minimize the risk of cytokine release syndrome, the first infusion of the first cycle in Phase 1 
will be preceded by a predose infusion the day before the scheduled full dose infusion. The 
predose infusion will be 10% of the full dose, but will never be more than 10 mg in total dose. 
Further measures to prevent cytokine release syndrome will include premedication with 
antihistamines, acetaminophen, and dexamethasone before each daratumumab infusion (both 
predose and full dose).
For Phase 1 and Phase 2, lenalidomide will be administered on Days 1 through 21 of each 28-day 
cycle at a dose of 25 mg/day PO. For the first cycle, Day 1 will be the day of the first full-dose 
infusion of daratumumab (ie, Cycle 1 Visit 2). Lenalidomide will be administered until the 
subject experiences disease progression or unacceptable toxicity, whichever comes first. All 
investigators must follow the guidelines of the lenalidomide RevAssistprogram in the US and 
Pregnancy Prevention Programme in the EU.
For Phase 1 and Phase 2, dexamethasone will be administered at a total dose of 40 mg/week
(except for the first week of daratumumab dosing; see below). On the day of the predose infusion 
of daratumumab (Cycle 1 Visit 1), dexamethasone will be administered at a dose of 20 mg IV 
before the infusion; no dose will be administered after the infusion. During daratumumab 
infusion weeks, dexamethasone will be administered on the day of daratumumab infusion as 
20 mg IV before the infusion and 20 mg PO the day after the infusion. An equivalent dose may 
be given in accordance with local standards (Attachment 4). During weeks when no 
daratumumab infusion is planned, dexamethasone will be administered at a dose of 40 mg/week 
PO. For both Phase 1 and Phase 2, after the completion of Cycle 6, the administration of 
dexamethasone may be adjusted at the discretion of the investigator; however, dexamethasone 
should always be administered at a dose of 20 mg IV on daratumumab infusion days. 
Dexamethasone will be administered until the subject experiences disease progression or 
unacceptable toxicity, whichever comes first.
At Cycle 1 Visit 2 (the first full-dose infusion of daratumumab), the subject may either remain 
hospitalized overnight and be released on the following day or may receive outpatient IV 
administration at the investigator’s discretion. This hospitalization should not be reported as an 
SAE. Hospitalization is not required for the predose infusion (Cycle 1 Visit 1) because no 
infusion-related SAEs have been observed during or after the predose infusion of 23 subjects 
during the GEN501 study.
All subsequent infusions will be performed as outpatient visits. If the subject has not experienced 
a significant medical event but is hospitalized overnight only for observation, the hospitalization 
should not be reported as an SAE.
Adverse events will be monitored closely during treatment. Escalation to a new dose level can 
only be done after evaluation of the safety profile of the previous dose level by the IDMC. After 
this evaluation, the IDMC will make a recommendation regarding dose escalation.

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If the subject must stop either daratumumab, lenalidomide, or dexamethasone, the subject may 
continue the other components until progression or commencing a new regimen for the treatment 
of multiple myeloma. However, subjects will still receive dexamethasone as premedication to 
daratumumab.
9.1.3.1.
Treatment Follow-up as per Amendment 8
As per Amendment 8, subjects will continue to be dosed as per the Amendment 7 schedule 
(1 cycle is 28 days) and Table 4. 
Data collection will be limited to SAEs and SPMs, see details in Section 12 and Attachment 9. 
Daratumumab will be provided by the sponsor until it is approved for use in combination with 
lenalidomide and dexamethasone for patients with relapsed refractory multiple myeloma and is 
commercially available or can be accessed from another source. Subjects receiving treatment
will be transitioned from study drug to commercial product once commercial product is available 
in their region (or when daratumumab can be accessed from another source). In these 
circumstances, the sponsor and investigator will support transition of the subject to ensure that 
treatment continues and remains uninterrupted. Subjects who are unable to switch to commercial 
supplies will continue to remain in the study. All subjects will be followed for 3 years after the 
last dose of lenalidomide, to enable collection of SPMs.
9.1.4.
Safety Follow-up Period
After their last dose of lenalidomide, subjects will be followed for 3 years to assess occurrence of 
new cancers. Investigators will be asked to contact the subjects every 3-6 months to collect this 
information. In case of the occurrence of a new cancer, the investigator must report this 
occurrence on an SAE form as described in Section 12.6.
9.2.
Assessments Following the Final Analysis 
As of Amendment 8, the final analysis will be achieved. All subjects in the study have either 
received at least 24 months of study drug or have discontinued. Ongoing subjects may continue 
treatment with study drug. Disease assessments/response evaluations will be performed per local 
institutional practice. Safety information will be limited to SAEs and SPMs
Data collection will only include SAEs and SPMs; see details in Section 12 and Attachment 9.
9.2.1.
Clinical Assessments
9.2.1.1.
Demographics
Date of birth, race, ethnicity, and gender will be recorded in the eCRF.
9.2.1.2.
Medical History
Any relevant past or current medical conditions will be recorded in the eCRF. In addition, all 
prior treatment regimens for multiple myeloma will be recorded. Nonserious AEs that occur 
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Cycle 1 Visit 1 should be recorded as medical history. Serious AEs occurring during this time 
should be reported as described in Section 12.6.2.
9.2.1.3.
Physical Examination
A general physical examination will be performed at time points as indicated in Table 1 and
Table 2. The examination should include general appearance and the following body systems: 
lymph nodes, mouth and throat, lungs, cardiovascular, abdomen, extremities, musculoskeletal, 
neurologic, and skin. Clinically significant physical examination findings should be recorded in 
the appropriate section of the eCRF.
Height (with the subject wearing no shoes) will be measured at the Screening Visit or before the 
first infusion and the EOT Visit, rounded to the nearest centimeter, and recorded in the eCRF. 
Body weight (with the subject wearing no overcoat or shoes) will be measured, rounded to the 
nearest kilogram, and recorded in the eCRF.
9.2.1.4.
Electrocardiogram
Electrocardiograms will be performed at the Screening Visit or before the first infusion and 
before and after each infusion for Phase 1 (Table 1) and before and after the daratumumab 
infusion on Day 1 of each Cycle for Phase 2 (Table 2) to investigate possible Table 1 cardiac 
effects of daratumumab and/or combination therapy with special attention to possible QT and 
corrected QT interval disturbance. A follow-up ECG will be performed at the EOT Visit. Any 
abnormal ECG finding that meets the criteria for an AE or SAE must be recorded and reported as 
such.
The ECGs will be recorded digitally at the sites by using the standard 12-leads. Three baseline 
ECGs should be performed before the first infusion of the study drug as described in the ECG 
Specification Manual. An overall interpretation of the ECGs will be performed by the 
investigator or by a local site cardiologist if the task is delegated by the investigator.
Before the ECGs are recorded, the subjects should be resting in a horizontal position for at least 
20 minutes. If any irregularity is observed or occurs during the ECG (eg, vomiting, cough), the 
occurrence should be recorded in the eCRF with a description and time of the event. In these 
cases, the ECG may be recorded again.
The date, time, and overall interpretation of the ECG will be recorded in the eCRF, along with 
blood pressure and heart rate.
9.2.1.5.
Vital Sign Measurements
Vital signs, defined as blood pressure, pulse, and temperature, will be measured at time points as 
indicated in Table 1 and Table 2 and recorded in the eCRF. On the days when daratumumab 
infusions are given, vital signs will be measured at the following time points:

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Phase 1:

Before infusion - just before the planned infusion start time

During infusion - at 15-minute intervals during the first 2 hours

During infusion - at 60-minute intervals after the first 2 hours

End of infusion

After infusion - at 10 minutes, 30 minutes, 1 hour, and 2 hours
Phase 2:

Before infusion - just before the planned infusion start time

End of infusion
Body temperature should be measured by using the same method (eg, ear thermometer) at all 
times for each individual subject. Likewise, blood pressure should be measured by using the 
same method (eg, manual or automated sphygmomanometer) and the same arm at all times for
each individual subject.
9.2.1.6.
Eastern Cooperative Oncology Group Performance Status
The ECOG performance status score should be assessed at time points as indicated in Table 1
and Table 2 and recorded in the eCRF.
9.2.1.7.
Concomitant Therapy
Concomitant therapies should be recorded as detailed in Section 8.
9.2.1.8.
Adverse Events
Adverse events will be reported and followed by the investigator as determined by the sponsor. 
Further details on AE reporting are provided in Section 12.
Dose-limiting toxicities will be assessed during the first treatment cycle (28 days). Details on the 
reporting and handling of DLTs are provided in Section 6.5.
9.2.1.9.
Skeletal Survey
A whole-body X-ray or CT scan, including the cranium, is required. Additional surveys (X-ray, 
CT scan, or magnetic resonance imaging scan) may be performed at the investigator’s discretion 
(eg, to confirm response, to evaluate new symptoms or bone pain). If additional surveys are 
warranted, the investigator should choose the imaging modality based on the clinical indication. 
Reading of the skeletal surveys will be done by a radiologist. The overall interpretation of the 
evaluation will be recorded in the eCRF, and a copy of the evaluation report should be kept in 
the subject’s file.
9.2.2.
Clinical Laboratory Assessments
Unless otherwise stated, all blood and urine samples must be taken before administration of 
daratumumab. Blood tests, such as a blood type assessment, performed after the infusion of 
daratumumab may be confounded by the drug. The scheduling for all assessments listed in this 

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section is detailed in Table 1 and Table 2. As of Amendment 7, clinical laboratory assessments
(safety and efficacy) will be performed locally and based on local institutional practice. 
Pregnancy testing will continue, every 4 weeks during treatment and at the EOT visit, but will be 
performed by a local laboratory (See Table 3 and Attachment 8). 
9.2.2.1.
Biochemistry
A blood sample will be drawn at each visit for analysis of the following: sodium, potassium, 
creatinine, blood urea nitrogen, AST, ALT, alkaline phosphatase, bone-specific alkaline 
phosphatase, albumin, calcium, glucose, total creatine kinase, total bilirubin, lactic 
dehydrogenase, uric acid, 2-microglobulin, and C-reactive protein.
9.2.2.2.
Hematology
A blood sample will be drawn at each visit for analysis of the following: red blood cell count, 
hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, white blood cell count with differential, platelet count, 
and reticulocyte count.
In Phase 1, at the Screening Visit or before the first infusion, direct and indirect Coombs tests 
and a blood type assessment will be performed. In Phase 2, the direct and indirect Coombs tests 
will only be performed at screening.
Daratumumab Interference with Indirect Antiglobulin Test (IAT) results 
Blood Type, Rh, and IAT should be done before the first dose of daratumumab.  Subject red 
blood cell (RBC) phenotyping (standard or extended) is an alternative option to the IAT test, if 
locally required. Either method must be completed prior to the first daratumumab infusion.
Daratumumab interferes with the Indirect Antiglobulin Test (IAT), which is a routine pre-
transfusion test performed to identify a patient’s antibodies to minor antigens so that suitable 
donor blood can be given for transfusion. Daratumumab does not interfere with ABO/Rh blood 
group, D antigen (RhD) typing. CD38 is expressed at very low levels on erythrocytes. 
Daratumumab binds to the CD38 on erythrocytes, which results in a positive IAT (Indirect 
Coombs Test). This positive result masks the detection of antibodies to minor antigens and may 
prevent or delay blood banks from issuing donor blood for transfusion. This effect occurs during 
daratumumab treatment and for up to 6 months after treatment ends. Subjects will receive a 
patient identification wallet card for the study that includes the blood profile (ABO, Rh, and 
IAT) determined before the first infusion of daratumumab along with information on the IAT 
interference for healthcare providers/blood banks. Subjects are to carry this card throughout the 
treatment period and for at least 6 months after treatment ends. Blood banks can eliminate the 
daratumumab IAT interference by treating reagent RBCs with dithiothreitol (DTT) 
(Chapuy 2015).4

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Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
a)
Providing ABO/RhD compatible, phenotypically or genotypically matched units
b)
Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is 
needed emergently as per local blood bank practice.
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in daratumumab studies. For additional details, refer to the 
Daratumumab IB.
9.2.2.3.
Serology for HIV, Hepatitis B, Hepatitis C, and Cytomegalovirus 
In the Phase 1 portion of this study, a blood sample will be drawn at the Screening Visit or 
before the first infusion for assessment of hepatitis B, as well as antibodies to cytomegalovirus 
antigen. Blood samples will be drawn for assessment of antibodies to cytomegalovirus antigen 
after study drug administration.
In the Phase 2 portion of this study, a blood sample will be drawn only at the Screening Visit for 
the assessment of hepatitis B, hepatitis C, HIV, and antibodies to cytomegalovirus antigen. 
9.2.2.4.
Pregnancy Test
As of Amendment 8, serum pregnancy tests will continue to be performed by the local laboratory 
on samples collected every 4 weeks during the Treatment Period (see Table 3).
A blood sample will be drawn at the Screening Visit or before the first infusion from all women 
of childbearing potential. The sample will be shipped to the central laboratory (BARC) for 
immediate analysis of human chorionic gonadotropin. Pregnant women will not be allowed to 
take part in this study and will be considered as screening failures.
Women are considered of childbearing potential unless they have undergone hysterectomy or 
tubal ligation within 1 year or have been postmenopausal for at least 1 year before the Screening 
Visit or before the first infusion.
9.2.3.
Myeloma-related Laboratory Efficacy Assessments
As of Amendment 8, efficacy laboratory assessments will be performed by the local laboratory 
and disease/response evaluations will be based on local institutional practice (see Table 4 and 
Attachment 9). Response to therapy will be evaluated by using the International Myeloma 
Working Group Uniform Response Criteria. Skeletal surveys will only be done if a subject has
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9.2.3.1.
Bone Marrow Assessments
Bone marrow biopsy and/ or aspirate will be performed at visits as indicated in Table 1 and
Table 2. The samples will be evaluated histologically for assessment of the percentage and 
monoclonality of plasma cells, and determination of other cells in the marrow. An aspirate will 
be evaluated by flow cytometry with CD45, CD38, CD56, CD138, CD19, CD28, CD117, 
cytoplasmic light chain kappa/lambda, cytoplasmic IgA+ and IgG+, CD20, and CD27 to 
characterize CD38, CD46, CD55, and CD59 expression in myeloma cells, as well as to 
characterize T, B, and NK cells. If the subject’s platelet count is low, a platelet transfusion may 
be given before the bone marrow sampling at the investigator’s discretion.
9.2.3.2.
Serum Immunoglobulin A, M, and G (M-component) 
A blood sample will be drawn for quantitation of M-component by serum protein electrophoresis 
at visits as indicated in Table 1 and Table 2. Subsequent Ig identification will be done by 
immunofixation. If the M-component is IgD or IgE, these Ig types should be included in the 
analysis. A second aliquot of serum shall be stored and analyzed as needed, if daratumumab 
interference is suspected in the post-treatment serum immunofixation assay. 
9.2.3.3.
Urinalysis for M-component
A 24-hour urine sample will be collected at the Screening Visit or before the first infusion, on the 
first day of each cycle, at the EOT, and at all follow-up visits for quantitation of total protein 
(including albumin) and CrCl, for quantitation of M-component by electrophoresis, and for 
immunofixation. 
Additional sampling may be performed at the investigator’s discretion.
9.2.3.4.
Serum Free Light Chain Ratio
A blood sample will be drawn for quantitation of the free light chain ratio by 
immunonephelometry at visits as indicated in Table 1 and Table 2.
9.2.3.5.
Prognostic Factors- Phase 1 only
A blood sample will be drawn at the Screening Visit or before the first infusion for later analysis 
of prognostic factors. The blood sample will be stored at the central laboratory (BARC) for up to 
1 year after the last subject’s last visit. Analysis of prognostic factors may be done in batches of 
several samples. Subjects will be asked to sign a separate informed consent form for this 
analysis.
Prognostic factors indicative of altered responsiveness to treatment and/or survival that may be 
analyzed include the following:

Serum 2-microglobulin and serum albumin in accordance with the International Staging 
System for multiple myeloma (Greipp 2005) 7

Genetic anomalies such as 17p deletion; translocations including t(4,14), t(6,14), t(11,14), 
t(14,16), t(14,20), t(20,20); and hyperdiploidy

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9.2.4.
Pharmacokinetics and Immunogenicity Assessments
As of Amendment 8, blood sample collection will stop and not be performed after the last dose 
of daratumumab. One final sample should be taken before the start of the last infusion per
Amendment 7.
Phase 2: Samples to assess both the serum concentration (pharmacokinetics) of daratumumab 
and the generation of antibodies to daratumumab (immunogenicity) will be obtained from all 
subjects according to the Time and Events Schedule (Table 2). At specified time points, venous 
blood samples (5 mL per sample) will be collected and the serum will be divided into 3 aliquots 
(1 aliquot for pharmacokinetic analysis, 1 aliquot for immunogenicity assessment [when 
appropriate], and 1 aliquot as a back- up). Blood samples should not be drawn from the arm in 
which the infusion was administered.
The exact dates and times of blood sampling must be recorded. Refer to the Laboratory Manual 
or equivalent document for sample collection requirements. Collected samples must be stored 
under the specified and controlled conditions for the temperatures indicated in the laboratory 
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Table 10:
Phase 1 Sample Collection Times for Determination of Daratumumab Concentration in Serum
Study Visits
Sample Collection
Screening
Cycle 1
Cycle 2a
Cycle 3-6
Cycle 7-24
FU
EOT
Visit Number
0
1
2
3
4
5
1
2
3
4
1
2
1
1-6
—
Day/Week/Month
21 days before 
Visit C1-1
0d
1d
1w
2w
3w
1d
1w
2w
3w
1d
2w
1d
Monthly
—
Visit Window
—
—
—
1d
1d
1d
4d
1d
1d
1d
4d
1d
4d
7d
2d
Before infusion
X
X
X
X
X
X
X
X
X
X
X
Xb
Xb
Xb
End of infusion
X
X
X
X
X
X
X
X
X
X
X
X
+ 2 hours after infusion
X
X
+ 5 hours after infusion
X
+ 12 hours after infusion
X
Key:
d = day; EOT = End of Trial; FU = Follow-up; w = week;
a
All cycles are 28-day cycles: the first visit of a cycle should be 4 weeks after the start of the previous cycle.
b
Because there is no infusion on these days, there is no requirement for the timing of the sample collection.

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9.2.5.
Analytical Procedures
Serum samples will be analyzed to determine concentrations of daratumumab or generation of 
antibodies to daratumumab using validated immunoassay methods by or under the supervision of 
the sponsor’s bioanalytical facility. 
For the immunogenicity assessments, serum samples will be screened for antibodies binding to 
daratumumab and serum titer will also be determined from confirmed positive samples. Other 
immunogenicity analyses (eg, assessment of neutralizing capabilities) may be performed to 
further characterize the immune responses that are generated. 
For Phase 2, all samples collected and received up to the time of the primary study endpoint 
analysis (first bioanalysis) will be analyzed for serum daratumumab concentration as indicated 
by the Time and Events Schedule. All data from this first analysis will be considered final and 
these samples will not be reanalyzed at the end of the study. The final bioanalysis will include all 
immunogenicity (from Phases 1 and 2) and any remaining pharmacokinetic samples that become 
available after the primary endpoint analysis. Adjustments to bioanalysis timing may be made if 
it is later determined that the timing for data needed to facilitate crucial decision-making differs 
from these 2 planned efforts. However, data from each round of bioanalysis will be considered 
final and samples will not be reanalyzed in any subsequent efforts.
9.2.6.
Pharmacokinetic Parameters
The pharmacokinetic parameters are defined as:
CL
Total systemic clearance of drug after IV administration
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
V
Volume of distribution
Pharmacokinetic samples to determine serum concentration of daratumumab will be obtained 
from all subjects. The pharmacokinetic parameters include but may not be limited to the 
following:

Minimum observed concentration (Cmin)

Maximum observed concentration (Cmax)
If sufficient data are available, then other pharmacokinetic parameters may be calculated, 
including but not limited to total systemic clearance of drug after IV administration (CL) and 
volume of distribution (V).
9.2.6.1.
Immunogenicity Assessments 
Serum from venous blood samples will be assessed for the generation of antibodies to 
daratumumab (immunogenicity) according to the Time and Events Schedule. Daratumumab 
concentration is also evaluated at all immunogenicity time points (Phases 1 and 2) to ensure 

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appropriate interpretation of immunogenicity data. When both serum concentration and 
immunogenicity analyses are specified, they are performed on aliquots from the same blood 
draw and no additional sampling is required. Procedures for sample collection, preparation, 
identification, storage, and shipment will be provided in the Laboratory Manual or equivalent 
document. 
A blood sample should be drawn, if possible, for determination of antibodies to daratumumab 
any time an infusion reaction is observed or reported during the study. Daratumumab serum 
concentration will also be determined from the same infusion reaction sample for the purpose of 
interpreting immunogenicity data. These samples will be stored and evaluated if deemed 
necessary. If the infusion reaction results in treatment discontinuation, then subjects should 
undergo all scheduled safety and efficacy evaluations. Samples collected for the analysis of 
daratumumab immunogenicity/serum concentration may additionally be used to evaluate safety 
or efficacy aspects that address concerns arising during or after the study period or for the 
evaluation of relevant biomarkers by the sponsor or sponsor’s designee.
9.2.6.2.
Biomarker Assessments
9.2.6.2.1.
Phase 1 Biomarker Analyses
9.2.6.2.1.1.
Levels of Soluble CD38
A blood sample will be drawn for analysis of soluble CD38. The samples will be stored at the 
central laboratory until a validated assay is available.
9.2.6.2.1.2.
Complement
A blood sample will be drawn for analysis of complement (CH50) at visits as indicated in 
Table 1. This blood sample must be drawn 2 hours after the end of infusions. Analysis of 
complement will be done in batches of several samples.
9.2.6.2.1.3.
Levels of Circulating NK Cells, B, and T Cells (Flow Cytometry)
A blood sample will be drawn for analysis of the following immune cell populations:
CD45+CD38+
CD45+CD19+
CD45+CD3+
CD45+CD3+CD4+
CD45-CD138+
CD45+CD3+CD8+
CD45+CD138+
CD3-CD56+
CD3-CD16+CD56+
CD45+CD138+CD38+
Additional flow cytometry subgroups may be added for exploratory purposes.
9.2.6.2.2.
Phase 2 Biomarker Analyses
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and may 
be deferred or not performed if during or at the end of the study it becomes clear that the analysis 
will have no scientific value, or if there are not enough samples or not enough responders to 
allow for adequate biomarker evaluation. In the event the study is terminated early or shows poor 
clinical efficacy, completion of biomarker assessments is based on justification and intended 

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utility of the data. Samples for biomarker evaluations will be collected for all subjects as 
specified in Table 2. 
Biomarker analyses will be focused on further understanding the MOA (ADCC/CDC/ADCP) of 
daratumumab in combination with lenalidomide and dexamethasone, evaluating predictive 
markers of response to daratumumab, and determining whether daratumumab can reduce 
minimal residual disease in patients who achieve a complete response. Whole blood samples will 
be utilized for immunophenotyping, which includes analysis of NK, T, and B cells. NK cells are 
known to express CD38 and early clinical data indicates they are rapidly depleted upon 
daratumumab dosing. Additional immune cell populations that may be studied include 
macrophages, dendritic cells, myeloid derived suppressor cells, or other flow cytometry 
subgroups that may be added for exploratory purposes. ADCC and CDC may be evaluated to 
determine whether lenalidomide and dexamethasone help preserve effective ADCC despite NK 
cell depletion. T-cell receptor sequences may be evaluated from whole blood PBMC DNA to 
determine if specific clonal CD8+ T-cell expansion occurs with daratumumab treatment and if 
this is associated with clinical response. 
In addition to whole blood collections, bone marrow aspirates will be collected for biomarker 
evaluations including multiple myeloma cell phenotyping, evaluation of CD38 and complement 
inhibitory protein (CIP) expression (CD46/CD55/CD59). Soluble CD38 expression levels may 
be evaluated in plasma to determine if sCD38 levels influence daratumumab serum levels and 
are associated with daratumumab response. Serum samples may also be analyzed for 
complement proteins or for complement dependent cytotoxicity (CDC), which is one mechanism 
of action for daratumumab. Exploratory proteomics may be utilized to evaluate cytokines, 
complement 
proteins, 
complement 
associated 
proteins, 
soluble 
CD38, 
soluble 
CD46/CD55/CD59, or other proteins associated with daratumumab response and/or resistance.
9.2.6.2.3.
Phase 2 Pharmacogenomics
A pharmacogenomic blood sample will be collected to allow for pharmacogenomic research, as 
necessary (where local regulations permit). Subject participation in the pharmacogenomic 
research is optional.
Several pharmacogenomics assessments may be performed for those subjects who consent to 
genomic analyses. A blood sample will be collected and processed to extract DNA, which may 
be evaluated for single nucleotide variation in genes associated with immune-mediated tumor 
cell lysis and potentially daratumumab response/resistance. The following single nucleotide 
polymorphisms (SNP) may be measured:  FcgR2A-R131H, FcgR2A-Q62R, FcgR2A-Q62X, 
FcgR3A-V158F, FcgR3A-V212F, FcgR2B-I232T, and C1QA-A276G. In addition, assessment 
of copy number variation in FcgR2C, FcgR3A, and FcgR3B may be performed on this sample. 
Additional polymorphisms, single nucleotide polymorphisms, or copy number variations may be 
added for exploratory purposes. These genotypes may be evaluated for potential predictive 
biomarkers as well as for association with daratumumab response and with levels of functional 
ADCC and CDC before daratumumab treatment. Pharmacogenomic assessments may also 

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include evaluation of T-cell response through T-cell receptor sequencing from PBMCs isolated 
from whole blood.
9.3.
Endpoints 
The primary endpoint for this study will be the incidence of AEs.
The secondary endpoints are:

The rate of response according to the International Uniform Response Criteria (Rajkumar 
2011) 21

PK variables (AUC, Cmax, minimum or trough concentration in serum [Cmin], time to Cmax
[Tmax], apparent clearance [CL], volume of distribution [V], and elimination half-life [t1/2])

Time to progression

Duration of response

Progression-free survival (PFS)
10.
SUBJECT COMPLETION/WITHDRAWAL
Completion
Subjects will be considered as having completed the study if he/she has consented to 
Amendment 8.
10.1.
Discontinuation of Study Treatment 
A subject's study treatment should be discontinued if:

The investigator believes that for safety reasons (eg, adverse event) it is in the best interest 
of the subject to discontinue study treatment

The subject becomes pregnant 

The subject has documented PD

The subject withdraws consent for further treatment

Treatment is delayed for more than 3 weeks and no approval to continue is given by the 
sponsor.
If a subject discontinues study treatment or is transferred to commercial supplies, as per 
Amendment 8, follow-up for the occurrence of SPM will continue for up to 3 years after the last 
dose of lenalidomide.
10.2.
Withdrawal 
A subject will be withdrawn from treatment for any of the following reasons:

DLT

DVT and/or PE

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
Tumor lysis syndrome

Grade 3 skin rash

Pregnancy

Subject choice

Investigator decision

Disease progression

Initiation of new treatment against multiple myeloma

Lost to follow-up

Intercurrent illness that precludes further participation or requires a prohibited concomitant 
treatment

Treatment is delayed for more than 3 weeks and no approval to continue is given by the 
sponsor

Other
If a subject discontinues study treatment or is transferred to commercial supplies, as per 
Amendment 8, follow-up for the occurrence of SPMs will continue for up to 3 years after the last 
dose of lenalidomide.
The investigator, in consultation with the subject, will decide the future course of treatment for 
multiple myeloma.
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.
A subject who withdraws from treatment will have the following options regarding the optional
research samples:

The collected samples will be retained and used in accordance with the subject's original 
separate informed consent for optional research samples.

The subject may withdraw consent for optional research samples, in which case the samples
will be destroyed and no further testing will take place. To initiate the sample destruction 
process, the investigator must notify the sponsor study site contact of withdrawal of consent 
for the optional research samples and to request sample destruction. The sponsor study site 
contact will, in turn, contact the biomarker representative to execute sample destruction. If 
requested, the investigator will receive written confirmation from the sponsor that the 
samples have been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The subject may withdraw consent for optional research samples while remaining in the study. In 
such a case, the optional research sample[s] will be destroyed. The sample destruction process 
will proceed as described above.

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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 [and in the separate ICF for optional research 
samples].
11.
STATISTICAL METHODS
The statistical analysis methods for this study are outlined in this section. Further details will be 
specified in the Statistical Analysis Plan.
11.1.
Subject Information
The 2 phases of this study will be analyzed separately. When appropriate, all subjects who are 
treated with daratumumab may be combined together for comprehensive safety assessment. 
Variables will be estimated by using descriptive statistics. Continuous variables will be 
summarized by using the number of observations (n), mean, standard deviation, median, 
minimum, and maximum, where n denotes the number of subjects with available data. 
Categorical variables will be summarized by using n and percentages, where the calculation of 
the percentages will be based on the number of subjects in the population (N) and the number of 
subjects with available data (n). Results will be presented by cohort as well as by all subjects 
combined.
The latest available measurements before study drug administration will serve as baseline values.
11.2.
Sample Size Determination
Between 42 and 58 subjects will be enrolled in this study, depending on the number of dose 
levels included during dose escalation in Phase 1. It is estimated that the screen failure rate will 
be 25% and that between 56 and 78 subjects will be screened in order to enroll the expected 
number. The screen failure rate is estimated based on data from the ongoing GEN501 study.
No formal sample size determination was performed for Phase 1 of this study because a standard 
dose escalation study design of 3 + 3 subjects in each cohort was chosen for Phase 1. For 
Phase 2, It is assumed that lenalidomide + dexamethasone would achieve an ORR of 50% in the 
targeted population. With a two-sided alpha of 0.10 and assuming that the addition of 
daratumumab improves the ORR to 75%, a sample size of approximately 30 subjects would 
achieve 89% power to detect such a difference. If the addition of daratumumab can improve the 
ORR to 80%, this sample size would achieve 97% power to detect such a difference.
11.3.
Analysis Sets
For Phase 1, one analysis population, the safety population, is defined, which includes all 
subjects who are exposed to the study drugs (daratumumab, lenalidomide, and dexamethasone).
For Phase 1, the safety population will be used for all efficacy and safety analysis.

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For Phase 2, three analysis populations are defined:

Intent-to-Treat (ITT), defined as all subjects enrolled in the study in Phase 2

Safety, defined as all subjects exposed to the study drugs (ie, daratumumab, lenalidomide, 
and dexamethasone) in Phase 2

Per-Protocol (PP), defined as all subjects included in the ITT population excluding those 
who had deviations from the protocol that might affect the assessment of response to 
treatment
For Phase 2, the ITT population will be the primary analysis population for all efficacy analyses. 
The Safety population will be used for all safety analyses. If the ITT and Safety populations are 
identical, only the ITT population will be used.
The PK evaluable population will be analyzed, which includes all treated subjects who have an 
evaluable PK profile. The PP population will be used for efficacy as sensitivity analyses. If the 
difference between the PP and ITT populations is less than 4 subjects, the PP analysis will not be 
performed.
11.4.
Efficacy Analyses 
Response to treatment will be determined by the sponsor in accordance with the guidelines 
provided in Attachment 5. The proportion of subjects with response to treatment (stringent CR 
[sCR], CR, very good PR [VGPR], and PR) will be estimated. The quality of response (also 
including subjects who achieve MR) will be summarized. Subjects for whom response cannot be 
evaluated will be categorized as not evaluable. A determination of not evaluable will count as 
nonresponse to treatment. The proportions will be presented with corresponding exact 2-sided 
95% confidence intervals.
Duration of response, time to progression, and PFS will be estimated using Kaplan-Meier 
techniques. Data for these variables will be censored in accordance with the FDA guidance on 
clinical study endpoints for the approval of cancer drugs and biologics (FDA 2011).
11.5.
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be performed on the pharmacokinetic-evaluable population, 
defined as subjects who have received one dose of daratumumab and at least one post infusion 
sample. All serum concentrations below the lowest quantifiable concentration or missing data
will be labeled as such in the concentration data presentation. Concentrations below the lowest 
quantifiable concentration will be treated as zero in the summary statistics. All subjects and 
samples excluded from the analysis will be clearly documented in the study report.
Phase 1: The PK variables, AUC, Cmax, Cmin, Tmax, CL, V, and t1/2, will be estimated by using 
noncompartmental methods. The AUC will be calculated separately for Cycles 1 and 2, and 
extrapolated to infinity. Geometric means will be plotted together for comparison of dose 
cohorts, and individual subject PK profiles will be plotted with both absolute and 
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Phase 2: Descriptive statistics will be used to summarize daratumumab serum concentrations at 
each sampling time point and pharmacokinetic parameters of daratumumab such as Cmin and 
Cmax. If sufficient data are available, then other pharmacokinetic parameters may be calculated, 
including but not limited to CL and V.
If sufficient data are available, population PK analysis of serum concentration-time data of 
daratumumab may be performed and the analysis may include data from other studies. If the 
population PK analysis is conducted, details will be specified in a population PK analysis plan,
and the results of the analysis will be presented in a separate report.
11.6.
Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, pharmacokinetic/pharmacodynamic modeling may be performed, 
including exploring the relationship between serum concentrations of daratumumab and 
endpoints of clinical efficacy. If performed, details and results of the analysis will be presented 
in a separate report.
11.7.
Subgroup and by Center Analyses
Analyses will be performed for the following subgroups:

Subjects with relapsed multiple myeloma versus subjects with relapsed and refractory 
multiple myeloma

Subjects by number of prior therapies
The number of subjects per site is expected to be very low; therefore, no by-center analyses are 
planned.
11.8.
Exploratory Modeling
Exploratory univariate modeling will be used to investigate preliminarily relationships between 
select efficacy and safety variables and possibly explanatory variables.
A model of the worst toxicity will be attempted to potentially provide a rationale for dose 
selection in subsequent studies. This model is included in Attachment 6.
11.9.
Immunogenicity Analyses 
The incidence of antibodies to daratumumab will be summarized for all subjects who receive a 
dose of daratumumab and have appropriate samples for detection of antibodies to daratumumab.
11.10. Biomarker and Pharmacogenomic Analyses
Biomarker studies are designed to identify markers predictive of response (or resistance) to 
daratumumab. Analyses will be stratified by clinical covariates or molecular subgroups using the 
appropriate statistical methods (eg, parametric or non-parametric, univariate or multivariate, 
analysis of variance [ANOVA], or survival analysis, depending on the endpoint). Correlation of 
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endpoints will identify responsive (or resistant) subgroups in addition to genes and pathways 
attenuated following treatment with daratumumab. 
Any biomarker, pharmacodynamic, and pharmacogenomic measures will be listed, tabulated, 
and where appropriate, plotted. Subjects will be grouped by prescribed dose. As this is an 
open-label study with an active control treatment, statistical analyses will be done to aid in the 
understanding of the results. Correlation of response and pharmacogenomic measures will be 
explored.
Results of biomarker, pharmacodynamics, and pharmacogenomic 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.
11.11. Safety Analyses
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
with onset during the treatment phase (ie, treatment-emergent adverse events, and adverse events 
that have worsened since baseline) will be included in the analysis. 
The number and percentage of subjects with treatment-emergent AEs will be summarized 
according to intensity by using the CTCAE v4.0, drug relationship, and outcome. Laboratory 
data will be summarized and descriptive statistics will be calculated. Changes in vital sign 
measurements, physical examination findings, and ECOG performance status will be 
summarized. Safety laboratory variables will be presented in figures (values versus time) and 
summarized by value and change from baseline (both absolute and relative).
11.12. Interim Analysis
Results from Phase 1 and Phase 2 will be presented separately. Data from Phase 1 will be 
analyzed when the MTD has been reached or dose escalation has been stopped. No formal 
interim analyses that require adjustments of type 1 or 2 errors are planned. However, as part of 
the preparations for subsequent studies, exploratory analyses of subsets of data may be 
performed.
11.13. Data Monitoring Committee
An IDMC will be established and have their first meeting before study start (first subject 
screened). At this meeting, the IDMC will decide the future format and the degree of the 
information they need in order to monitor safety.
The functions and responsibilities of the IDMC will be described in the IDMC Charter, which 
will be approved by the IDMC.
The IDMC will receive a package of safety data, including all reported AEs and laboratory data, 
after each cohort has completed the first cycle of treatment. The IDMC will receive a report of 
any SAE immediately after review of the event by the sponsor.

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Subjects will be enrolled in cohorts of 3 subjects per dose level. The “3 + 3” rules for dose 
escalation will be applied. However, if the study sites have identified 4 eligible subjects to start a 
new dose level, all 4 subjects may be enrolled. For each cohort, the IDMC will evaluate 
aggregate safety data for the 3 subjects in order to recommend whether it is safe to escalate to the 
next dose level. Before the IDMC review of safety data, at least 3 subjects in a cohort must 
receive at least 4 full infusions of daratumumab in combination with Len/Dex. The third subject 
in the cohort must have received all 4 full doses of daratumumab, and data from an observation 
period of 6 days after the last infusion must be available for the IDMC to review. Dose escalation 
or de-escalation will follow these rules:

An initial cohort of 3 subjects will be enrolled at any new dose level, when escalation from 
the previous dose level has been accepted by the IDMC.

If a subject at any dose level experiences a DLT, the cohort will be expanded by up to 
3 additional subjects, or until a second subject experiences a DLT.

If, however, no additional DLTs are reported at this dose level, dose escalation may take 
place to the next planned dose level, or to an intermediate dose level as recommended by the 
IDMC and approved by the sponsor.

If no DLTs are experienced by the first 3 subjects at any dose level, the IDMC or sponsor 
may decide to add 3 more subjects at this dose level based on the need for additional safety 
data before an escalation can take place.

If 2 or more subjects out of 6 or less subjects experience DLTs, additional subjects must be 
included at the previous dose level or at an intermediate dose level as recommended by the 
IDMC and approved by the sponsor.

The MTD will be defined as the highest dose level where no subjects or 1 subject out of 
6 subjects experiences a DLT.
Noncompliance with the protocol-defined requirements for infusion of the study drug may 
influence the evaluation of DLTs by the IDMC.
In the dose escalation/de-escalation part, the MTD and/or RP2D will be decided by the sponsor, 
based upon recommendations by the IDMC and after review of the aggregated safety data.
At least every 6 months, the IDMC will evaluate safety data from this study, including the 
occurrence of new cancers as noted during the Safety Follow-up Period, and provide a 
recommendation as to whether the study should continue based on evaluation of these safety data 
and the reported benefits of daratumumab treatment. The IDMC will no longer be evaluating 
safety data after the primary analysis. 
Minutes from the IDMC meetings will be shared with the regulatory agencies.
There are no current plans to establish an Independent Response Committee for this early-phase 
study. Response to treatment will be evaluated by the coordinating investigator in collaboration 
with the sponsor.

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12.
ADVERSE EVENT REPORTING
12.1.
Study Disease
Deterioration of the subject’s condition due to multiple myeloma and signs and symptoms that, 
according to the investigator, are expected and well known consequences of multiple myeloma, 
both in intensity and frequency should not be reported as AEs or SAEs.
12.2.
Pre-existing Conditions
In this study, a pre-existing condition (ie, a disorder that was present before the AE reporting 
period started and noted in the medical history or physical examination eCRF) should not be 
reported as an AE. If a pre-existing condition worsens during the Treatment Period, the event 
should then be reported as an AE.
12.3.
Diagnostic and Therapeutic Noninvasive and Invasive Procedures
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. A medical condition for which an unscheduled procedure was performed 
should, however, be reported if it meets the definition of an AE. For example, acute appendicitis 
should be reported as an AE, but not the appendectomy.
12.4.
Definitions
12.4.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.6.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

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
Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
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 12.4.2.
12.4.2.
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.

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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).
12.4.3.
Severity Criteria 
The severity assessment for an adverse event or serious adverse event should be completed using 
the NCI CTCAE Version 4.0. Any adverse event or serious adverse event not listed in the NCI 
CTCAE Version 4.0 will be graded according to investigator clinical judgment by using the 
standard grades as follows: 
Grade 1 (Mild): Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities.
Grade 2 (Moderate): Sufficient discomfort is present to cause interference with normal activity.
Grade 3 (Severe): Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities.
Grade 4: Life-threatening or disabling adverse event
Grade 5: Death related to the adverse event
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.5.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)

Occurrence of SPM
Special reporting situations should be reported to the sponsor. Any special reporting situation 
that meets the criteria of a serious adverse event should be reported as an SAE to the sponsor.

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12.6.
Procedures
As per Amendment 8, only SAEs and SPMs will be collected (see Table 4 and Attachment 9). 
The SAE and SPM data should be entered in the subject file/notes.
Any SPM that occurs during a subject’s participation in the study or for 3 years after the last 
dose of lenalidomide is considered an immediately reportable event. It must be reported to the 
sponsor within 24 hours after the investigator has gained knowledge of it by using the SPM form 
attached to the regular SAE form. 
12.6.1.
All Adverse Events
The investigator must report all directly observed AEs and all AEs reported by the subject, 
whether spontaneously or in response to general, nondirected questioning (eg, “How has your 
health been since the last visit?”). For each AE reported by the subject, the investigator should 
obtain all the information required to complete the AE page of the eCRF, in accordance with the 
guidelines that accompany it.
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until 30 days after the last dose of any 
component of the treatment regimen. As of Amendment 7, only SAEs will be collected (see 
Table 3 and Attachment 8). Nonserious medical events (signs, symptoms, diagnosis) that occur 
between the Screening Visit or before the first infusion and the first study drug treatment at 
Cycle 1 Visit 1 should be documented in the medical history. All AEs that occur in subjects 
during the AE reporting period must be reported, whether or not the event is treatment related.
Serious adverse events, including those spontaneously reported to the investigator within 30 days 
of the last dose of any component of the treatment regimen, must be reported using the Serious 
Adverse Event Form. The sponsor will evaluate any safety information that is spontaneously 
reported by an investigator beyond the time frame specified in the protocol.
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 CRF. 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 CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all serious adverse events that are unlisted (unexpected) and associated 
with the use of the study drug. The investigator (or sponsor where required) must report these 
events to the appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
that approved the protocol unless otherwise required and documented by the IEC/IRB. 

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The investigator must also record in the eCRF the outcome of the AE by using the following 
terms: 

Recovered

Recovered with sequelae

Not recovered

Fatal

Unknown
Instructions for reporting changes in an ongoing AE during the subject’s participation in the 
study are provided in the eCRF completion guidelines.
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the treatment indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.6.2.
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 treatment 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

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
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

If the subject has not experienced a significant medical event but is hospitalized overnight 
only for observation following infusion of daratumumab, then the hospitalization should not 
be reported as a serious adverse event. 

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.
Disease progression should not be submitted as serious adverse event term. Instead, signs and
symptoms of clinical sequelae resulting from disease progression/lack of efficacy will be 
reported if they fulfill the serious adverse event definition (refer to Section 12.4.1, Adverse 
Event Definitions and Classifications).
12.6.3.
Pregnancy 
Lenalidomide is an analog of thalidomide, which is a known human teratogen that causes life-
threatening birth defects. Results of an embryo-fetal development study in nonhuman primates 
indicated that lenalidomide produced malformations in the offspring of female monkeys that 
received the drug during pregnancy. These malformations were similar to birth defects observed 
in humans after women were exposed to thalidomide during pregnancy. If lenalidomide is used 
during pregnancy, it may cause birth defects or death to a developing fetus. Women of 
childbearing potential must be advised to avoid pregnancy while receiving lenalidomide. 
Effective contraceptive methods should be used for 4 weeks before the first infusion of 
daratumumab, during therapy, during therapy interruptions, and for at least 6 months after 
completing therapy. The lenalidomide label warnings and advice must be followed throughout 
this study. See Exclusion Criterion #27 (Section 4.3) for definitions of effective, adequate 
methods of contraception.
12.6.3.1.
Pregnancy Reporting
Any pregnancy that occurs during a subject’s participation in this study is considered an 
immediately reportable event. It must be reported to the sponsor within 24 hours after the 
investigator has gained knowledge of it, by using the Pregnancy Form. The pregnancy must be 

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followed to determine outcome (including premature termination) and status of mother and 
infant. Pregnancy complications and elective terminations for medical reasons must be reported 
as an SAE. Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, and congenital 
anomaly) are considered serious adverse events and must be reported using the Serious Adverse 
Event Form. After birth, the infant must be followed to at least 1 month of age.
Any SAE occurring in association with a pregnancy that is brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as related to the 
study drug must be promptly reported to the sponsor.
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the study. 
Pregnancy information must be reported to the sponsor.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form.
12.7.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.6.2, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the sponsor.

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13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
The daratumumab supplied for this study is a clear to opalescent, colorless to slightly yellow 
concentrated solution for IV infusion. It is intended for administration after dilution in sterile, 
pyrogen-free 0.9% sodium chloride (NaCl) solution. It will be manufactured and provided under 
the responsibility of the sponsor.
Lenalidomide and dexamethasone will be supplied by each site and should be stored, prepared, 
and administered in accordance with the label specifications.
14.2.
Packaging
Daratumumab is supplied in glass vials containing 5 mL of daratumumab at a concentration of 
20 mg/mL (ie, a total of 100 mg of daratumumab per vial). Daratumumab will be supplied to the 
site/pharmacy as bulk supply cartons containing 5 vials each. 
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage 
A detailed description with instructions for the preparation of the study drug will be supplied to 
each pharmacy.
Preparation of infusion bags should be done on the day of the planned infusion, and the time of 
the dilution should be written on the infusion bag. Daratumumab must be administered as an IV 
infusion. The infusion should be given through a well-functioning IV catheter by using an 
infusion pump. The study drug must be filtered by using an inline filter (0.2 m) during the 
infusion.
For the predose and full-dose infusions, the initial infusion rates should be set as recommended 
in Table 5 and Table 6. Infusion rates may be adjusted at the investigator’s discretion in response
to infusion-related reactions (Section 6.6).
Daratumumab must be stored in an appropriate restricted area, which may be accessed only by 
the investigator, pharmacist, or other duly designated person. 
The drug should be stored in a refrigerator at 2C to 8C and must not be frozen. A log of daily 
thermometer readings must be kept to document the temperature.

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14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects, or their legally acceptable representatives where applicable, must 
be instructed to return all original containers, whether empty or containing study drug. 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, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes, and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. 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
As per Amendment 8, the investigator will be provided with the following supplies:

Drug Accountability Forms

Pharmacy manual/study site investigational product manual

Sample ICF

Investigator Drug Brochure
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
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 

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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 considered to be considered to be within the normal 
range allowed for this study population.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.

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During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s). Furthermore, where required, progress reports/written summaries of the study 
status will be submitted to the IRB/IEC annually, or more frequently if requested.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
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 
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Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment 
of his or her disease. Subjects will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that the investigator will maintain a subject identification register for the purposes of long-term 
follow up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF the subject or legally acceptable 
representative is authorizing such access, and agrees to allow his or her study physician to 
recontact the subject for the purpose of obtaining consent for additional safety evaluations, if 
needed, and subsequent disease-related treatments, or to obtain information about his or her 
survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
Subjects will be asked for consent to provide optional samples for research (where local 
regulations permit). After informed consent for the study is appropriately obtained, the subject or 
his or her legally acceptable representative will be asked to sign and personally date a separate 
ICF indicating agreement to participate in the optional research component. Refusal to 
participate in the optional research will not result in ineligibility for the study. A copy of this 
signed ICF will be given to the subject.
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 

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study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, pharmacokinetic/pharmacodynamic, biomarker, and immunogenicity research 
is not conducted under standards appropriate for the return of data to subjects. In addition, the 
sponsor cannot make decisions as to the significance of any findings resulting from exploratory 
research. Therefore, exploratory research data will not be returned to subjects or investigators, 
unless required by law or local regulations. Privacy and confidentiality of data generated in the 
future on stored samples will be protected by the same standards applicable to all other clinical 
data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand daratumumab, to 
understand multiple myeloma, to understand differential drug responders, and to develop 
tests/assays related to daratumumab and multiple myeloma. The research may begin at any time 
during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.2 Withdrawal).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.

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During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF 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
Documents that must be provided to the sponsor before study drug shipment are as follows:

Up-to-date curriculum vitae for each investigator and subinvestigator.

Signed and dated Investigator Agreement.

Applicable local regulatory documentation (eg, FDA 1572 Form).

A copy of the formal written notification to the investigator regarding approval of the 
protocol by an IEC/IRB that is in compliance with regulatory guidelines. The written 
notification is to be signed by the chairman or authorized designee and must identify the 
specific protocol. In cases where an IEC/IRB member has a known conflict of interest, 
abstention of that individual from voting should be documented; an investigator (or 
subinvestigator) may be a member of the IEC/IRB, but may not vote on any research in 
which he or she is involved.

Name and address of the IEC/IRB with a statement that it is organized and operates 
according to GCP and the applicable laws and regulations, and a current list of the IEC/IRB 
members. If accompanied by a letter of explanation from the IEC/IRB, a general statement 
may be substituted for this list.

A copy of the IEC/IRB approved informed consent form and other adjunctive materials 
(eg, advertising) to be used in the study, including written documentation of IEC/IRB 
approval of these items.

Name and address of any local laboratory conducting tests for the study, a dated copy of the 
laboratory reference values for tests to be performed during the study, and a copy of the 
certification or other documentation establishing adequacy of the facility.

Required financial agreement.
In addition to the documents required before the study, other documentation may be required 
during the course of the study.

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17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: 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. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
The following data will be recorded directly into the CRF and will be considered source data: 

Race

History of smoking all nicotine use, eg, cigarettes, cigars, chewing tobacco, patch, gum

Blood pressure and pulse/heart rate (except if primary efficacy or significant safety issue)

Height and weight (except if primary efficacy or significant safety issue)

Details of physical examination
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. Electronic Data Capture 
(eDC) will be used for this study. The study data will be transcribed by study-site personnel from 
the source documents onto an electronic CRF, and transmitted in a secure manner to the sponsor 

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within the timeframe agreed upon between the sponsor and the study site. The electronic file will 
be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Study site personnel must complete the CRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible. The investigator must verify that all data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
study-site personnel must adjust the CRF (if applicable) and complete the query.
If corrections to a CRF are needed after the initial entry into the CRF, this can be done in 
3 different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Study site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor or designated 
representative., and direct transmission of clinical laboratory data from a central laboratory
(BARC) into the clinical database. Written instructions will be provided for collection, handling, 
storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. eCRFs will be reviewed for accuracy and completeness by the sponsor or 
designated representative 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 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 Study, and 

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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 or designated representative will perform on-site monitoring visits as frequently as 
necessary. As per Amendment 8, on site visits are usually made at intervals of at least 24 weeks. 
A phone call will be done in between (at 12 weeks). The dates of the visits will be recorded by 
the monitor in a study site visit log to be kept at the site. At these visits, the monitor will monitor 
the adequate reporting and follow-up of SAEs, SPMs, drug receipt/dispensing/return records and 
ensure subjects who showed progressive disease stopped the study treatment. 
17.9.
Close-out of Extended Safety Follow-up
The extended safety follow-up will be completed 3 years after the last subject took the last 
lenalidomide dose and completed follow-up for the occurrence of SPMs. The final data from the 
study site will be sent to the sponsor (or designee) after completion of the final subject 
assessment at that study site, in the time frame specified in the Clinical Trial Agreement Per the 
study design, The final data from the study site will be sent to the sponsor (or designee) after 
completion of the final subject assessment at that study site, in the time frame specified in the 
Clinical Trial Agreement.
Study Termination
The sponsor reserves the right to close the study site or terminate the safety follow-up 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.

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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:

Successful completion of the study at the site

The required number of subjects for the study has been recruited

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

Safety concerns

Sufficient data suggesting lack of efficacy

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor’s or designated representative’s Clinical Quality Assurance 
department may visit the site to carry out an audit of the study in compliance with regulatory 
guidelines and company policy. Such audits will require access to all study records, including 
source documents, for inspection and comparison with the eCRFs. Subject privacy must, 
however, be respected. Sufficient prior notice will be provided to allow the investigator to 
prepare properly for the audit.
Similar auditing procedures may also be conducted by agents of any regulatory body reviewing 
the results of this study in support of a Licensing Application. The investigator should 
immediately notify the sponsor if they have 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 pharmacogenomic or 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 

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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 CRF data from all study sites that participated in the study. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomic or
exploratory biomarker analyses performed after the Clinical Study Report has been issued will 
be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study subject identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.

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REFERENCES
1.
American Cancer Society. Cancer Facts and Figures 2010. Atlanta: American Cancer Society; 2010.
2.
Attal M, Moreau P, Avet-Loiseau H, Harousseau JL. Stem cell transplantation in multiple myeloma. 
Hematology Am Soc Hematol Educ Program. 2007:311-316.
3.
Bringhen S, Larocca A, Rossi D, et al. Efficacy and safety of once-weekly bortezomib in multiple myeloma 
patients. Blood. 2010;116(23):4745-4753.
4.
Chapuy, C, Nicholson R, Aguad MD, et al. Resolving the daratumumab interference with blood compatibility 
testing. Transfusion. 2015; 55:1545-1554.
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(3):1840-1848.
6.
Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory 
multiple myeloma. N Engl J Med. 2007;357(21):2123-2132.
7.
Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 
2005;23(15):3412-3420.
8.
Howe HL, Wingo PA, Thun MJ, et al. Annual report to the nation on the status of cancer (1973 through 1998), 
featuring cancers with recent increasing trends. J Natl Cancer Inst. 2001;93(11):824-842.
9.
Klein B, Zhang XG, Jourdan M, et al. Paracrine rather than autocrine regulation of myeloma-cell growth and 
differentiation by interleukin-6. Blood. 1989;73(2):517-526.
10.
Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies. J 
Hematol Oncol. 2009;2:36.
11.
Kropff MH, Bisping G, Wenning D, et al. Bortezomib in combination with dexamethasone for relapsed 
multiple myeloma. Leuk Res. 2005;29(5):587-590.
12.
Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice 
guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25(17):2464-2472.
13.
Lacy MQ, Gertz MA, Dispenzieri A, et al. Long-term results of response to therapy, time to progression, and 
survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc. 
2007;82(10):1179-1184.
14.
Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in 
renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247-254.
15.
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern 
Med. 2009;150:604-612.
16.
Lonial S, Vij R, Harousseau J, et al. Elotuzumab in combination with lenalidomide and low-dose 
dexamethasone in relapsed or refractory multiple myeloma: a phase I/II study [abstract no. 8020]. J Clin Oncol. 
2010;28(15s).
17.
Ludwig H and Consensus Panel 1 [Internet]. Consensus guidelines for the management of anemia with 
erythropoiesis stimulating agents (ESAs) in multiple myeloma. Presented at the 13th International Myeloma 
Workshop; 2011 May 3-6; Paris, France [cited on 28 November 2011]. Available from: 
http://www.myeloma-paris2011.com/files/files/ConsensusPanel1AnemiaTheFinal.pdf.
18.
Moreau P, Richardson P, Lonial S, et al. Elotuzumab in combination with lenalidomide and low-dose 
dexamethasone in patients with relapsed multiple myeloma: a randomized Phase 2 study [abstract no. 1007]. 
Haematologica. 2011;96(s2):420.
19.
National Comprehensive Cancer Network [Internet]. NCCN Clinical Practice Guidelines in Oncology [NCCN 
Guidelines]: Multiple Myeloma. Version 1.2012 [cited 22 November 2011]. Available from: 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

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20.
Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide 
compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised 
controlled trial. Lancet. 2006;367(9513):825-831.
21.
Rajkumar SV, Harousseau JL, 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(18):4691-4695.
22.
Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus 
lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-
label randomised controlled trial. Lancet Oncol. 2010;11(1):29-37.
23.
Rajkumar SV, Rosiñol L, Hussein M, et al. Multicenter, randomized, double-blind, placebo-controlled study of 
thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed 
multiple myeloma. J Clin Oncol. 2008;26(13):2171-2177.
24.
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed 
multiple myeloma. N Engl J Med. 2005;352(24):2487-2498.
25.
San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment 
of multiple myeloma. N Engl J Med. 2008;359(9):906-917.
26.
Tai YT, Dillon M, Song W, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell 
adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 
2008;112(4):1329-1337.
27.
Tai YT, Li XF, Catley L, et al. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 
SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res. 
2005;65(24):11712-11720.
28.
Vallet S, Palumbo A, Raje N, Boccadoro M, Anderson KC. Thalidomide and lenalidomide: mechanism-based 
potential drug combinations. Leuk Lymphoma. 2008;49(7):1238-1245.
29.
van der Veer MS, de Weers M, van Kessel B, et al. Towards effective immunotherapy of myeloma: enhanced 
elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody 
daratumumab. Haematologica. 2011;96(2):284-290.
30.
Vidriales MB, Anderson KC. Adhesion of multiple myeloma cells to the bone marrow microenvironment: 
implications for future therapeutic strategies. Mol Med Today. 1996;2(10):425-431.

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Attachment 1: Eastern Cooperative Oncology Group Performance Status
Grade
ECOG Performance Status
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55.

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Attachment 2: Prior Cancer Therapy for Multiple Myeloma
A line of therapy is defined as one or more cycles of a planned treatment program. This may 
consist of one or more planned cycles of single-agent therapy or combination therapy, as well as 
a sequence of treatments administered in a planned manner. For example, a planned treatment 
approach of induction therapy followed by autologous stem cell transplantation, followed by 
maintenance is considered one line of therapy. A new line of therapy starts when a planned 
course of therapy is modified to include other treatment agents (alone or in combination) as a 
result of disease progression, relapse, or toxicity. A new line of therapy also starts when a 
planned period of observation off therapy is interrupted by a need for additional treatment for the 
disease. 
Source: Rajkumar 201121

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Attachment 3: New York Heart Association Criteria for Functional Classification
Functional Capacity
Objective Assessment
Class I. Patients with cardiac disease but without resulting limitation of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
A. No objective evidence 
of cardiovascular disease
Class II. Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain.
B. Objective evidence of 
minimal cardiovascular 
disease
Class III. Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain.
C. Objective evidence of 
moderately severe 
cardiovascular disease
Class IV. Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the anginal 
syndrome may be present even at rest. If any physical activity is undertaken, 
discomfort is increased.
D. Objective evidence of 
severe cardiovascular 
disease
The Criteria Committee of the New York Heart Association. Nomenclature and criteria for diagnosis of diseases of 
the heart and great vessels. 9th ed. Boston, Mass: Little, Brown, & Co; 1994:253-6.

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Attachment 4: Conversion Table for Glucocorticoid Dose
Generic Name
Oral or Intravenous 
Dose (mg)
Dexamethasone
0.75
Hydrocortisone
20
Methylprednisolone
4
Prednisolone
5
Prednisone
5

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Attachment 5: International Myeloma Working Group Uniform Response Criteria
The following criteria for response to multiple myeloma treatment were presented by Rajkumar, et al.21
Response
Response Criteria
Stringent complete 
response (sCR)

CR as defined below, plus

Normal FLC ratio, and

Absence of clonal PCs by immunohistochemistry or 2- to 4-color flow 
cytometry
Complete response (CR)a

Negative immunofixation of serum and urine, and

Disappearance of any soft tissue plasmacytomas, and

< 5% PCs in bone marrow
Very good partial 
response (VGPR)a

Serum and urine M-component detectable by immunofixation but not on 
electrophoresis, or

90% reduction in serum M-component plus urine M-component 
< 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 serum and urine M-protein are not measurable, a decrease 50% in the 
difference between involved and uninvolved FLC levels is require in place of 
the M-protein criteria

If serum and urine M-protein are not measurable, and serum free light chain 
assay is also not measurable, 50% reduction in bone marrow PCs is required 
in place of M-protein, provided baseline percentage was 30%

In addition to the above criteria, if present at baseline, 50% reduction in the 
size of soft tissue plasmacytomas is also required.
Minimal response (MR)

In patients with relapsed refractory myeloma adopted from the EBMT criteria:

25% but 49% reduction of serum M-protein and reduction in 24-hour 
urine M-protein by 50% to 89%

In addition to the above criteria, if present at baseline, 25% to 49% reduction 
in the size of soft tissue plasmacytomas is also required

No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response)
Stable disease

Not meeting criteria for CR, VGPR, PR, or progressive disease
Progressive diseaseb

Increase of 25% from lowest response value in any of the following:

Serum M-component (absolute increase must be 0.5 g/dL), and/or

Urine M-component (absolute increase must be 200 mg/24 hours), and/or

Only in patients without measurable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels (absolute increase 
must be > 10 mg/dL)

Only in patients without measurable serum and urine M-protein levels and 
without measurable disease by FLC levels, bone marrow PC percentage 
(absolute percentage must be 10%)

Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas

Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that 
can be attributed solely to the PC proliferative disorder

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Key:
CR = complete response; EBMT = European Group for Blood and Marrow Transplantation; 
FLC = free light chain; MR = minimal response; PC = plasma cell; PR = partial response; 
sCR = stringent complete response; VGPR = very good partial response.
a
Clarifications to the criteria for coding CR and VGPR in patients in whom the only measurable disease is 
by serum FLC levels: CR in such patients indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR 
criteria listed above. VGPR in such patients requires a > 90% decrease in the difference between involved 
and uninvolved FLC levels.
b
Clarifications to the criteria for coding progressive disease: bone marrow criteria for progressive disease are 
to be used only in patients without measurable disease by M-protein and by FLC levels; “25% increase” 
refers to M-protein, FLC, and bone marrow results, and does not refer to bone lesions, soft tissue 
plasmacytomas, or hypercalcemia and the “lowest response value” does not need to be a confirmed value.
Notes:
All response categories (CR, sCR, VGPR, PR, and progressive disease) require 2 consecutive 
assessments made at any time before the institution of any new therapy; CR, sCR, VGPR, PR, and 
stable disease categories also require no known evidence of progressive or new bone lesions if 
radiographic studies were performed. VGPR and CR categories require serum and urine studies 
regardless of whether disease at baseline was measurable on serum, urine, both, or neither. 
Radiographic studies are not required to satisfy these response requirements. Bone marrow 
assessments need not be confirmed. For progressive disease, serum M-component increases of 
1 g/dL are sufficient to define relapse if starting M-component is 5 g/dL.
Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus recommendations 
for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. 
Blood. 2011 May 5;117(18):4691-5.

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Attachment 6: Model of Worst Toxicity
As part of the rationale for dose selection in subsequent studies, the following modeling of worst toxicity will be 
attempted. It is based on Model 1 in Simon, et al.a
,
)
(
2
2
1
1
2
1
ij
i
ij
ij
ij
ij
ij
e
b
D
a
D
a
d
d
Ln
y






where
i = 1, 2, …, n, the number of patients
j denotes the treatment cycle number
d1ij denotes the total amount of daratumumab (mg) that patient i receives in course j
d2ij denotes the total amount of lenalidomide (mg) that patient i receives in course j
D1ij denotes the total amount of daratumumab (mg) that patient i has received prior to course j
D2ij denotes the total amount of lenalidomide (mg) that patient i has received prior to course j
a1 represents the influence of prior total dose (a1 = 0 indicates no cumulative toxicity)
a2 represents the influence of prior total dose (a2 = 0 indicates no cumulative toxicity)
bi is a random, normally distributed intersubject effect with mean μb and standard deviation σb
eij is the normally distributed error term, with mean zero and standard error σe, reflecting the within-subject 
variation
The unobserved variable yij translates to the observed discrete toxicity levels by means of 3 additional parameters, k1
< k2 < k3, which divide the line into the 4 regions representing “minimal” toxicity (usually CTCAE grades 0-1), 
“moderate” toxicity (usually CTCAE grade 2), DLT, and “unacceptable” toxicity. 
Note that the model described above handles the case where subjects receive doses that deviate from the protocol-
planned ones.
The following will be estimated from the model:

Maximum likelihood estimates (MLEs) of the parameters a1, a2, σb, σe, k1, k2, and k3, which yield estimated 
probabilities of seeing moderate toxicity and DLT at the various dose levels

Confidence intervals for parameters with nonzero MLE

Graph of probabilities of CTCAE grades 2+, 3+, and 4+ toxicities, for the first course averaged over the 
population of patients

Graphs of probabilities of CTCAE grades 2+, 3+, and 4+ toxicities (for the first course) for patients with b equal 
to MLE - SD, MLE and MLE + SD. 
There are no guarantees that the model will converge and it may need simplifying modifications in order to do so. 
                                                
a
Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. Accelerated titration designs for phase I 
clinical trials in oncology. J Natl Cancer Inst. 1997 Aug 6;89(15):1138-47.

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Attachment 7: Calculated Creatinine Clearance
Cockcroft-Gault formula:
To calculate the subject’s creatinine clearance (CrCl), use the following Cockcroft-Gault formula:
CrCl =
(140 - age [in years]) x weight (kg)
(x 0.85 for females)
(72 x serum creatinine [mg/dL])
If the serum creatinine is obtained using the International System of Units (SI) (ie, micromol/L), use the following 
formula to convert SI units to conventional (mg/dL) units (Manual of Laboratory & Diagnostic Tests, 2004):
•
serum creatinine (micromol/L) divided by 88.4 = serum creatinine (mg/dL).
Modification of Diet in Renal Disease (MDRD)
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
Alternatively, creatinine clearance may be calculated or measured according to the MDRD (Levey 2006)14 or the 
CKD-EPI (Levey 2009)15. 
For online calculators, please go to https://www.kidney.org/professionals/KDOQI/gfr_calculator.

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Attachment 8: Limited Schedule of Events for Subjects Continuing Daratumumab as of 
Amendment 7
Protocol Amendment 7 will allow those subjects who were receiving daratumumab after the primary analysis to 
continue receiving study drug. All subjects have received at least 12 months of therapy with daratumumab or have 
discontinued. Table 3 provides a limited schedule of assessments for subjects who remain on study drug after the 
primary analysis.
Dosage and Administration
Daratumumab, lenalidomide, and dexamethasone will be administered according to the regimen established prior to 
Amendment 7. 
Treatment Period
As of Amendment 7, subjects will complete their ongoing cycle of treatment and all assessments for that cycle. 
Subjects must then sign an updated informed consent form to continue receiving study drug. At the start of the next 
cycle of treatment, follow the schedule outlined in Table 3. For consistency, the cycle number will not restart.
Subjects who had discontinued study drug and who were in Follow-up before Amendment 7, will complete an EOT 
visit and enter the Follow-up Period per Table 3.
EOT Visit  
This visit must occur with 3 to 5 weeks after the last dose of study drug. Week 4 immunogenicity sampling should 
occur at this visit (see Table 3). 
Follow-up Period
As of Amendment 7, subjects who are in Follow-up (Table 2) will complete an EOT visit and immunogenicity 
assessments (if not yet completed) and will enter the modified Follow-up in the Time and Events Schedule 
(Table 3). Follow-up with Amendment 7 will include collection of best response and new antimyeloma therapy 
(disease assessments should be per local institutional practice), survival information, and occurrence of new cancers 
every 6 months for 3 years after the last dose of study drug or termination of the study by the sponsor, whichever 
occurs first.
Efficacy Evaluations 
Investigators should monitor and assess the subjects for response to treatment or disease progression according to 
local institutional practice.
Safety Evaluations 
Study drug administration and SAEs (including secondary malignancies) will be collected. Pregnancy testing will 
continue every 4 weeks during the Treatment Period and at the EOT visit. Concomitant medications associated with 
SAEs will also be collected. Serious adverse event reporting should continue as described in Section 12.6.2. The 
SAEs should be entered in the subject file/source notes. 
Source Documentation
At a minimum, the type and level of detail of source data available for a study subject should be consistent with
that commonly recorded at the site as a basis for standard medical care. This should also include: subject
identification and study identification; study discussion and date of updated informed consent; dates of visits; 
drug dispensing/return records and study drug administration information.

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Attachment 9: Limited Schedule of Events for Subjects Continuing Daratumumab as of 
Amendment 8
Protocol Amendment 8 will allow those subjects who are receiving daratumumab after the final analysis to continue 
receiving study drug. All subjects have received at least 24 months of therapy with daratumumab, or have 
discontinued. 
Dosage and Administration 
Daratumumab, lenalidomide, and dexamethasone will be administered according to the regimen established prior to 
Amendment 8.
Visits will occur on a monthly schedule, assessments done need to be captured in the source notes only.
Daratumumab will be provided by the sponsor until daratumumab in combination with lenalidomide and 
dexamethasone has been approved for use in patients with relapsed/ refractory multiple myeloma and is 
commercially available in the respective countries.
Treatment Period
As of Amendment 8, subjects will continue until progressive disease, unacceptable toxicity, withdrawal of consent, 
the investigator decides to stop treatment, the start of subsequent anticancer therapy, or the sponsor ends the study.
Efficacy Evaluations
Investigators should monitor and assess subjects for response to treatment or disease progression according to local 
institution practice. The assessments and outcome should be entered in the subject file/source notes. 
Safety Evaluations
SAEs will be collected. SAE reporting should continue as described in Section 12.6.2. The SAEs should be entered 
in the subject file/source notes.
SPMs will be collected. SPM reporting should continue as described in Section 12.6.2. The SPMs should be entered 
in the subject file/source notes.
Source Documentation
At a minimum, the type and level of detail of source data available for a study subject should be consistent with that 
commonly recorded at the site as a basis for standard medical care. This should also include: subject identification 
and study identification, study discussion, and data of updated informed consent, dates of visits, drug 
dispensing/return records, and study drug administration information.