A Randomized Study of Daratumumab Plus Lenalidomide Versus Lenalidomide Alone as Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma Who Are Minimal Residual Disease Positive After Frontline Autologous Stem Cell Transplant
Phase: PHASE3
Conditions: Multiple Myeloma
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Approved, Date: 12 August 2024
Janssen Research & Development *
Clinical Protocol
A Randomized Study of Daratumumab Plus Lenalidomide Versus Lenalidomide Alone as
Maintenance Treatment in Patients with Newly Diagnosed Multiple Myeloma Who Are
Minimal Residual Disease Positive After Frontline Autologous Stem Cell Transplant
AURIGA
Protocol 54767414MMY3021; Phase 3
Amendment 4
DARZALEX® (daratumumab)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Scientific Affairs, LLC, Janssen Biotech, Inc.; Janssen
Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutical NV;
Janssen, Inc; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor”
is used throughout the protocol to represent these various legal entities; the sponsor is identified on the
Contact Information page that accompanies the protocol.
Status: 
Approved
Date: 
12 August 2024
Prepared by: 
Janssen Research & Development
EDMS number: 
EDMS-ERI-179577971, 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT03901963

DARZALEX®(daratumumab)
Clinical Protocol 54767414MMY3021 Amendment 4
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Approved, Date: 12 August 2024
TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 7
SYNOPSIS.................................................................................................................................................... 8
TIME AND EVENT SCHEDULE –PART 1: OVERALL STUDY PROCEDURES..................................... 14
TIME AND EVENTS SCHEDULE –PART 2: DETAILS FOR BONE MARROW TESTING..................... 28
ABBREVIATIONS...................................................................................................................................... 29
1. 
INTRODUCTION................................................................................................................................ 31
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 32
2.1. 
Objectives and Endpoints .............................................................................................................. 32
2.2. 
Hypothesis ..................................................................................................................................... 34
3. 
STUDY DESIGN AND RATIONALE................................................................................................. 34
3.1. 
Overview of Study Design.............................................................................................................. 34
3.2. 
Study Design Rationale.................................................................................................................. 37
3.2.1. 
Overall Rationale for Study Design ............................................................................................ 37
3.2.2. 
Daratumumab............................................................................................................................. 39
3.2.2.1. 
Intravenous Daratumumab Administration.............................................................................. 40
3.2.2.2. 
Rationale for Subcutaneous Daratumumab Administration .................................................... 41
3.2.3. 
Subcutaneous Daratumumab Dosing and rHuPH20 Concentration Chosen for This
Study........................................................................................................................................... 42
3.2.4. 
Minimal Residual Disease Conversion Rate as the Primary Endpoint....................................... 42
3.2.5. 
MRD Assessment Using NGS.................................................................................................... 44
3.2.6. 
Summary of Anticipated Benefits and Risks............................................................................... 45
4. 
PATIENT POPULATION................................................................................................................... 46
4.1. 
Inclusion Criteria ............................................................................................................................ 46
4.2. 
Exclusion Criteria ........................................................................................................................... 49
4.3. 
Prohibitions and Restrictions ......................................................................................................... 51
5. 
STUDY TREATMENT AND ALLOCATION AND BLINDING........................................................... 53
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 53
6.1. 
Daratumumab and Lenalidomide Dosing and Supply ................................................................... 53
6.2. 
Daratumumab ................................................................................................................................ 54
6.2.1. 
Preparation and Administration .................................................................................................. 54
6.2.2. 
Daratumumab Pre- and Post-administration Medications and Patient Observation.................. 56
6.2.2.1. 
Pre-administration Medications ............................................................................................... 56
6.2.2.2. 
Post-administration Medications.............................................................................................. 57
6.2.3. 
Management of Injection-site and Injection-related Reactions .................................................. 58
6.2.3.1. 
Local Injection-site Reactions.................................................................................................. 58
6.2.3.2. 
Daratumumab Injection-related Reactions .............................................................................. 58
6.2.3.2.1. 
Injection-related Reactions of Grade 1 or Grade 2 .............................................................. 59
6.2.3.2.2. 
Injection-related Reactions of Grade 3 or Higher................................................................. 59
6.2.3.2.3. 
Recurrent Injection-related Reactions.................................................................................. 59
6.3. 
Dose Delays and Dose Modifications ............................................................................................ 59
6.3.1. 
Cycle Delay................................................................................................................................. 60

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6.3.2. 
Daratumumab............................................................................................................................. 61
6.3.2.1. 
Daratumumab Dose Modification ............................................................................................ 61
6.3.2.2. 
Daratumumab-related Toxicity Management .......................................................................... 61
6.3.2.3. 
Daratumumab Interruption or Missed Doses........................................................................... 62
6.3.3. 
Lenalidomide .............................................................................................................................. 62
6.4. 
Overdose........................................................................................................................................ 62
6.4.1. 
Daratumumab............................................................................................................................. 62
6.4.2. 
Lenalidomide .............................................................................................................................. 63
7. 
STUDY TREATMENT(S) COMPLIANCE ......................................................................................... 63
8. 
PRE-STUDY AND CONCOMITANT THERAPY............................................................................... 63
8.1. 
Recommended Therapies.............................................................................................................. 64
8.1.1. 
Prevention of Deep Venous Thrombosis and Pulmonary Embolism ......................................... 64
8.1.2. 
Therapy for Tumor Lysis Syndrome ........................................................................................... 66
8.1.3. 
Prophylaxis Against Pneumocystis carinii Pneumonia............................................................... 66
8.1.4. 
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 66
8.1.5. 
Prevention of Hepatitis B Virus Reactivation.............................................................................. 66
8.1.6. 
Prevention of Steroid-induced Gastritis...................................................................................... 66
8.1.7. 
Drugs Affecting Bone Structure and Mineralization.................................................................... 66
8.2. 
Permitted Therapies....................................................................................................................... 67
8.3. 
Prohibited Therapies...................................................................................................................... 67
8.4. 
Subsequent Therapies................................................................................................................... 68
9. 
STUDY EVALUATIONS.................................................................................................................... 68
9.1. 
Study Procedures........................................................................................................................... 68
9.2. 
Evaluations Specific to Entry Criteria and/or Other Study Measures ............................................ 69
9.2.1. 
ECOG Performance Status ........................................................................................................ 69
9.2.2. 
Calculated Creatinine Clearance................................................................................................ 69
9.2.3. 
Serum Calcium Corrected for Albumin....................................................................................... 70
9.2.4. 
Asthma Guidelines...................................................................................................................... 70
9.3. 
Efficacy Evaluations....................................................................................................................... 70
9.3.1. 
Response.................................................................................................................................... 70
9.3.2. 
β2-microglobulin and Lactic Acid Dehydrogenase...................................................................... 72
9.3.3. 
Myeloma Protein Measurements in Serum and Urine................................................................ 72
9.3.4. 
Bone Marrow Examination and Minimal Residual Disease Assessment................................... 73
9.3.5. 
Assessment of Lytic Disease...................................................................................................... 74
9.3.6. 
Documentation of Extramedullary Plasmacytomas.................................................................... 74
9.4. 
Patient-Reported Outcomes .......................................................................................................... 74
9.5. 
Safety Evaluations ......................................................................................................................... 75
9.5.1. 
Adverse Events........................................................................................................................... 76
9.5.2. 
Clinical Laboratory Tests ............................................................................................................ 76
9.5.2.1. 
Hematology, Chemistry, Pregnancy, HCV, and HBV Tests.................................................... 76
9.5.2.2. 
Indirect Antiglobulin Test......................................................................................................... 77
9.5.3. 
ECGs, Chest Imaging, Physical Examination, and Spirometry.................................................. 78
9.5.4. 
Vital Signs Including Weight....................................................................................................... 78
9.5.5. 
Eastern Cooperative Oncology Group Performance Status....................................................... 78
9.6. 
Benefit-risk Evaluation ................................................................................................................... 78
10. PATIENT COMPLETION/DISCONTINUATION OF TREATMENT(S)/ WITHDRAWAL
FROM THE STUDY........................................................................................................................... 78
10.1. 
Study Completion........................................................................................................................... 78
10.2. 
Discontinuation of Study Treatment/Withdrawal from the Study ................................................... 79
10.2.1. 
Discontinuation of Study Treatment ........................................................................................... 79
10.2.2. 
Withdrawal From the Study ........................................................................................................ 80
10.3. 
Withdrawal From the Use of Samples In Future Research ........................................................... 80
11. STATISTICAL METHODS................................................................................................................. 80

DARZALEX®(daratumumab)
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11.1. 
Patient Information......................................................................................................................... 80
11.2. 
Sample Size Determination ........................................................................................................... 81
11.3. 
Efficacy Analyses........................................................................................................................... 81
11.3.1. 
Primary Endpoint and Analysis................................................................................................... 81
11.3.2. 
Secondary Endpoints and Analysis............................................................................................ 81
11.3.2.1. 
Progression-free Survival, Overall Survival, and Minimal Residual Disease .......................... 81
11.3.2.2. 
Patient-reported Outcomes ..................................................................................................... 82
11.4. 
Safety Analyses ............................................................................................................................. 82
11.5. 
Benefit-risk Analyses...................................................................................................................... 83
11.6. 
Interim Analyses............................................................................................................................. 83
11.7. 
Independent Data Monitoring Committee ...................................................................................... 83
12. ADVERSE EVENT REPORTING ...................................................................................................... 83
12.1. 
Definitions ...................................................................................................................................... 84
12.1.1. 
Adverse Event Definitions and Classifications ........................................................................... 84
12.1.1.1. 
Adverse Event ......................................................................................................................... 84
12.1.1.2. 
Serious Adverse Event............................................................................................................ 84
12.1.1.3. 
Unlisted (Unexpected) Adverse Event/Reference Safety Information .................................... 85
12.1.1.4. 
Adverse Event Associated With the Use of the Intervention................................................... 85
12.1.1.5. 
Adverse Event Associated With Progression of Disease........................................................ 85
12.1.2. 
Attribution Definitions.................................................................................................................. 85
12.1.3. 
Severity Criteria .......................................................................................................................... 86
12.2. 
Special Reporting Situations.......................................................................................................... 87
12.3. 
Procedures..................................................................................................................................... 87
12.3.1. 
All Adverse Events...................................................................................................................... 87
12.3.2. 
Serious Adverse Events ............................................................................................................. 88
12.3.3. 
Pregnancy................................................................................................................................... 90
12.4. 
Contacting Sponsor Regarding Safety........................................................................................... 90
13. PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 90
13.1. 
Procedures..................................................................................................................................... 90
13.2. 
Contacting Sponsor Regarding Product Quality............................................................................ 90
14. STUDY TREATMENT INFORMATION ............................................................................................. 91
14.1. 
Physical Description and Packaging of Daratumumab.................................................................. 91
14.2. 
Labeling.......................................................................................................................................... 91
14.3. 
Preparation, Handling, and Storage............................................................................................... 91
14.4. 
Study Treatment Accountability..................................................................................................... 91
15. STUDY-SPECIFIC MATERIALS....................................................................................................... 92
16. ETHICAL ASPECTS......................................................................................................................... 92
16.1. 
Study-specific Design Considerations ........................................................................................... 92
16.2. 
Regulatory Ethics Compliance....................................................................................................... 93
16.2.1. 
Investigator Responsibilities ....................................................................................................... 93
16.2.2. 
Institutional Review Board .......................................................................................................... 93
16.2.3. 
Informed Consent ....................................................................................................................... 95
16.2.4. 
Privacy of Personal Data ............................................................................................................ 96
16.2.5. 
Long-term Retention of Samples for Additional Future Research.............................................. 96
17. ADMINISTRATIVE REQUIREMENTS.............................................................................................. 97
17.1. 
Protocol Amendments.................................................................................................................... 97
17.2. 
Regulatory Documentation ............................................................................................................ 97
17.2.1. 
Regulatory Approval/Notification ................................................................................................ 97
17.2.2. 
Required Pre-study Documentation ........................................................................................... 97
17.3. 
Patient Identification, Enrollment, and Screening Logs ................................................................. 98
17.4. 
Source Documentation................................................................................................................... 98
17.5. 
Case Report Form Completion ...................................................................................................... 99
17.6. 
Data Quality Assurance/Quality Control ...................................................................................... 100

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17.7. 
Record Retention ......................................................................................................................... 100
17.8. 
Monitoring .................................................................................................................................... 101
17.9. 
Study Completion/Termination..................................................................................................... 101
17.9.1. 
Study Completion/End of Study................................................................................................ 101
17.9.2. 
Study Termination..................................................................................................................... 102
17.10. On-site Audits............................................................................................................................... 102
17.11. Use of Information and Publication .............................................................................................. 102
REFERENCES.......................................................................................................................................... 104
Attachment 1: 
Asthma Guidelines....................................................................................................... 107
Attachment 2: 
Anticipated Events ....................................................................................................... 110
Attachment 3: 
Contraceptive (and Barrier) Guidance and Collection of Pregnancy Information........ 111
Attachment 4: 
Protocol Amendment History....................................................................................... 122
INVESTIGATOR AGREEMENT............................................................................................................... 134
LIST OF ATTACHMENTS
Attachment 1: 
Asthma Guidelines ................................................................................................... 107
Attachment 2: 
Anticipated Events.................................................................................................... 110
Attachment 3: 
Contraceptive (and Barrier) Guidance and Collection of Pregnancy
Information................................................................................................................ 111
Attachment 4: 
Protocol Amendment History.................................................................................... 122

DARZALEX®(daratumumab)
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Objectives and Endpoints ......................................................................................................... 33
Table 2: 
Daratumumab Dosing Schedule............................................................................................... 55
Table 3: 
Re-treatment Criteria Before the Start of Each Cycle............................................................... 60
Table 4: 
Daratumumab-related Toxicity Management ........................................................................... 62
Table 5: 
ECOG Performance Status Scale ............................................................................................ 69
Table 6: 
Serum Calcium Corrected for Albumin ..................................................................................... 70
Table 7: 
IMWG Consensus Recommendations for Multiple Myeloma Treatment Response
Criteria ...................................................................................................................................... 71
Table 8: 
Criteria for Loss of Complete Response Without Disease Progression................................... 72
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 37
Figure 2: POLLUX Updated Analysis: Overall Response Rate and Minimal Residual Disease-
negative Rates.......................................................................................................................... 44
Figure 3: Individual and Myeloma-related Risk Factors........................................................................... 65

DARZALEX®(daratumumab)
Clinical Protocol 54767414MMY3021 Amendment 4
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Approved, Date: 12 August 2024
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 4 
12 August 2024
Amendment 3 
24 June 2021
Amendment 2 
08July 2020
Amendment 1 
09 December 2019
Original Protocol 
13 February 2019
Amendment 4 (12 August 2024)
Overall Rationale for the Amendment:  Protocol clarification and revision to allow for additional IMWG
response assessments per the investigator during Follow-up visits after study treatment completion.
The changes made to the clinical protocol 54767414MMY3021 as part of Protocol Amendment 4 are listed
below, including the rationale of each change and a list of all applicable sections. Changes made in previous
protocol amendments are listed in Attachment 4: Protocol Amendment History.
Section Number 
and Name
Description ofChange 
Brief Rationale
Time And Event 
Schedule –Part 1: 
Overall Study 
Procedures 
Revised the time and events schedule to include
IMWG response evaluation per investigator’s
assessments during study conduct and for
follow-up visits.
To clarify when response
assessments need to be performed.
6.2.1 Preparation 
and Administration  
7 Study
Treatment(s)
Compliance
14.3 Preparation,
Handling, and
Storage
Updated language to “…Commercial Prescribing
Instruction for drug preparation and
administration…”
Investigational Product Preparation
Instructions are no longer
applicable due to a shift in the
daratumumab commercial supply.
9.1 Study 
Procedures 
Revised language to include the bolded language,
“Every effort should be made to keep patients on
the study schedule as planned from C1D1. At each
visit, whether in-person or via telemedicine,
study assessments should be completed before the
administration of study treatment. Daratumumab
administration and study-specific
tests/procedures must be completed by study
staff”
To clarify that study visits during
study conduct can be in-person or
conducted via telemedicine.
9.3.1 Response 
Added language to clarify that investigator
assessment of IMWG response after completion or
premature discontinuation of study treatment is to
be performed based on local laboratory results.
To clarify that local laboratory
results will be utilized for IMWG
assessments during Follow-up
visits after completion or premature
discontinuation of study treatment.

DARZALEX®(daratumumab)
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SYNOPSIS
STUDY TITLE
A Randomized Study of Daratumumab Plus Lenalidomide Versus Lenalidomide Alone as Maintenance
Treatment in Patients with Newly Diagnosed Multiple Myeloma Who Are Minimal Residual Disease
Positive After Frontline Autologous Stem Cell Transplant
DARATUMUMAB MAINTENANCE TREATMENT
Daratumumab (JNJ-54767414) is a human immunoglobulin G1 kappa monoclonal antibody that binds with
high affinity to a unique epitope on CD38. The addition of daratumumab to bortezomib and dexamethasone
or to lenalidomide and dexamethasone in the CASTOR and POLLUX studies, respectively, tripled the
minimal residual disease (MRD) negative rate in patients with relapsed multiple myeloma, and patients
who attained MRD negativity had significantly longer progression-free survival (PFS) than patients who
remained positive. Similarly, in newly diagnosed myeloma patients, addition of daratumumab to standard
of care regimens such as bortezomib  plus melphalan and prednisone, bortezomib plus thalidomide and
dexamethasone, as well as lenalidomide and dexamethasone, improved the MRD negativity rate and PFS
significantly, as observed in the ALCYONE, CASSIOPEIA, and MAIA studies, respectively. Maintenance
therapy with lenalidomide is the standard of care following frontline autologous stem cell transplant
(ASCT) for multiple myeloma. Attainment of MRD negativity following ASCT and maintenance therapy
has been shown to improve long-term outcomes. However, lenalidomide alone may not be sufficient to
convert MRD positive patients post-transplant to MRD negativity. Therefore, to improve the likelihood of
converting patients to MRD negativity, addition of subcutaneous (SC) daratumumab to lenalidomide
maintenance treatment will be evaluated in Study MMY3021. We expect that the benefits of addition of
SC daratumumab to lenalidomide, as maintenance treatment, will outweigh the risks, even among patients
who may achieve a complete response (CR) or better after transplant. Prolonged administration of
daratumumab in conjunction with lenalidomide does not result in an increased total risk of adverse events
(AEs). In the MAIA study of IV daratumumab and Rd versus Rd alone in newly diagnosed patients with
myeloma, the incidence of serious treatment-emergent (TE) AEs was similar in both treatment groups
(62.9% in the DRd group and 62.7% in the Rd group). Of the most frequently reported (>10%) Grade 3 or
4 adverse events, higher rates of neutropenia (DRd: 50.0%; Rd: 35.3%), lymphopenia (DRd: 15.1%; Rd:
10.7%), leukopenia (DRd: 11.0%; Rd: 4.9%), and pneumonia (DRd: 13.7%; Rd: 7.9%) were observed in
the DRd group, while Grade 3 or 4 anemia occurred more frequently in the Rd group (DRd: 11.8%; Rd:
19.7%). Although Grade 4 TEAEs were reported in a higher percentage of patients in the DRd group
compared with the Rd group, fewer patients in the DRd group (7.1%) discontinued study treatment due to
a TEAE compared with the Rd group (15.9%); however, the percentage of patients discontinuing
lenalidomide was similar in both arms.
We hypothesize that the addition of daratumumab to lenalidomide maintenance therapy following frontline
ASCT may increase the MRD negativity rate and improve clinical outcomes. The proposed study will
evaluate improvement in MRD negativity rate in newly diagnosed multiple myeloma patients following
maintenance treatment with SC daratumumab and lenalidomide in comparison with maintenance treatment
with lenalidomide alone.
HYPOTHESIS
The addition of daratumumab to lenalidomide maintenance treatment in anti-CD38treatment naïve, newly
diagnosed multiple myeloma patients who are MRD positive following high-dose therapy (HDT) and
ASCT will improve the conversion rate to MRD negativity.

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OVERVIEW OF STUDY DESIGN
This is a Phase 3, randomized, open-label, active-controlled, multicenter study to be conducted at sites in
the United States (US) and Canada to primarily evaluate the conversion rate to MRD negativity following
12 months of maintenance treatment with SC daratumumab in combination with lenalidomide relative to
treatment with lenalidomide alone in patients with newly diagnosed multiple myeloma who have received
a minimum of 4 cycles of induction, have undergone HDT and ASCT within 12 months of the start of
induction therapy, are within 6 months of ASCT  on the date of randomization, have very good partial
response or better, are MRD positive at the time of screening, and are anti-CD38 treatment naïve.
The study includes a Screening Period; a Maintenance Phase; an End of Treatment (EOT) Visit; and a
Follow-up Phase as described below.
Screening Period: 
Screening is to be conducted within 60 days prior to randomization; randomization
must occur within 6 months of the transplant date. Eligible patients must have
undergone HDT and a single ASCT within 12 months of the start of induction
treatment and be MRD positive at the time of screening. Adaptive
Biotechnologies’ next generation sequencing (NGS)-based MRD assay will be
used to assess MRD positivity during screening for enrollment and randomization
of treatment. Residual bone marrow sample, if available, will be banked for future
tests, if required. Note that, if results of post-ASCT NGS assay  (ie, Adaptive
Biotechnologies’ NGS-based MRD assay) conducted previously as part of
institutional standards are available at screening, these results are to be recorded in
the electronic case report form (eCRF).
Maintenance Phase: Comprised of up to thirty-six, 28-day  cycles. Patients will be randomized to
receive maintenance treatment with SC  daratumumab  in combination with
lenalidomide or lenalidomide alone. Study treatment will continue until confirmed
progressive disease (PD), unacceptable toxicity, withdrawal from study or the end
of study maintenance phase.
EOT Visit: 
An EOT visit is to be scheduled 30 days (± 7 days) after the last dose of study
treatment(s) or, if a patient begins new therapy for multiple myeloma, as soon as
possible prior to the start of next-line therapy.
Follow-up Phase: 
After the EOT visit, patients will continue to be followed until the end of the study,
every 6 months. The end of the study is defined as 36 months from the date of
randomization of last patient.
Planned enrollment includes a total of 214 patients to be randomly allocated in a 1:1 ratio to one of the two
treatment arms, with randomization stratified by cytogenetic risk (high versus standard/unknown).
PATIENT POPULATION
Key entry criteria include the following. A patient must:
1. Be 18 to 79 years of age,
2. Have newly diagnosed multiple myeloma with a history of a minimum of 4 cycles of induction
therapy, have received HDT and ASCT within 12 months of the start of induction therapy, and be
within 6 months of the date of ASCT at the time of randomization.

DARZALEX®(daratumumab)
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3. Have a very good partial response or better assessed per the International Myeloma Working Group
(IMWG) 2016 criteria at the time of randomization.
4. Have archived bone marrow samples collected before induction treatment (ie, at diagnosis) or
before transplant (eg, at the end of induction) or have existing results on the index MM clone based
on Adaptive Biotechnologies’ NGS-based MRD assay. Archived bone marrow samples will be
used for calibration of myeloma clonal cells to facilitate assessment of the primary endpoint by
NGS. Any one of the following archived bone marrow samples are required:
o Greater than 1 mL viable frozen bone marrow aspirated aliquot (preferred) collected in an
ethylenediaminetetraacetic acid tube, and stored at a temperature of −80°C, or
o Non-decalcified diagnostic bone marrow aspirate clot sections (block or slides) for MRD
assessment:
A Formalin fixed paraffin embedded (FFPE) block of bone marrow aspirate clot,
or slides (preferably 5 slides, if available), 5 m each, of non-decalcified bone
marrow, or
Slides (preferably 5 slides, if available), bone marrow aspirate smear.
Please note: bone marrow core sections are not acceptable samples for analysis.
In exceptional circumstances when index myeloma clone cannot be identified from
the archived bone marrow sample, a post-transplant sample can be used to identify
myeloma clone with permission from the Sponsor.
o If an existing result on index myeloma clone is available from Adaptive Biotechnologies’
NGS-based MRD assay, conducted as part of institutional procedures, then archived bone
marrow sample is not required as long as Adaptive Biotechnologies is able to retrieve
historical results on the index myeloma clone from the clinical database.
5. Have residual disease as defined by detectable MRD by NGS (Adaptive Biotechnologies’ NGS-
based MRD assay). If this assay was conducted post ASCT as part of institutional procedures and
MRD results are available during screening, then patients who were MRD positive at 10-5 based on
existing NGS test result are also eligible to participate in the study (such patients will NOT  be
required to undergo MRD assessment by NGS again at the time of screening),
6. Be anti-CD38 treatment naïve.
DOSAGE AND ADMINISTRATION
The 2 treatment arms comprise ofdaratumumab in combination with lenalidomide or lenalidomide alone
as follows (each treatment cycle will be 28 days, with a maximum duration of maintenance treatment of
36 cycles):
1. Daratumumab 1800 mg administered by SC injection:
- Weekly during C1 and C2,
- Every 2 weeks during C3 to C6, and
- Every 4 weeks from C7 onwards until confirmed PD, unacceptable toxicity, or until end of
study treatment.
2. Lenalidomide 10 mg PO:
- Days 1 to 28 (continuously) of each 28-day cycle until confirmed PD, unacceptable toxicity, or
until end of study treatment. If a patient experiences toxicity to lenalidomide, dose and/or
schedule may be modified per institutional standard.

DARZALEX®(daratumumab)
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- After 3 cycles of maintenance therapy, if well tolerated, the lenalidomide dose may be increased
to 15 mg daily, at the discretion of the investigator.
STUDY EVALUATIONS
Study evaluations will include the following:
Standard baseline screening evaluations for this patient population, including assessment of
MRD status by NGS assay (Adaptive Biotechnologies’ NGS-based MRD assay), and
treatments to be administered
Calibration by NGS on archived bone marrow samples collected before induction treatment
or before transplant.
Efficacy: MRD  assessment by NGS  at 12, 18, 24, and 36 months during maintenance
treatment, myeloma proteins, bone marrow examinations, skeletal surveys, and
extramedullary soft tissue plasmacytomas. Disease status will be assessed in accordance with
IMWG 2016 response criteria.
Patient-reported outcomes (PROs): 
European Organization for Research and Treatment
of Cancer Quality of Life Questionnaires-C30 (EORTC QLQ-C30) and -Multiple Myeloma
Module (EORTC QLQ-MY20), and the European Quality of Life Five Dimensions
Questionnaire-5-level (EQ-5D-5L) scale (questionnaire).
Safety/tolerability: Adverse events, clinical laboratory evaluations (to include pregnancy
screening), vital signs, and Eastern Cooperative Oncology Group (ECOG) performance status.
In addition, patients will be followed for onset of other malignancy, next-line therapy, including date of PD
on next-line therapy, and survival.
STATISTICAL METHODS
Datasets for Analysis
Intent-to-treat Population: 
Includes all randomized patients.
Safety Population: 
Includes all treated patients who receive at least 1 dose of
randomized therapy.
Sample Size Determination
Based on previous reports of MRD negativity rate in lenalidomide-treated myeloma patients, the anticipated
MRD (at 10-5) negativity conversion rate is estimated to be 20% for patients treated with lenalidomide alone
following post ASCT. Assuming a 20% absolute increase in MRD negativity rate (40% daratumumab plus
lenalidomide versus 20% lenalidomide alone) by the end of 12-month maintenance treatment, a sample size
of 214 patients (ie, 107 patients per treatment group at a 1:1 randomization) will be needed to achieve at
least 85% power to detect such a treatment difference at a 2-sided alpha of 0.05 using continuity corrected
chi-squared test.
Statistical Methods
Data will be summarized using descriptive statistics as appropriate, ie, continuous variables will be
summarized using mean, standard deviation, and range. Categorical variables will be summarized using
frequency tables. For time-to-event variables, the Kaplan-Meier method will be used for descriptive
summaries. All statistical testing will be conducted at 2-sided alpha level of 0.05 without multiplicity

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adjustments. Response to study treatment and PD will be evaluated by a validated computer algorithm
based on IMWG 2016 criteria.
Primary Endpoint Analysis
The primary endpoint will be compared between the 2 treatment groups in the intent-to-treat population
using the stratified Cochran Mantel-Haenszel test with baseline cytogenetic risk (high versus
standard/unknown) as stratification factor. A Mantel-Haenszel odds ratio along with its 2-sided 95%
confidence intervals (CIs) will be calculated.
The primary analysis will be performed after all randomized patients have completed 12 months of
maintenance treatment, have disease progression, died, or have been discontinued from study treatment
by this time point. Afterwards, an annual analysis will be performed to update secondary endpoints and
safety. A final analysis will occur at the end of study ie, 36 months from the date ofrandomization of
last patient.
Secondary Endpoints and Analysis
PFS, OS, MRD, and clinical response:
Time-to-event secondary endpoints including PFS and OS will be analyzed using a stratified log-rank
test for the comparison of the distribution between the 2 treatment groups. The Kaplan-Meier method
will be used to estimate the distribution for each treatment. The treatment effect (hazard ratio) and its
2-sided 95% CIs are to be estimated using a stratified Cox regression model. The stratification factor
is baseline cytogenetic risk (high versus standard/unknown).
The overall MRD negativity rate at any time after randomization and MRD negative durability will be
analyzed.
The binary secondary endpoints including rate of CR and stringent CR(sCR) will be analyzed similarly
to MRD negativity rate.
A descriptive summary for duration of response will be provided. No statistical comparison will be
made.
Patient-reported Outcomes
The EORTC QLQ-C30 and EORTC QLQ-MY20 scale scores and EQ-5D-5L utility and visual analog
scores will be descriptively summarized by treatment group at each time point. Within-group and
between-group treatment effects of the PRO endpoints will be assessed by change from baseline using
mixed models for repeated measures. Full details on meaningful change thresholds and statistical
analyses will be provided in the Statistical Analysis Plan.
Safety Analyses
Safety data will be summarized using descriptive statistics and/or listed as appropriate; no inferential
statistical analyses are planned for safety data.

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TIME AND EVENT SCHEDULE –PART 1: OVERALL STUDY PROCEDURES
PROCEDURE
STUDY PHASES/VISITS a
SCREENING
MAINTENANCE
(CYCLES 1 –36)
EOT
FOLLOW-UP (FROM THE DATE
OF LAST STUDY TREATMENT
UNTIL THE END OF STUDY) 
NOTES
Informed consent 
X 
- 
- 
-
Must be signed before any study-related
procedures are performed.
Eligibility criteria 
X 
- 
- 
- 
For further details refer to Section 4.
Demographics and medical history  
X 
- 
- 
-
Clinically significant medical history, within the
past 2 years, including surgery or procedures
planned prior to randomization. History of
malignancy at any time in the past prior to
randomization should also be entered in the
eCRF.
Height 
X 
- 
- 
- 
-
Chest x-ray or full chest CT scan  
X 
As clinically indicated 
- 
-
Not required if performed as part of standard of
care within 30 days prior to screening.
a 
Study Phases/Visits:
Screening Phase: 
Screening is to be conducted within 60 days prior to randomization; randomization must be within 6 months of the transplant date. Patients must have undergone HDT
and ASCT within 12 months of the start of induction therapy. Tandem transplants are not allowed.
Maintenance Phase: Comprised of up to thirty-six, 28-day cycles. Patients are to receive study treatment (ie, daratumumab in combination with lenalidomide or lenalidomide alone), until
confirmed PD, unacceptable toxicity, or the end of study treatment.
Note: 
PD based on 1 of the laboratory tests alone must be confirmed by at least 1 repeat investigation performed at least 1 day later. Clinical judgment should prevail;
however, repeat assessments within 3 weeks can be used as a general guideline.
EOT Visit: 
An EOT visit is to be scheduled 30 days (± 7 days) after the last dose of study treatment(s) or, if a patient begins new therapy for the treatment of multiple myeloma, as
soon as possible prior to the start of next-line therapy.
In this study, in accordance with the IMWG 2016 criteria consensus recommendations, a line of subsequent therapy is defined as one or more cycles of a planned
treatment program. A new line of therapy starts when a planned course of therapy is modified to include other treatment agents (alone or in combination) because of
PD, relapse, or toxicity.
Follow-up Phase: 
After the EOT visit, patients will continue to be followed until the end of the study. The end of the study is defined as 36 months from the date of randomization of the last
patient. If a patient has died, the date and cause of death will be collected and documented in the eCRF.
- After confirmed PD or the start of a new treatment for multiple myeloma, patients will be contacted by telephone for follow-up information on secondary primary
malignancy, next-line therapy, date of PD on next-line therapy, and/or survival (all patients). Written documentation of information obtained via telephone call must be
available for review in source documents.

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PROCEDURE
STUDY PHASES/VISITS a
SCREENING
MAINTENANCE
(CYCLES 1 –36)
EOT
FOLLOW-UP (FROM THE DATE
OF LAST STUDY TREATMENT
UNTIL THE END OF STUDY) 
NOTES
Spirometry test (ie, FEV1)
(only in patients with known or suspected
COPD or asthma)
X 
As clinically indicated 
- 
-
Spirometry (ie, measurement of FEV1) is
required at screening in patients with known or
suspected COPD or asthma, unless if performed
as part of standard of care anytime from 60 days
prior to transplant up to randomization.
ECOG performance status 
X 
D1 ofodd cycles (ie, C1,
C3, C5, C7, and 
so on)
X 
-
ECOG performance status assessments should be
obtained prior to any other study procedures
planned for the same day whenever possible.
12-Lead ECG  
X 
As clinically indicated 
- 
- 
-
Physical examination  
X 
Symptom and disease
directed exam as clinically 
indicated
- 
-
During screening, a complete physical
examination is to be conducted with
measurement of height. Thereafter, only a
symptom and disease directed physical
examination is required as clinically indicated.
Weight 
X 
On C1D1  
- 
- 
-
Vital signs 
X
Lenalidomide only arm:
- D1 of odd cycles (ie,
C1, C3, C5, C7, and
so on).
Daratumumab +
lenalidomide arm:
- C1D1: Up to 30
minutes before
administration; at
end of
administration; and
at 0.5 and 1 hour (+/-
5 minutes) after end
of administration.
- C3 onwards:
Immediately before
and at the end of
daratumumab
administration on D1
of odd cycles (ie,
C3D1 C5D1, C7D1,
etc.
- 
-
To include pulse, temperature, and blood
pressure measured in a sitting position after
approximately 5 minutes of rest

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PROCEDURE
STUDY PHASES/VISITS a
SCREENING
MAINTENANCE
(CYCLES 1 –36)
EOT
FOLLOW-UP (FROM THE DATE
OF LAST STUDY TREATMENT
UNTIL THE END OF STUDY) 
NOTES
C4D1, C5D1, C6D1), and
every 3rd cycle thereafter
(ie, C9D1, C12D1, C15D1
C18D1, C21D1, C24D1,
C27D1, C30D1, C33D1
and C36D1)
Lenalidomide +
Daratumumab arm: D1,
D8, D15, D22 of Cycles 1-
2; D1, D15 of Cycles 3-6;
D1 of every 3rd cycle
thereafter (ie, C9D1,
C12D1, C15D1, C18D1,
C21D1, C24D1, C27D1,
C30D1, C33D1 and
C36D1)
On C1D1 and D1 of
subsequent cycles, there is
no need to repeat the tests
if performed within the
past 3 days. In addition,
tests may be repeated as
clinically indicated.
Results must be evaluated
before each daratumumab
administration or
beginning of new cycle of
lenalidomide
administration.

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PROCEDURE
STUDY PHASES/VISITS a
SCREENING
MAINTENANCE
(CYCLES 1 –36)
EOT
FOLLOW-UP (FROM THE DATE
OF LAST STUDY TREATMENT
UNTIL THE END OF STUDY) 
NOTES
deemed necessary by the
investigator, patients may
also be observed after
subsequent injections.
Administration Medications for patients
treated with daratumumab
Lenalidomide 10 mg PO:
- Days 1 to 28 (continuously) of each 28-day
cycle until confirmed PD, unacceptable
toxicity, or until end of study treatment. If
a patient experiences toxicity to
lenalidomide, dose and/or schedule may be
modified per institutional standard.
- After 3 cycles of maintenance therapy, if
well tolerated, the lenalidomide dose may
be increased to 15 mg daily, at the
discretion of the investigator.
- The start of each cycle may occur ±3 days
of the scheduled day to accommodate the
schedule of the site or patient. Day 1 of
subsequent cycles should be adjusted
accordingly to maintain the intended cycle
duration. Any delays ≥4 days of the
scheduled day will need to be discussed
with the sponsor.

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PROCEDURE
STUDY PHASES/VISITS a
SCREENING
MAINTENANCE
(CYCLES 1 –36)
EOT
FOLLOW-UP (FROM THE DATE
OF LAST STUDY TREATMENT
UNTIL THE END OF STUDY) 
NOTES
next
column)
myeloma will have samples tested for IgE or
IgD.
Note that screening SPEP, UPEP, serum IFE,
and urine IFE must be done within 21 days
before randomization.
For patients with light chain multiple
myeloma, both serum and urine
immunofixation tests will be performed at D1
of every 3rd cycle (ie, every 3 months) during
the first year, followed by every 6th cycle (ie,
every 6 months) during Year 2 and Year 3.
Serum QIg (IgG,
IgA, IgM, IgD, 
and IgE)
X 
X 
-
Serum IFE
X* (see 
Note in 
next 
column) 
D1 of every 3rd cycle (ie,
every 3 months) beginning
with C1D1, during the
first Year (ie, C1D1,
C3D1, C6D1, C9D1,
C12D1), followed by
every 6th cycle (ie, C18D1,
C24D1, C30D1, C36D1)
during Year 2 and Year 3
and whenever CR or sCR
is suspected or
maintained. 
Note: SPEP, UPEP, serum
IFE, and urine IFE assays
must be done during
screening (21 days before
C1D1) as well as on
C1D1.
X 
-
Urine IFE
X* (see 
Note in 
next
column) 
X 
-
Serum FLC assay  
X 
D1 of every 3rd cycle,
beginning with C1D1 (ie,
C1D1, C3D1, C6D1,
C9D1, C12D1, C15D1,
C18D1, C21D1, C24D1, 
C27D1, C30D1, C33D1,
C36D1) and whenever CR
or sCR is suspected or
maintained
X 
-

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PROCEDURE
STUDY PHASES/VISITS a
SCREENING
MAINTENANCE
(CYCLES 1 –36)
EOT
FOLLOW-UP (FROM THE DATE
OF LAST STUDY TREATMENT
UNTIL THE END OF STUDY) 
NOTES
C13D1, C19D1, C25D1
and at the EOT visit)
other assessments, only bone marrow
aspirates are required.
PC clonality and morphology assessments to
be conducted at the central laboratory.
Bone marrow aspirate collected within ±30
days of the scheduled visit during the
maintenance phase is acceptable.
If a bone marrow biopsy was conducted up to
30 days prior to the start of screening AND a
positive MRD result based on Adaptive
Biotechnologies’ NGS-based MRD assay is
available, a repeat biopsy during screening is
not required. In this situation, local PC
clonality and morphology may be used.

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PROCEDURE
STUDY PHASES/VISITS a
SCREENING
MAINTENANCE
(CYCLES 1 –36)
EOT
FOLLOW-UP (FROM THE DATE
OF LAST STUDY TREATMENT
UNTIL THE END OF STUDY) 
NOTES
Cytogenetics -
FISH aspirate (performed centrally)
X 
- 
- 
-
Central cytogenetics assessment is not
required during screening if local laboratory
assessment included del(17p), t(4;14), and
t(14;16) performed as part of standard of care
at any time from the time of diagnosis of
multiple myeloma to randomization.
Central FISH testing to include del(1p), gain
of 1q, del(17p), t(11;14), t(4;14), t(14;16), and
t(14;20).
Any existing cytogenetics results from the local
laboratory, if available, should be entered in the
eCRF. Note: Stratification will be based on central
laboratory results or local laboratory results, if
available. For stratification purposes, if central
cytogenetic results are not available (ie, due to
technical reasons), or if central cytogenetic testing was
not conducted due to availability of local cytogenetic
results, then local cytogenetics may be used with the
approval of the medical monitor. If central and local
cytogenetic results are unavailable, the patient will be
stratified with patients with standard cytogenetics.

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MRD (aspirate) by NGS  
X (NGS)
At the end of 12, 18, 24,
and 36 months (NGS), (ie,
C13D1, C19D1, C25D1
and at the EOT visit)
X 
-
During Screening:
NGS assay (Adaptive Biotechnologies’
NGS-based MRD assay) to be done on bone
marrow aspirate collected during screening to
determine eligibility for study entry. Residual
samples, if available, will also be banked for
future tests.
Two sequential NGS assays will be done
during screening. The first NGS assay will be
conducted on archived bone marrow samples
for calibration and identification of the index
myeloma clone. Obtain archived bone
marrow samples as described in Inclusion
Criterion #4. If an existing result on index
myeloma clone is available from Adaptive
Biotechnologies’ NGS-based MRD assay,
conducted as part of institutional procedures,
then archived bone marrow sample is not
required as long as Adaptive Biotechnologies
is able to retrieve historical results on the
index myeloma clone from the clinical
database. Following index clone calibration
(or verification of existing index clone results
from a previously conducted Adaptive
Biotechnologies’ NGS-based MRD assay),
MRD will be assessed by NGS (Adaptive
Biotechnologies’ NGS-based MRD assay),
using fresh bone marrow aspirate sample
collected during screening.
Note: If Adaptive Biotechnologies’ NGS-
based MRD assaywas conducted post-ASCT
as part of institutional procedures and MRD
results are available at screening, these
results are to be recorded in the eCRF.
Patients who are MRD positive at 10-5 based
on an existing post-ASCT NGS assay
conducted by Adaptive Biotechnologies, are
eligible to participate. Such patients will not
be required to undergo NGS based MRD
assessment again during screening.
After the start of study treatment (after
C1D1):

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PROCEDURE
STUDY PHASES/VISITS a
SCREENING
MAINTENANCE
(CYCLES 1 –36)
EOT
FOLLOW-UP (FROM THE DATE
OF LAST STUDY TREATMENT
UNTIL THE END OF STUDY) 
NOTES
Concomitant medications
concomitant therapies that occur within 30 days
(± 7 days) after the last dose of study
treatment(s).
See Section 8and Section 11.1 for detailed
instructions regarding concomitant medication
use and reporting adverse events, respectively.
Key: 
β-hCG = beta hormone human chorionic gonadotropin; ALT = alanine aminotransferase; antiHBc = antibody to hepatitis B core antigen; antiHBs = antibody to hepatitis B surface
antigen; ASCT = autologous stem cell transplant; AST = aspartate aminotransferase; BUN = blood urea nitrogen; C = cycle (cycle number); COPD = chronic obstructive pulmonary
disease; CR = complete response; CT = computed tomography; D = day (day number of cycle); ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF =
electronic case report form; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30; EORTC QLQ-MY20 = European
Organization for Research and Treatment of Cancer Quality of Life Questionnaire- Multiple Myeloma Module EOT = end of treatment; EQ-5D-5L = EuroQoL Group-5D-5-level
scale (questionnaire); FEV1 = forced expiratory volume (in 1 second); FISH = fluorescence in situ hybridization; FLC = free light chain; HBV = hepatitis B virus; HBsAg = hepatitis
B surface antigen; HCV = hepatitis C virus; Hgb = hemoglobin; IFE = immunofixation electrophoresis; Ig = immunoglobulin; IMWG = International Myeloma Working Group;
LDH = lactic acid dehydrogenase; M-protein = myeloma protein; MRD = minimal residual disease; NGS = next generation sequencing; PC = plasma cell; PCR = polymerase chain
reaction; PD = progressive disease; PRO = patient-reported outcome; RBC = red blood cell (count); SC = subcutaneous; SPEP = serum M-protein quantitation by electrophoresis;
UPEP = urine M-protein quantitation by electrophoresis; VGPR = very good partial response; WBC = white blood cell (count). Note:
*Local and central laboratory tests should be conducted within 3 days of Day 1 of each lenalidomide cycle (control arm) OR within 3 days of each daratumumab administration.
**Urine sample collected and refrigerated up to 3 days prior to visit are acceptable for disease evaluation.

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TIME AND EVENTS SCHEDULE –PART 2: DETAILS FOR BONE MARROW TESTING
Test to Perform  
Lab
During Screening:
Collect bone marrow aspirate and/or Biopsy
During the Maintenance Phase (Cycles 1 to 36):
In addition, aspirate will be requested at time
of PD if feasible.
PC clonality assay: Flow
cytometry
Central
PC clonality assay and morphology to be conducted during screening
At the end of12, 24, and 36 months, (ie, C13D1, C25D1 and
EOT visit). Bone marrow aspirate collected within ±30 days of
the scheduled visit during the maintenance phase is acceptable.
Morphology (aspirate
and/or biopsy)
Cytogenetics
FISH aspirate to include
del(1p), gain of 1q, del(17p),
t(4;14), t(11;14), t(14;16),
and t(14;20)
Central
Central cytogenetics assessment is not required during screening if local
laboratory assessment included del(17p), t(4;14) and t(14;16) performed as
part of standard of care at any time from the time of diagnosis of multiple
myeloma to randomization.
Central FISH testing to include del(1p), gain of 1q, del(17p), t(11;14), t(4;14),
t(14;16), and t(14;20).
Any existing cytogenetics results from the local laboratory, if available, should
be entered in the eCRF. Note: Stratification will be based on central
laboratory results or local laboratory results, if available. For stratification
purposes, if central cytogenetic results are not available (ie, due to
technical reasons), or if central cytogenetic testing was not conducted due
to availability of local cytogenetic results, then local cytogenetics may be
used with the approval of the medical monitor. If central and local
cytogenetic results are not available, the patient will be assumed to have
normal cytogenetics.
Cytogenetics not required
MRD (aspirate) by NGS  
Central
MRD by (Adaptive Biotechnologies’ NGS-based MRD assay)on bone marrow
aspirate obtained during screening.
Note that archived samples collected prior to induction therapy or prior to
transplant will also be obtained as described in Inclusion Criterion #4 for
calibration of MRD by NGS. If an existing result on index myeloma clone is
available from Adaptive Biotechnologies’ NGS-based MRD assay, conducted as
part of institutional procedures, then archived bone marrow sample is not
required as long as Adaptive Biotechnologies is able to retrieve historical results
on the index myeloma clone from the clinical database. 
In addition, if Adaptive Biotechnologies’ NGS-based MRD assaywas conducted
post ASCT as part of institutional procedures and MRD results are available at
screening, then this information is to be recorded in the eCRF. Patients who are
MRD positive at 10-5 based on an existing post-ASCT NGS assay conducted by
Adaptive Biotechnologies, are eligible to participate. Such patients will not be
required to undergo NGS based MRD assessment again during screening.
Bone marrow aspirate collected within ±30 days of the
scheduled visit during the maintenance phase is acceptable.
MRD by NGS to be conducted at the end of 12, 18, 24, and
36 months (NGS), (ie., C13D1, C19D1, C25D1 and EOT visit)
Key: 
ASCT = autologous stem cell transplant; C = cycle (cycle number); CR = complete response; D = day (day number of cycle); eCRF  = electronic case report form; FISH =
fluorescence in situ hybridization; Lab = laboratory; MRD = minimal residual disease; NGS = next generation sequencing; PC = plasma cell; PD = progressive disease; sCR =
stringent complete response; VGPR = very good partial response.

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ABBREVIATIONS
ADCC  
antibody-dependent cell-mediated cytotoxicity
AE 
adverse event
antiHBc 
antibody to hepatitis B core antigen
antiHBs 
antibody to hepatitis B surface antigen
ASCT  
autologous stem cell transplantation
C 
Cycle
CI 
confidence interval
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration
COPD  
chronic obstructive pulmonary disease
CR  
complete response
CrCl 
creatinine clearance
CSR  
Clinical Study Report
CT  
computed tomography
D(s) 
Day(s)
ECG 
electrocardiogram
ECOG  
Eastern Cooperative Oncology Group
eCRF  
electronic case report form
eDC  
electronic data capture
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of Life
Questionnaires-C30
EORTC QLQ-MY20 
European Organization for Research and Treatment of Cancer Quality of Life
Questionnaires-Multiple Myeloma Module
EQ-5D-5L 
European Quality of Life Five Dimensions Questionnaire-5-level
EOT  
end oftreatment
FEV1 
forced expiratory volume in 1 second
FLC  
free light chain
GCP  
Good Clinical Practice
HBsAg 
hepatitis B surface antigen
HBV  
hepatitis B virus
HCV  
hepatitis C virus
HDT  
high-dose therapy
HR  
hazard ratio
HRQoL 
health-related quality of life
IAT  
indirect antiglobulin test (also known as indirect Coombs test)
IB  
investigator’s brochure
ICF  
informed consent form
ICH  
International Conference on Harmonisation
ICMJE  
International Committee of Medical Journal Editors
IFE 
immunofixation electrophoresis
IMWG  
International Myeloma Working Group
IRB  
Institutional Review Board
IRR  
injection-related reactions
ISR  
injection-site reactions
IV  
intravenous(ly)
IWRS  
interactive web response system
LMWH  
low molecular weight heparin
mAb  
monoclonal antibody
MFC  
multiparametric flow cytometry
M-protein  
myeloma protein
MDRD  
Modification of Diet in Renal Disease
MRD  
minimal residual disease
MRI 
magnetic resonance imaging
NCI-CTCAE  
National Cancer Institute-Common Terminology Criteria for Adverse Events
NGF  
next generation flow
NGS  
next generation sequencing

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OS  
overall survival
PCR  
polymerase chain reaction
PD 
progressive disease
PFS  
progression-free survival
PO 
per os (by mouth; orally)
PQC  
product quality complaint
PR 
partial response
PRO  
patient-reported outcome
RBC  
red blood cell
REMS  
risk evaluation and mitigation strategy
rHuPH20 
recombinant human hyaluronidase
SAC  
Safety Assessment Committee
SAP  
Statistical Analysis Plan
SC 
subcutaneous(ly)
sCR  
stringent complete response
SIPPM  
Site Investigational Product Procedures Manual
SPE  
serum protein electrophoresis
SUSAR  
suspected unexpected serious adverse reactions
ULN  
upper limit of normal
VGPR  
very good partial response
VTE  
venous thromboembolism

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1. 
INTRODUCTION
Despite advances in treatment, multiple myeloma remains a challenging disease to cure. The
addition of the anti-CD38 monoclonal antibody  (mAb), daratumumab, to standard of care
regimens has been associated with a 44% to 68% significant reduction in the risk of death or
progression in multiple myeloma compared with standard of care, as observed in 5 randomized
controlled studies: the POLLUX and CASTOR Phase 3 clinical studies in relapsed or refractory
myeloma and the ALCYONE, CASSIOPEIA16,29, and MAIA Phase 3 clinical studies in newly
diagnosed myeloma. Recently, daratumumab was approved in combination with bortezomib,
melphalan, and dexamethasone for frontline treatment of newly diagnosed multiple myeloma
patients who are ineligible for transplant. Maintaining remission and improving the duration of
response after successful induction, high-dose therapy (HDT) followed by autologous stem cell
transplant (ASCT) and consolidation therapy are important goals in treating patients with newly
diagnosed multiple myeloma.1
Despite these treatment modalities, most multiple myeloma patients relapse after ASCT.
Conventional means of assessing response (ie, measurement of serum and urine M-proteins) are
not sufficiently sensitive to measure low-levels of residual bone marrow disease or minimal
residual disease (MRD), and the attainment of MRD negativity (ie, MRD is not detectable by
highly sensitive next generation flow [NGF] cytometry of sequencing) is associated with improved
long-term outcomes. Therefore, achievement of MRD negativity is evolving as an important
clinical efficacy endpoint in multiple myeloma, particularly in the maintenance setting following
frontline ASCT.
The addition of daratumumab to bortezomib and dexamethasone or lenalidomide and
dexamethasone in the CASTOR and POLLUX studies, respectively, tripled the MRD negative rate
in patients with relapsed multiple myeloma, and patients who attained MRD negativity had
significantly longer progression-free survival (PFS) than patients who remained positive.
Similarly, addition of daratumumab to standard of care regimens in newly diagnosed transplant
ineligible myeloma patients tripled the MRD negative rate and significantly improved PFS in the
ALCYONE, CASSIOPEIA, and MAIA Phase 3 clinical studies. In the CASSIOPEIA study16,29, a
higher rate of MRD negativity was observed in newly diagnosed transplant eligible patients treated
with daratumumab based regimen versus standard of care treatment (64% vs. 44%, p<0.0001).
Maintenance therapy with lenalidomide is standard of care following frontline ASCT for multiple
myeloma. However, lenalidomide alone may not be sufficient to convert MRD positive patients
post-transplant to MRD negativity, as it is expected that most patients would have previously been
treated with lenalidomide as part of induction therapy. Attainment of MRD negativity following
ASCT and maintenance therapy has been shown to improve long-term outcomes.21,29 Therefore,
to improve the likelihood of converting patients to MRD negativity, addition of SC daratumumab
to lenalidomide maintenance treatment will be evaluated in Study MMY3021. We expect that the
benefits of addition of SC daratumumab to lenalidomide, as maintenance treatment, will outweigh
the risks, even among patients who may achieve a complete response (CR) or better after
transplant. Prolonged administration of daratumumab in conjunction with lenalidomide does not
result in an increased total risk of adverse event (AEs). In the MAIA study of IV daratumumab
and Rd versus Rd alone in newly diagnosed patients with myeloma, the incidence of serious

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treatment-emergent adverse events (TEAEs) was similar in both treatment groups (62.9% in the
DRd group and 62.7% in the Rd group). Of the most frequently reported (>10%) Grade 3 or 4
adverse events, higher rates of neutropenia (DRd: 50.0%; Rd: 35.3%), lymphopenia (DRd: 15.1%;
Rd: 10.7%), leukopenia (DRd: 11.0%; Rd: 4.9%), and pneumonia (DRd: 13.7%; Rd: 7.9%) were
observed in the DRd group, while Grade 3 or 4 anemia occurred more frequently in the Rd group
(DRd: 11.8%; Rd: 19.7%). Although Grade 4 TEAEs were reported in a higher percentage of
patients in the DRd group compared with the Rd group, fewer patients in the DRd group (7.1%)
discontinued study treatment due to a TEAE compared with the Rd group (15.9%); however, the
percentage of patients discontinuing lenalidomide was similar in both arms.
The current study is being conducted to evaluate the MRD negativity conversion rate following
the addition of daratumumab (compound number JNJ-54767414) to lenalidomide, when
administered as maintenance treatment to patients with newly diagnosed multiple myeloma who
have received a minimum of 4 cycles of induction therapy, have undergone HDT and ASCT within
12 months of the start of induction, are MRD positive at the time of screening, and have never
been treated with an anti-CD38 antibody (ie, are anti-CD38 naïve). Further details on the overall
rationale for the study, study design, assessments chosen for evaluation, and the potential risks and
benefits are described in Section 3.2.
Throughout the protocol, the term “study treatment” refers to the treatments being administered
for multiple myeloma and the term "sponsor" refers to the entities listed in the Contact Information
page(s), which will be provided as a separate document.
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1. 
Objectivesand Endpoints
The objectives and endpoints of this study are shown in Table 1.

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2.2. 
Hypothesis
The addition of daratumumab to lenalidomide maintenance treatment in  anti-CD38 treatment
naïve, newly diagnosed multiple myeloma patients who are MRD positive following HDT and
ASCT will improve the conversion rate to MRD negativity.
3. 
STUDY DESIGN AND RATIONALE
3.1. 
Overview of Study Design
This is a Phase 3, randomized, open-label, active-controlled, multicenter study to be conducted at
sites in the United States (US) and Canada to primarily evaluate the MRD conversion rate
following 12 months of maintenance treatment with SC daratumumab in combination with
lenalidomide relative to lenalidomide alone in patients with newly diagnosed multiple myeloma
who have received a minimum of 4 cycles of induction therapy, have undergone HDT and ASCT
within 12 months of the start of induction, are within 6 months of the ASCT date at the time of
randomization, are MRD positive at the time of screening, and are anti-CD38 treatment naïve.
The study includes a Screening Period; a Maintenance Phase comprised of thirty-six, 28-day
cycles; an End of Treatment (EOT) Visit; and a Follow-up Phase as described in the Time and
Events Schedule –Part 1 (see footnote a).
Planned enrollment includes a total of 214 patients to be randomly allocated in a 1:1 ratio to 1 of
2 treatment arms, with randomization stratified by cytogenetic risk (high versus
standard/unknown).
For inclusion in the study, a patient must:
1. Be 18 to 79 years of age,
2. Have newly diagnosed multiple myeloma, with a history ofa minimum of4 cycles of induction
therapy, have received HDT and ASCT within 12 months of the start of induction therapy, and
are within 6 months of ASCT on the date of randomization,
3. Have a very good partial response (VGPR) or better assessed per International Myeloma
Working Group (IMWG) 2016 criteria at the time of randomization,
4. Have archived bone marrow samples collected before induction treatment (ie, at diagnosis) or
before transplant (eg, at the end of induction) or have existing results on the index MM clone
based on Adaptive Biotechnologies’ next generation sequencing (NGS)-based MRD assay.
Archived bone marrow samples will be used for calibration of myeloma clonal cells to
facilitate assessment of the primary endpoint by NGS. Any one of the following archived bone
marrow samples are required:
- Greater than 1 mL viable frozen bone marrow aspirated aliquot (preferred), collected
in a ethylenediaminetetraacetic acid tube, and stored at a temperature of −80°C or
- Non-decalcified diagnostic bone marrow aspirate clot sections (block or slides) for
MRD assessment:

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A Formalin fixed paraffin embedded (FFPE) block of bone marrow aspirate
clot, or slides (preferably 5 slides, if available), 5 m each, of non-decalcified
bone marrow, or
Slides (preferably 5 slides, if available), bone marrow aspirate smear.
Please note, bone marrow core sections are not acceptable samples for analysis.
In exceptional circumstances when index myeloma clone cannot be identified
from the archived bone marrow sample, a post-transplant sample can be used to
identify myeloma clone with permission from the Sponsor.
- If an existing result on index myeloma clone is available from  Adaptive
Biotechnologies’ NGS-based MRD assay, conducted as part of institutional procedures,
then archived bone marrow sample is not required as long as Adaptive Biotechnologies
is able to retrieve historical results on the index myeloma clone from the clinical
database.
5. Have residual disease as defined by detectable MRD by NGS (Adaptive Biotechnologies’
NGS-based MRD assay) at the time of screening. If this assay was conducted post ASCT as
part of institutional procedures and MRD results are available during screening, then patients
who were MRD positive at 10-5 based on the existing NGS test result are also eligible to
participate in the study (such patients will NOT be required to undergo MRD assessment by
NGS again at the time of screening),
6. Be anti-CD38treatment naïve
Refer to Section 4 for a complete list of entry criteria.
The 2 treatment arms comprise of daratumumab in combination with lenalidomide or lenalidomide
alone as follows (each treatment cycle will be 28 days for a maximum duration of 36 cycles):
1. Daratumumab 1800 mg administered by subcutaneous (SC) injection:
- Weekly during Cycle (C)1 and C2,
- Every 2 weeks during C3 to C6, and
- Every 4 weeks from C7 onwards until confirmed progressive disease (PD),
unacceptable toxicity, or until end of study treatment
2. Lenalidomide 10 mg PO:
- Days (D)1 to 28 (continuously) of each 28-day cycle until confirmed PD, unacceptable
toxicity, or until end of study treatment. If a patient experiences toxicity to
lenalidomide, dose and/or schedule may be modified per institutional standard.
- After 3 cycles of maintenance therapy, if well tolerated, the lenalidomide dose may be
increased to 15 mg daily, at the discretion of the investigator.
Study assessments include the following:
Standard baseline screening evaluations for this patient population, including assessment of
MRD status by NGS assay (Adaptive Biotechnologies’ NGS-based MRD assay), and
treatments to be administered.
Calibration by NGS on archived bone marrow sample collected before induction treatment.

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Disease evaluations including MRD by NGS at the end of 12, 18, 24, and 36 months after the
start of study treatment(s) (ie, after C1D1), myeloma proteins (M-proteins), bone marrow
examinations, skeletal surveys, and extramedullary soft tissue plasmacytomas. Disease status
will be assessed in accordance with IMWG 2016 response criteria.
Patient-reported Outcomes (PROs), including the European Organization for Research and
Treatment of Cancer Quality of Life Questionnaires-C30 (EORTC QLQ-C30), European
Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Multiple
Myeloma Module (EORTC QLQ-MY20), and European Quality of Life Five Dimensions
Questionnaire-5-level (EQ-5D-5L).
Safety/tolerability evaluated by AEs, clinical laboratory evaluations, vital signs, and Eastern
Cooperative Oncology Group (ECOG) performance status.
In addition, patients will be followed for onset of other malignancy, next-line therapy, including
date of PD on next-line therapy, and survival. Refer to the Time and Events Schedule –Part 1 for
full details on study assessments to be performed.
The end of the study is defined as 36 months from the date of randomization of last patient. If a
patient has died, the date and cause of death will be collected and documented in the electronic
case report form (eCRF). A diagram of the study design is provided in Figure 1. An Independent
Data Monitoring Committee will be commissioned for this study. Refer to Section 11.7 for details.

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According to data from the National Cancer Institute, Surveillance, Epidemiology, and End
Results Program in 2018, multiple myeloma accounted for 1.8% of all new cancer cases and 2.1%
of all cancer deaths. In addition, there were approximately 30,770 new cases of multiple myeloma
with approximately 12,770 deaths due to this disease in 2018. Based on data from 2008 to 2014,
the 5-year survival rate is 50.7%.
Treatment choices for multiple myeloma have advanced in recent years and vary with age,
performance status, comorbidity, aggressiveness of the disease, and related prognostic factors. The
standard treatment approach for newly diagnosed patients who are considered eligible for HDT
includes multiple phases of therapy: induction, HDT  and ASCT, and consolidation and
maintenance.
The current standard of care in the maintenance setting includes treatment with lenalidomide after
ASCT, based on randomized Phase 3 studies showing improvement in clinical outcomes with the
use of maintenance therapy1,27 (see also the lenalidomide package insert). As of 2018, according
to the National Cancer Comprehensive Network (NCCN), continuous treatment with lenalidomide
is the preferred choice for maintenance treatment of multiple myeloma.18 For the most
comprehensive nonclinical and clinical information on lenalidomide refer to the most current
package insert.
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.17 Direct tumor effect is described both as growth
inhibition of myeloma cell lines and induction of apoptosis. The microenvironment support is
affected by downregulation of cell adhesion molecules (eg, intercellular adhesion molecule), thus
inhibiting stromal cell interaction with tumor cells, and inhibition of growth factors (eg, insulin
growth factor 1 and vascular endothelial growth factor) induced by myeloma cell adhesion.
Finally, 
lenalidomide 
exhibits 
immunomodulatory 
activity 
including 
inhibition 
of
proinflammatory signaling molecules (cytokines) such as TNF  , IL-1 , and IL-6, the latter of
which is a known growth factor for myeloma cells.43
Importantly, it has also been shown that lenalidomide causes upregulation of natural killer cells in
myeloma17 and enhances the effector cells of antibody-dependent cell-mediated cytotoxicity
(ADCC), a known mechanism of action of daratumumab as demonstrated in preclinical
studies.41,42 This effect has also been demonstrated in patients during or just after lenalidomide
treatment where peripheral blood mononuclear cells isolated from patients showed a significantly
increased capacity to mediate daratumumab-dependent ADCC against multiple myeloma cells
alone.44 Additionally, the upregulation of CD38 by pomalidomide or lenalidomide can enhance
the activity of anti-CD38 antibodies including daratumumab.5
Despite these treatment modalities, most multiple myeloma patients relapse after ASCT. However,
improved depth of response, as measured by eradication of MRD, has been observed in multiple
myeloma patients treated with a daratumumab-based combination therapy. For example, the
addition of daratumumab to standard of care regimens has been associated with a 44% to 68%
significant reduction in the risk of death or progression in multiple myeloma compared with

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standard of care, as observed in 5 randomized controlled studies: the POLLUX and CASTOR
Phase 3 clinical studies in relapsed or refractory myeloma and, the ALCYONE, CASSIOPEIA16,29,
and MAIA Phase 3 clinical studies in newly diagnosed myeloma. The addition of daratumumab to
bortezomib and dexamethasone or lenalidomide and dexamethasone in the CASTOR and
POLLUX studies, respectively, tripled the MRD negative rate in patients with relapsed multiple
myeloma, compared with the control arm. In addition, patients who attained MRD negativity had
significantly longer PFS than patients who remained MRD positive.4,26 Similarly, addition of
daratumumab to standard of care regimens in newly diagnosed transplant ineligible myeloma
patients tripled the MRD negative rate in the ALCYONE, CASSIOPEIA16,29, and MAIA Phase 3
clinical studies. Maintenance therapy with lenalidomide is standard of care following frontline
ASCT for multiple myeloma. However, lenalidomide alone may not be sufficient to convert MRD
positive patients post-transplant to MRD negativity, as it is expected that most patients would have
previously been treated with  lenalidomide as part of induction therapy. Attainment of MRD
negativity following ASCT and maintenance therapy has been shown to improve long-term
outcomes.21,29 Therefore, to improve the likelihood of converting patients to MRD negativity,
addition of SC daratumumab  to lenalidomide maintenance treatment will be evaluated in
Study MMY3021. We expect that the benefits of addition of SC daratumumab to lenalidomide, as
maintenance treatment, will outweigh the risks, even among patients who may achieve a CR or
better after transplant. Prolonged administration of daratumumab in conjunction with lenalidomide
does not result in an increased total risk of AEs. In the MAIA study of IV daratumumab and Rd
versus Rd alone in newly diagnosed patients with myeloma, the incidence of serious TEAEs was
similar in both treatment groups (62.9% in the DRd group and 62.7% in the Rd group). Of the
most frequently reported (>10%) Grade 3 or 4 adverse events, higher rates of neutropenia (DRd:
50.0%; Rd: 35.3%), lymphopenia (DRd: 15.1%; Rd: 10.7%), leukopenia (DRd: 11.0%; Rd: 4.9%)
and pneumonia (DRd: 13.7%; Rd: 7.9%) were observed in the DRd group, while Grade 3 or 4
anemia occurred more frequently in the Rd group (DRd: 11.8%; Rd: 19.7%). Although Grade 4
TEAEs were reported in a higher percentage of patients in the DRd group compared with the Rd
group, fewer patients in the DRd group (7.1%) discontinued study treatment due to a TEAE
compared with the Rd group (15.9%); however, the percentage of patients discontinuing
lenalidomide was similar in both arms.
The current study is being conducted to evaluate the MRD negativity rate following the addition
of daratumumab to lenalidomide, when administered as maintenance treatment to patients with
newly diagnosed multiple myeloma who have received a minimum of 4  cycles of induction
therapy, have undergone HDT and ASCT within 12 months of the start of induction therapy, are
within 6 months of ASCT on the date of randomization, are MRD positive at the time ofscreening,
and have never been treated with an anti-CD38 antibody (ie, are anti-CD38 naïve).
3.2.2. 
Daratumumab
Daratumumab (JNJ-54767414) is a human immunoglobulin G1 kappa (IgG1κ) mAb that binds
with high affinity to a unique epitope on CD38. It is a targeted immunotherapy that attacks tumor
cells that overexpress CD38, a transmembrane glycoprotein, in a variety of hematological
malignancies including multiple myeloma. Daratumumab induces lysis of CD38-expressing tumor
cells, including multiple myeloma tumor cells that were freshly isolated from patients, by a wide

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spectrum of mechanisms including complement-dependent cytotoxicity, ADCC, and antibody-
dependent cellular phagocytosis, through activation of complement proteins, natural killer cells,
and macrophages, respectively.12,35 Furthermore, daratumumab has immunomodulatory
properties, including inhibition of CD38 positive T regulatory cells and myeloid-derived
suppressor cells and stimulation of helper and cytotoxic T cells.
3.2.2.1. 
Intravenous Daratumumab Administration
In the European Union (EU), daratumumab, administered as a 16 mg/kg intravenous (IV) infusion,
is approved for the following indications:
As monotherapy for the treatment of adult patients with relapsed and refractory multiple
myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory
agent and who have demonstrated disease progression on the last therapy.
In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for
the treatment of adult patients with multiple myeloma who have received at least one prior
therapy.
In combination with lenalidomide and dexamethasone or with bortezomib, melphalan, and
prednisone for the treatment of patients with newly diagnosed multiple myeloma who are
ineligible for ASCT.
In the US, daratumumab, administered as a 16 mg/kg IV infusion, is approved for the following
indications:
As monotherapy for the treatment of patients with multiple myeloma who have received at
least 3 prior lines of therapy. including a proteasome inhibitor and an immunomodulatory
agent or who are double refractory to a proteasome inhibitor and an immunomodulatory agent.
In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for
the treatment of patients with multiple myeloma who have received at least one prior therapy.
In combination with lenalidomide and dexamethasone in newly diagnosed patients who are
ineligible for ASCT and in patients with relapsed or refractory multiple myeloma who have
received at least one prior therapy.
In combination with pomalidomide and dexamethasone for the treatment of patients with
multiple myeloma who have received at least 2 prior therapies, including lenalidomide and a
proteasome inhibitor.
In combination with bortezomib, melphalan, and prednisone for the treatment of patients with
newly diagnosed multiple myeloma who are ineligible for ASCT.
In combination with bortezomib, thalidomide and dexamethasone for adult patients with
newly diagnosed multiple myeloma who can receive an ASCT.
Daratumumab administered as an IV infusion has been generally well tolerated. The most common
side effect has been infusion-related reactions, with approximately half of patients receiving a
daratumumab IV infusion-based regimen experiencing one or more of these events. Most
infusion-related reactions (>90%) have occurred during the first infusion. Due to the risk of these
reactions, the IV infusion requires a large volume (500 mL to 1000 mL), and the median infusion

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time for the first infusion is 7 hours (up to 23.5 hours); subsequent infusions are approximately
3 to 4 hours.
3.2.2.2. 
Rationale for Subcutaneous Daratumumab Administration
To mitigate the risk of infusion-related reactions as well as the long infusion time that frequently
requires hospitalization with IV infusions of daratumumab, the sponsor has developed a new
formulation of daratumumab for SC administration.
Daratumumab for SC administration is a co-formulated product of daratumumab and recombinant
human hyaluronidase (rHuPH20). The rHuPH20 cleaves the repeating disaccharide subunits
(N-acetyl-D-glucosamine and D-glucuronic acid) of hyaluronan, a polymeric, gel-like
glycosaminoglycan (mucopolysaccharide) that are present in the SC tissue matrix. The HuPH20
acts locally and transiently within the SC space to increase the tissue dispersion and absorption of
other injected drugs and fluids.
The SC route of administration for daratumumab was first evaluated by the sponsor in
Study MMY1004 (PAVO), a Phase 1b, open-label, multicenter, 2-part dose escalation study in
patients with relapsed or refractory multiple myeloma. In this ongoing study, SC daratumumab is
being administered according to the approved monotherapy  schedule (ie, weekly for 8 weeks,
every 2 weeks for an additional 16 weeks, and every 4 weeks thereafter until PD or unacceptable
toxicity). The PAVO study assessed the safety, pharmacokinetics, and efficacy of
SC administration of daratumumab plus rHuPH20 (DARA-PH20). After a median follow-up of
6.5 months (clinical cutoff date of 13 Dec 2017), 25 patients received at least 1 dose of 1800 mg
SC daratumumab in Study MMY1004.9 The injection-related reaction rate was 16% and consisted
of Grade 1 or 2 chills, dyspnea, sneezing, and allergic rhinitis, and two Grade 3 events of
hypertension. None of the injection-related reaction (IRR) events led to treatment discontinuation.
Injection-site reactions (ISRs) occurred in 12% (n=3) of patients, all were Grade 1. The events
were discoloration/injection site induration, hematoma, and erythema. The overall response rate
(ORR) was 52% with 28% VGPRs. Median PFS has not been reached. The efficacy and adverse
event profile are consistent with that of IV daratumumab with a lower rate of injection-related
reactions. Based on these clinical data and supported by the pharmacokinetic profile of Dara-SC,
the safety and efficacy of Dara-SC appear equivalent to and may be better than Dara-IV. Together
these findings suggest that co-formulated SC daratumumab 1800 mg plus rHuPH20 is well
tolerated and achieves response rates similar to those observed with daratumumab administered
by IV infusion. In addition, the daratumumab SC administration has an added benefit of shorter
administration time (3 to 5 minutes for SC daratumumab injection versus a median duration of
7 hours when administered by IV infusion).
Following results observed in PAVO study, 6 studies are ongoing that utilize SC administration of
daratumumab, including COLUMBA, AQUILA, APOLLO, PERSEUS, CEPHEUS, and
ANDROMEDA.
In the randomized Phase 3 COLUMBA study of SC versus IV daratumumab, the infusion-related
reaction rate was significantly lower with SC daratumumab compared with IV daratumumab
(12.7% vs. 34.5%). Furthermore, SC daratumumab was associated with only a 1.5% incidence of

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Grade 3 infusion reactions. The safety profile (Grade ≥3 AEs other than infusion reactions, AEs
leading to treatment discontinuation) was similar between SC and IV daratumumab. In addition,
IRRs (erythema, induration) occurred in 6.9% of patients and these were all Grade 1-2 and fully
reversible.24
For the most comprehensive nonclinical and clinical information regarding daratumumab, refer to
the latest version of the Investigator's Brochure (IB) and Addenda as well as the most current
product label.
DARZALEX FasproTM  (daratumumab and hyaluronidase-fihj) injection, for subcutaneous use,
received FDA approval on 01 May 2020 to be administered at a dose of 1800 mg of daratumumab
and 30,000 units hyaluronidase per 15 mL (120 mg and 2000 units/mL) solution in a single-dose
vial.
3.2.3. 
Subcutaneous Daratumumab Dosing and rHuPH20 Concentration
Chosen for This Study
The dosed concentration of rHuPH20 in daratumumab in this study will be 2000 U/mL. This is the
same concentration and total amount of rHuPH20 administered in Part 2 of PAVO study and other
ongoing Phase 3 studies using SC administration of daratumumab.
In the proposed study, daratumumab 1800 mg SC will be administered in 28-day cycles using the
standard dosing schedule for daratumumab monotherapy (ie, weekly during Cycles 1 and 2, every
2 weeks during Cycles 3 through 6, and every 4 weeks from Cycle 7 onward for a maximum of
36 cycles) to quickly achieve and maintain effective daratumumab concentrations. Patients will be
randomized in a 1:1 ratio to maintenance therapy with SC daratumumab and lenalidomide or
lenalidomide alone.
3.2.4. 
Minimal Residual Disease Conversion Rate as the Primary Endpoint
Minimal residual disease negativity has been associated with improvement in PFS and overall
survival (OS). In 2 recent meta-analyses, 21,30 the achievement of MRD negativity correlated with
improvement in PFS and OS regardless of transplant eligibility in patients with newly diagnosed
multiple myeloma or treatment regimen. In the meta-analysis by Landgren  et al, 4 studies
consisting of transplant-eligible patients were evaluated; results showed that patients who achieved
MRD negativity (versus those who remained MRD positive) had better PFS (hazard ratio
[HR]=0.35; 95% confidence interval [CI]: 0.27, 0.46; p <0.001). In the meta-analysis by Munshi
et al, 14 studies provided data on the impact of MRD status on PFS (1,273 patients, 660 MRD
negative and 613 MRD positive), and 12 studies provided data on the impact of MRD status on
OS (1,100 patients, 599 MRD negative and 501 MRD positive). Compared with MRD positivity,
MRD negativity was associated with better significantly improved PFS (HR=0.41; 95% CI: 0.36,
0.48; p <0.001) and OS (HR=0.57; 95% CI: 0.46, 0.71; p <0.001) outcomes.
In addition, in a recent pooled analysis,20 the achievement of MRD negativity has been correlated
with improvement in PFS and OS regardless of transplant eligibility or treatment regimen. Three
Spanish studies in newly diagnosed patients with multiple myeloma were pooled and analyzed for
correlation of MRD negativity to PFS and OS. In this report, 609 transplant-eligible patients from

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Studies GEM2000 (n=256) and GEM2005 (n=226) and 127 transplant-ineligible patients from
Study GEM2010 (n=127) were analyzed for MRD at 9 months after study enrollment, regardless
of the treatment regimen. The MRD negative status measured by flow cytometry (10-4 to 10-5) was
strongly associated with prolonged PFS (median: 63 months; p<0.001) compared with patients
with CR (median: 49 months) and OS (median: not reached; p<0.001) compared with patients with
CR (median: 128 months). Importantly, this analysis was independent of prior transplantation, ISS
stage, cytogenetic risk category, or conventional response category. In fact, for patients who had
achieved CR but remained MRD positive, their outcomes were similar to those patients with near
complete response VGPR, and partial response (PR) with median PFS of 27, 27, and 29 months,
respectively; and median OS of 59, 64, and 64 months, respectively.
Among multiple myeloma patients treated with bortezomib, lenalidomide, and dexamethasone
followed by 1 year of lenalidomide maintenance, 48.3% of multiple myeloma patients were
negative for MRD assessed using NGS.3 In a prospective analysis of 50 myeloma patients with at
least a VGPR, who were treated with ASCT or cyclophosphamide-lenalidomide-dexamethasone,
followed by lenalidomide-based maintenance, 19 (38%) patients achieved MRD-negativity
(assessed by flow cytometry after consolidation), including 12 patients in the ASCT group and 7
in the cyclophosphamide-lenalidomide-dexamethasone group. During maintenance, 7 (14%)
additional patients achieved MRD negativity (2 patients in the lenalidomide-prednisone group and
5 patients in the lenalidomide group).34
The addition of daratumumab to standard of care treatment regimens has been found to improve
MRD negativity rates. For example, data from 2 studies (POLLUX and CASTOR) utilizing
daratumumab 
in 
combination 
with 
either 
lenalidomide 
and 
dexamethasone
(MMY3003/POLLUX) or bortezomib (Velcade) and dexamethasone (MMY3004/CASTOR) in
patients with relapsed/refractory multiple myeloma have shown improvement in both the number
of patients achieving MRD negativity as compared to the control arms, as well as improvement in
PFS for patients who achieved MRD negative status.2 Similarly, addition of daratumumab to
standard of care regimens in newly diagnosed transplant ineligible myeloma patients tripled the
MRD negative rate in the ALCYONE25 and MAIA13 Phase 3 clinical studies. In the Phase 3
CASSIOPEIA16,29 study, higher rate of MRD negativity was observed in newly diagnosed
transplant eligible patients treated with daratumumab based regimen versus standard of care
treatment (64% vs. 44%, p<0.0001).
These studies (CASTOR, POLLUX, ALCYONE, and MAIA) utilized NGS, and data shown
below (Figure 2) reflect a sensitivity of 10-5. Furthermore, in the Phase 3 POLLUX study  of
previously treated multiple myeloma patients, addition of daratumumab to lenalidomide and
dexamethasone treatment was associated with >3-fold MRD negativity rate (30% versus 5% at the
10 5 threshold) compared to treatment with lenalidomide and dexamethasone alone.4 In the MAIA
study, 24% of patients in the DRd arm achieved MRD negativity at 10-5, compared with only 7%
of patients in the Rd arm. More importantly, daratumumab treatment was associated with durable
MRD negative response (DRd: 6.0%, Rd: 1.1%). Thus, addition of daratumumab to lenalidomide
significantly improved the depth of response in previously treated multiple myeloma patients.

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Figure 2: 
POLLUX Updated Analysis: Overall Response Rate and Minimal Residual Disease-negative
Rates
Abbreviations: CR = complete response; MRD = minimal residual disease; ORR = overall response rate;
PR = partial response; sCR = stringent complete response; VGPR = very good partial response.
Therefore, the sponsor proposes that the addition of daratumumab to lenalidomide maintenance
treatment in newly diagnosed multiple myeloma patients who are MRD positive post ASCT will
improve the MRD conversion rate by ≥20%.
3.2.5. 
MRD Assessment Using NGS
The most commonly used sensitive methods to monitor MRD include allele-specific
oligonucleotide polymerase chain reaction (PCR) and multiparametric flow cytometry (MFC).38,40
Each method offers distinct advantages and disadvantages. The MFC has been widely applied in
the diagnostic and prognostic evaluations of patients with myeloma and may have value in
response assessment, particularly in the context of patients undergoing ASCT.36,40 The Adaptive
Biotechnologies’ NGS-based assay approved by the Food and Drug Administration (FDA) for
assessment of MRD in acute lymphoblastic leukemia or multiple myeloma, is the most sensitive
validated assay available withthe ability to detect one malignant cell in the background of a million
normal cells.
In this study, MRD will be assessed using Adaptive Biotechnologies’ NGS-based MRD assay for
rapid determination of study participation eligibility during screening. Residual samples collected
during screening will also be banked for future tests. Two sequential NGS assays will be conducted

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during screening. The first NGS assay will be conducted on archived bone marrow sample for
calibration of index myeloma clone. If an existing result on index myeloma clone is available from
Adaptive Biotechnologies’ NGS-based MRD assay, conducted as part of institutional procedures,
then archived bone marrow sample is not required as long as Adaptive Biotechnologies is able to
retrieve historical results on the index myeloma clone from the clinical database. Following index
clone calibration (or verification of existing index clone results from a previously conducted
Adaptive Biotechnologies’ NGS-based MRD assay), MRD will be assessed by NGS (Adaptive
Biotechnologies’ NGS-based MRD assay), using fresh bone marrow aspirate sample collected
during screening. Note that ifpatients had an NGS assay (Adaptive Biotechnologies’ NGS-based
MRD assay) performed post ASCT as part of institutional procedures, then those who tested
positive for MRD at 10-5 based on these results are eligible to participate in the study and such
patients will not be required to undergo MRD assessment by NGS again at the time of screening.
If a bone marrow biopsy was conducted up to 30 days prior to the start of screening AND a positive
MRD result based on Adaptive Biotechnologies’ NGS-based MRD assay is available, a repeat
biopsy during screening is not required. In this situation, local PC clonality and morphology may
be used.
After the start of study treatments (ie, after C1D1), MRD will be assessed by NGS at the end of
12, 18, 24, and 36 months using NGS. The primary endpoint for evaluation is the rate of MRD
conversion at 12 months. During the bone marrow aspirate procedure, the first aspirate sample that
is drawn will be sent to the central laboratory to determine MRD by NGS. All bone marrow
aspirates to be sent to the central laboratory should be at least 3 mL. Additional bone marrow
aspirate samples may be taken and used for local laboratory testing.
Other parameters chosen for evaluation of efficacy  (eg, best response, OS, PFS, time-to-new
treatment, etc.) as well as safety/tolerability measures are standard for these study treatment(s)
and/or oncology studies.
The PRO data directly reported by the patient complements data collected by clinicians and
laboratory findings to describe the patient experience. The PRO data is supportive of the clinical
endpoints and captures inputs required for cost-effectiveness modeling. In addition, the PRO data
provide the patient perspective to communicate the value of treatment to patients, clinicians,
regulators, and payers.
3.2.6. 
Summary of Anticipated Benefits and Risks
The combination of lenalidomide with SC administration of daratumumab is anticipated to have a
positive benefit-risk profile when used for maintenance treatment of patients with newly diagnosed
multiple myeloma who are MRD  positive and anti-CD38 antibody  naïve. Please refer to
Section 3.2.1 for additional information. This assessment is based on the following:
Strategies directed at improving and/or maintaining depth of response are needed to improve
clinical outcomes for patients with newly diagnosed multiple myeloma.

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The addition of daratumumab to the standard of care lenalidomide, which is the current a
standard of care regimen for maintenance treatment in patients with newly diagnosed multiple
myeloma, may improve long-term outcomes through improvement in MRD conversion rate.
Given the potential advantages of SC administration of daratumumab (refer to Section 3.2.2.2
for detailed information), including shorter time of administration, fewer injection-related
reactions, and comparable clinical response rates when  compared with administration of
daratumumab via IV infusion, the SC route of administration will be used in this study.
The assessment of primary endpoint of MRD negativity at 12 months post-maintenance will
be conducted using a sensitive NGS  (sensitivity cutoff of 10-5) assay  (Adaptive
Biotechnologies’ NGS-based MRD assay), thus providing valuable data on the depth of
response achieved with the combination of daratumumab and lenalidomide maintenance
treatment in newly diagnosed multiple myeloma patients.
We expect that the benefits of addition of SC daratumumab to lenalidomide, as maintenance
treatment, will outweigh the risks, even among patients who may achieve a CR or better after
transplant. As discussed in Section 3.2.1, prolonged administration of daratumumab in
conjunction with lenalidomide does not result in an increased total risk of AEs based on data
from ongoing trials.
The potential risks for the study will be mitigated by monitoring via the Independent Data
Monitoring Committee and the sponsor’s medical monitor during the conduct of the study.
In summary, there is a strong rationale for evaluating SC daratumumab in combination with
lenalidomide as maintenance treatment for patients with newly diagnosed multiple myeloma who
are anti-CD38 naïve and MRD positive after frontline ASCT.
4. 
PATIENT POPULATION
Screening for eligible patients will be performed within 60 days before randomization.
The inclusion and exclusion criteria for enrolling patients in this study are described in the
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the
investigator must consult with the appropriate sponsor representative and resolve any issues before
enrolling a patient in the study. Waivers are not allowed.
4.1. 
Inclusion Criteria
Each potential patient must satisfy all of the following criteria to be enrolled in the study. Each
patient:
1. Must be 18 to 79 years of age.
1. Must have newly diagnosed multiple myeloma with a history of a minimum of 4 cycles of
induction therapy, have received HDT and ASCT within 12 months of the start of induction
therapy, and be within 6 months of ASCT on the date of randomization.
2. Must have a VGPR or better response assessed per IMWG 2016 criteria at the time of
randomization.
3. Must have archived bone marrow samples collected before induction treatment (ie, at
diagnosis) or before transplant (eg, at the end of induction) or have existing results on the

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index MM clone based on Adaptive Biotechnologies’ NGS-based MRD assay. Archived bone
marrow samples will be used for calibration of myeloma clonal cells to facilitate assessment
of the primary end point by NGS. If an existing result on index myeloma clone is available
from Adaptive Biotechnologies’ NGS-based MRD assay, as part of institutional procedures,
an archived bone marrow sample is not required as long as Adaptive Biotechnologies is able
to retrieve historical results on the index myeloma clone form the clinical database. Any one
of the following archived samples are required:
a. Greater than  1 mL viable frozen bone marrow aspirated aliquot (preferred)
collected in an EDTA tube, frozen, and stored at a temperature of −80°C, or
b. Non-decalcified diagnostic bone marrow aspirate clot sections (block or slides)
for MRD assessment:
i. 
An FFPE block of bone marrow aspirate clot, or slides (preferably 5, if available),
5 m each, of non-decalcified bone marrow, or
ii. 
Slides (preferably 5, if available), bone marrow aspirate smear,
iii. 
Please note, bone marrow core sections are not acceptable samples for analysis.
iv. 
In exceptional circumstances when index myeloma clone cannot be identified
from the archived bone marrow sample, a post-transplant sample can be used to
identify myeloma clone with permission from the Sponsor.
4. Must have residual disease as defined by detectable MRD (Adaptive Biotechnologies’
NGS-based MRD assay). If this assay  was conducted post ASCT as part of institutional
procedures and MRD results are available during screening, then patients who were MRD
positive at 10-5 based on the existing NGS test result are also eligible to participate in the study
(such patients will NOT be required to undergo MRD assessment by NGS again at the time
of screening).
5. Must have an ECOG performance status score of 0, 1, or 2 (see Section 9.2.1).
6. Must have pretreatment clinical laboratory values meeting the following criteria during
screening (laboratory tests should be repeated if not done within 3 days of C1D1):
Adequate bone marrow function:
a. Hemoglobin ≥7.5 g/dL (≥4.65 mmol/L). Prior red blood cell (RBC) transfusion or
recombinant human erythropoietin use is permitted, however transfusions are not
permitted within 7 days of randomization to achieve this minimum hemoglobin
count.
b. Absolute neutrophil count ≥1.0×109/L. Granulocyte colony stimulating factor use is
permitted.
c. Platelet count 75×109/L for patients in whom <50% of bone marrow nucleated cells
are plasma cells. Otherwise, 50×109/L (transfusions are not permitted within 7 days
of testing to achieve this minimum platelet count).
Adequate liver function:
a. Aspartate aminotransferase ≤2.5 folds of the upper limit of normal (ULN).
b. Alanine aminotransferase ≤2.5 folds of the ULN.

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c. Total bilirubin ≤2.0 folds of the ULN (except in patients with congenital bilirubinemia,
such as Gilbert syndrome, direct bilirubin ≤2.0 folds of the ULN)
Adequate renal function:
a. Estimated creatinine clearance ≥30 mL/min. Creatinine clearance may be calculated
using Cockcroft-Gault, estimated glomerular filtration rate (Modification of Diet in
Renal Disease [MDRD]), or Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) formula; refer to Section 9.2.2.
b. Corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium
≤6.5 mg/dL (≤1.6 mmol/L); refer to Section 9.2.3.
7. If a female:
a. 
Must not be of childbearing potential: defined as premenarchal; postmenopausal
(>45 years of age with amenorrhea for at least 12 months or any age with amenorrhea
for at least 6 months and a serum follicle stimulating hormone level >40 IU/L);
permanently sterilized (eg, bilateral tubal occlusion [which includes tubal ligation
procedures as consistent with local regulations], hysterectomy, bilateral
salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy.
or
b. 
If of childbearing potential:
i. Must commit to either abstain continuously from heterosexual sexual intercourse
or to use 2 methods of reliable birth control simultaneously during the treatment
period.
Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associated
with the study drug.
Methods of reliable birth control include 1 highly effective form of contraception
(tubal ligation, intrauterine device, hormonal [birth control pills, injections,
hormonal patches, vaginal rings, or implants], or partner’s vasectomy) and 1
additional effective contraceptive method (male latex or synthetic condom,
diaphragm, or cervical cap).
Contraception must begin 4 weeks prior to dosing.
Reliable contraception is indicated even where there has been a history of infertility,
unless due to hysterectomy or bilateral oophorectomy.
and
ii. Must have 2 negative serum or urine pregnancy tests during screening, first within
10 to 14 days prior to dosing and the second within 24 hours prior to dosing.
and
iii. Must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for 4 weeks after the last dose of lenalidomide
and for 3 months after the last dose of daratumumab

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8. If a man who is sexually active with a female of childbearing potential:
a. 
Must agree to use a latex or synthetic condom, even if he had a successful vasectomy.
and
b. 
Must agree to not donate sperm during the study and for 4 weeks after the last dose of
lenalidomide and for 3 months after the last dose of daratumumab.
9. Must sign (or have his/her legally acceptable representative sign) an informed consent form
(ICF) indicating that he or she understands the purpose of and procedures required for the
study and is willing to participate in the study.
10. Is able, and agrees, to the prohibitions and restrictions specified in this protocol.
4.2. 
Exclusion Criteria
Any potential patient who meets any of the following criteria will be excluded from participating
in the study. Each patient must not:
1. A history of malignancy (other than multiple myeloma) unless all treatment of that malignancy
was completed at least 2 years before consent and the patient has no evidence of disease before
the date of randomization. Exceptions are squamous and basal cell carcinomas of the skin,
carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the
investigator, with concurrence with the sponsor's medical monitor, is considered cured with
minimal risk of recurrence within 3 years.
2. Must not have progressed on MM therapy at any time prior to screening.
3. Have had prior treatment/therapy with:
a. 
Daratumumab or any other anti-CD38 therapies,
b. 
Focal radiation therapy within 14 days prior to randomization with the exception of
palliative radiotherapy for symptomatic management but not on measurable
extramedullary plasmacytoma. Radiotherapy within 14 days prior to randomization on
measurable extramedullary plasmacytoma is not permitted even in the setting of
palliation for symptomatic management.
c. 
Plasmapheresis within 28 days of randomization.
4. Be exhibiting clinical signs of meningeal or central nervous system involvement due to
multiple myeloma.
5. Have known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume
in 1 second (FEV1) <50% of predicted normal.
Note that FEV1 testing is required for patients with suspected COPD or asthma. Patients with
FEV1 <50% of predicted normal (or for patients ≥65 years of age, old FEV1 <50% or Diffusing
capacity of the lung [DLCO] <50%) on screening assessment must be excluded.

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6. Have known moderate or severe persistent asthma within the past 2 years (see Section 9.2.4),
or current uncontrolled asthma of any classification. Note that patients who currently have
controlled intermittent asthma or controlled mild persistent asthma are allowed in the study,
provided that FEV1 is ≥50% of predicted normal.
7. Have any of the following:
a. Known history of seropositivity for human immunodeficiency virus (HIV).
b. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen
[HBsAg]). Patients with resolved infection (ie, patients who are HBsAg negative but
positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis
B surface antigen [anti-HBs]) must be screened using real-time PCR measurement of
hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.
EXCEPTION: Patients with serologic findings suggestive of HBV vaccination (anti-HBs
positivity as the only serologic marker) AND a known history of prior HBV vaccination,
do not need to be tested for HBV DNA by PCR.
c. Seropositive for hepatitis C (anti- hepatitis C virus [HCV] antibody positive or HCV-RNA
quantitation positive), except in the setting of a sustained virologic response, defined as
aviremia at least 12 weeks after completion of antiviral therapy).
Note, patients who completed treatment for hepatitis C at least 6 months prior to screening and
have no detectable circulating HCV during screening may participate in the study. Such
patients will be required to undergo regular assessments for HCV reactivation during the study
and are to be withdrawn from the study if he/she test positive at any time during the study.
8. Have a concurrent medical or psychiatric condition or disease (eg, active systemic infection,
uncontrolled diabetes, acute diffuse infiltrative pulmonary disease, Waldenström’s
macroglobulinemia, POEMS syndrome [polyneuropathy, organomegaly, endocrinopathy,
monoclonal protein, and/or skin changes], or light chain amyloidosis) that is likely to interfere
with the study procedures or results, or that in the opinion of the investigator, would constitute
a hazard for participating in this study and/or current or history of CNS involvement by the
disease under investigation.
9. Have any of the following:
a. Myocardial infarction within 6 months of randomization, or an unstable or uncontrolled
disease/condition related to or affecting cardiac function (eg, unstable angina, congestive
heart failure, New York Heart Association Class III-IV),
b. Uncontrolled cardiac arrhythmia
10. Have known allergies, hypersensitivity, or intolerance to boron or mannitol, sorbitol,
corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the IB)
or known sensitivity to lenalidomide.

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11. Be known or suspected of not being able to comply with the study protocol (eg, because of
alcoholism, drug dependency, or psychological disorder).
12. Have any condition for which, in the opinion of the investigator, participation would not be in
the best interest of the patient (eg, compromise the well-being) or that could prevent, limit, or
confound the protocol-specified assessments. Patient is taking any prohibited concomitant
therapy per Section 8.3.
13. Be pregnant, or breast-feeding, or planning to become pregnant or breast-feed while enrolled
in this study or within 3 months after the last dose of study treatment(s). Or, if male, planning
to father a child while enrolled in this study or within 3 months after the last dose of study
treatment(s).
14. Have had major surgery within 2 weeks before randomization or will not have fully recovered
from surgery, or has surgery planned during the time the patient is expected to participate in
the study or within 2 weeks after the last dose of study treatment. Note, patients with planned
surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or
vertebroplasty are not considered major surgery.
15. Have received an investigational drug (including investigational vaccines) or used an invasive
investigational medical device within 4 weeks or 5 pharmacokinetic half-lives, whichever is
longer, before randomization or is currently enrolled in an interventional investigational study.
16. Have contraindications to the use of lenalidomide or daratumumab, per local prescribing
information.
17. Have gastrointestinal disease that may significantly alter the absorption of oral drugs.
18. Have received vaccination with live attenuated vaccines within 4 weeks of first study agent
administration
19. Be unable or unwilling to undergo antithrombotic prophylactic treatment.
NOTE: Investigators should ensure that all study enrollment criteria have been met during
screening. If a patient's clinical status changes (including any available laboratory results or receipt
of additional medical records) after screening but before the first dose of study treatment is given,
such that he or she no longer meets all eligibility criteria, then the patient should be excluded from
participation in the study. Section 17.4, Source Documentation, describes the required
documentation to support meeting the enrollment criteria.
4.3. 
Prohibitions and Restrictions
Potential patients must be willing and able to adhere to the following prohibitions and restrictions
during the course of the study to be eligible for participation. For restrictions related to concomitant
medications, please refer to Section 8.

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1. A woman of childbearing potential must remain on a highly effective method of birth
control (see inclusion criteria). Contraception must begin 4 weeks before initiating
treatment with daratumumab and continue during the Treatment Phase, during dose
interruptions and continuing for 4 weeks after the last dose of lenalidomide and 3 months
following of the last dose of daratumumab.
Reliable contraception is indicated even where there has been a history of infertility, unless
due to hysterectomy. In addition, women must not donate ova during the study, for 4 weeks
after the last dose of lenalidomide, and for 3 months after the last dose of daratumumab.
2. A man who has not had a vasectomy and who is sexually active with a woman of
childbearing potential must agree to use a barrier method of birth control (eg, condom with
spermicidal foam/gel/film/cream/suppository), and all men must not donate sperm during
the study, for 4 weeks after the last dose of lenalidomide, and for 3 months after the last
dose of daratumumab. The exception to this restriction is that if the patient’s female partner
is surgically sterile, a second method of birth control is not required.
3. All patients must adhere to the local lenalidomide Risk Evaluation and Mitigation Strategy
(REMS) program (when lenalidomide is supplied locally), or the lenalidomide Global
Pregnancy Prevention Plan (when lenalidomide is supplied centrally and no local
lenalidomide REMS program exists) in Attachment 3.
4. During the Treatment Phase, pregnancy test requirements during the study are shown in the
Time and Event Schedule - Part 1. Additional pregnancy tests may be required, as specified
in the local lenalidomide REMS  (where lenalidomide is supplied locally) or the
lenalidomide Global Pregnancy Prevention Plan (where lenalidomide is supplied centrally,
and no local lenalidomide REMS program exists).
5. Typically, IV contrast is not used in CT  scanning of patients with secretory multiple
myeloma because of the risk to the kidney. If administration of IV contrast is necessary,
then adequate precautions including hydration are indicated.
6. Patients must not donate blood during therapy and for at least 4 weeks following
discontinuation of lenalidomide.

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5. 
STUDY TREATMENT AND ALLOCATION AND BLINDING
Treatment Allocation
Patients will be assigned in a randomized manner to receive either 1800 mg SC daratumumab in
combination with lenalidomide or lenalidomide alone as maintenance therapy and will be stratified
prior to randomization by cytogenetic risk (standard risk/unknown versus high risk as defined by
presence of del17p, t(4;14), or t[14;16]).
For stratification purposes, if central cytogenetic results are not available (ie, due to technical
reasons)or if central cytogenetics assessment was not conducted due to availability of local results,
local cytogenetic results may be used with the approval of the medical monitor. If central and local
cytogenetic results are not available, the patient will be assumed to have normal/standard
cytogenetics. The investigator will screen patients for enrollment and if eligible, randomize each
patient using an interactive web response system (IWRS). Each patient will be assigned a unique
patient number. For enrollment and treatment randomization, MRD status will be assessed using
the Adaptive Biotechnologies’ NGS-based MRD assay, if available.
Blinding
As this is an open study, blinding procedures are not applicable.
6. 
DOSAGE AND ADMINISTRATION
6.1. 
Daratumumab and Lenalidomide Dosing and Supply
Maintenance treatment regimens in this study comprise of SC daratumumab in combination with
lenalidomide or lenalidomide alone as follows (each cycle will be 28 days in duration with a total
of 36 cycles, the planned maximum duration of treatment; every effort should be made to keep
patients on the planned dosing schedule):
Daratumumab 1800 mg administered by SC injection:
- Weekly during C1 and C2,
- Every 2 weeks during C3 to C6, and
- Every 4 weeks from C7 onwards until confirmed PD, unacceptable toxicity, or until
end of study treatment.
Lenalidomide 10 mg PO:
- D1 to D28 (continuously) of each 28-day cycle until confirmed PD, unacceptable
toxicity, or until end of study treatment. If a patient experiences toxicity to
lenalidomide, dose and/or schedule may be modified per institutional standard.
- After 3 cycles of maintenance therapy, if well tolerated, the lenalidomide dose may be
increased to 15 mg daily, at the discretion of the investigator.

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The start of each cycle may occur ±3 days of the scheduled day to accommodate the schedule of
the site or patient. Day 1 of subsequent cycles should be adjusted accordingly to maintain the
intended cycle duration. Any delays ≥4 days of the scheduled day will need to be discussed with
the sponsor.
Daratumumab will be prepared and administered on site, on an out-patient basis, as described in
Section 6.2. Guidelines for the prevention and management of daratumumab administration
reactions are also described in this section. For further instructions on dose delays due to
daratumumab toxicity, please refer to Section 6.3.2.
Lenalidomide will be obtained and administered in accordance with the requirements of the
REVLIMID REMS® program  or the lenalidomide Global Pregnancy Prevention Plan (when
lenalidomide is supplied centrally and no local lenalidomide REMS program exists) in
Attachment 3. Patients will self-administer lenalidomide and be instructed as follows:
To swallow capsules whole with water once a day; preferably at the same time each day.
Lenalidomide may be taken with or without food.
To not open, break, or chew capsules.
To not handle capsules any more than needed. If a broken lenalidomide capsule or the
medicine inside the capsule is touched, the patient should wash the area of his/her body with
soap and water.
If a dose is missed and it has been less than 12 hours since the prior dose, the patient should
take lenalidomide as soon as remembered. If it has been more than 12 hours, he/she should
skip the missed dose. Two doses should not be taken at the same time.
How to store lenalidomide for at-home use.
How to document lenalidomide intake in the diary provided by the site.
Guidelines for dose adjustment of lenalidomide in the event of toxicity or for renal impairment are
provided in Section 6.3.3, Lenalidomide.
For patients receiving both daratumumab and lenalidomide, it is recommended that lenalidomide
be taken either prior to or at the same time (preferred) as the daratumumab pre-administration
medications that are to be taken within 1 to 3 hours prior to daratumumab administration (see
Section 6.2.2.1).
6.2. 
Daratumumab
6.2.1. 
Preparation and Administration
Detailed instructions for preparation, administration, and storage of daratumumab will be supplied
in study reference materials; please refer to the Commercial Prescribing Instructions for drug
preparation and administration. An overview of this information is provided below.
In the SC daratumumab  group, daratumumab will be provided as a fixed-dosed (1800 mg),
combination drug product containing rHuPH20 drug substance (2000 U/mL) and daratumumab

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drug substance (120 mg/mL) in a single vial. Manuals with detailed descriptions for preparation
and administration of daratumumab will be supplied to each pharmacy and site.
Daratumumab (1800 mg) will be administered by SC injection by manual push over approximately
3 to 5 minutes in the abdominal SC tissues in left/right locations, alternating between individual
doses. The volume of the SC solution will be 15 mL for the 1800 mg dose. Refer to the Site
Investigational Product Procedures Manual (SIPPM) for additional guidance on SC administration
of daratumumab. All patients will be observed for at least 6 hours after the end of the SC injection
during Cycle 1 Day 1 and, if deemed necessary by the investigator, after subsequent injections.
Reasons for continued observation on subsequent daratumumab injections may include but are not
limited to the following: patients with a higher risk of respiratory complications (eg, patients with
mild asthma or patients with COPD who have an FEV1 <80% at screening or developed FEV1
<80% during the study without any medical history), patients with IRR with first injection of study
drug, patient with a decreased condition on day of dosing compared to prior dosing day. The dose
of daratumumab will remain constant throughout the study.
Table 2: 
Daratumumab Dosing Schedule
Cycles 
Schedule
Cycles 1 to 2 
weekly (total of 8 doses)
Cycles 3 to 6a 
every two weeks (total of 8 doses)
Cycle 7 onwards until confirmed disease 
progression, unacceptable toxicity, or end of study
treatmentb
every four weeks
aFirst dose of the every-2-week dosing schedule is given at Week 9
bFirst dose of the every-4-week dosing schedule is given at Week 25
All daratumumab administrations will be in an outpatient setting. Patients will receive pre-
injection medications and post-injection medications as outlined in Section 6.2.2.1 and
Section 6.2.2.2, respectively.
As noted in the Time and Event Schedule, vital signs should be monitored extensively on Cycle 1
Day 1 before, and after the first administration of daratumumab. For all other administrations, vital
signs should be measured before the start of injection and at the end of the injection as shown in
the Time and Events Schedule –Part 1. If the patient experiences any significant medical event,
then the investigator should assess whether the patient should stay overnight for observation. If
the patient has not experienced a significant medical event but is hospitalized overnight only for
observation, then the hospitalization should not be reported as a SAE. Patients will be provided
with a diary to record intake of pre- and post-administration medications taken while off-site; sites
will use information to complete exposure information in the eCRF.

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If an IRR develops, then the injection should be temporarily interrupted or slowed down. In the
event of a life-threatening IRR (which may include pulmonary or cardiac events) or anaphylactic
reaction, SC daratumumab should be discontinued, and no additional SC daratumumab should be
administered to the patient. See Section 6.2.3 for instructions on the management of IRR and local
ISRs.
Every effort should be made to keep  patients on the planned dosing schedule; however, doses
given ±3 days of the scheduled dose are permitted. Any delays ≥4 days of the scheduled day will
need to be discussed with the sponsor.
6.2.2. 
Daratumumab Pre- and Post-administration Medications and Patient
Observation
The following subsections provide information on medications to be administered prior to and
after daratumumab administration to prevent or ameliorate potential administration reactions.
Instructions for patient observation following daratumumab administration are also described.
If an IRR develops, then the injection should be temporarily interrupted or slowed down. In the
event of a life-threatening IRR (which may include pulmonary or cardiac events) or anaphylactic
reaction, SC daratumumab should be discontinued and no additional SC daratumumab should be
administered to the patient. For management of administration reactions related to daratumumab
refer to Section 6.2.3, and for instructions on dose delays due to other toxicities assessed as related
to daratumumab or lenalidomide, refer to Section 6.3.
6.2.2.1. 
Pre-administration Medications
In an effort to prevent IRR, on daratumumab administration days, patients will receive the
following medications 1 to 3 hours prior to administration of daratumumab:
Acetaminophen 
(paracetamol)
650 - 1000 mg IV or per os (PO)
Antihistamine 
Diphenhydramine 25 - 50 mg IV or PO, or equivalent (eg, cetirizine,
fexofenadine, loratadine, clemastine, dexchlorpheniramine, or
promethazine [note: avoid using IV promethazine]). Antihistamine
may be discontinued after Cycle 2 at the investigator’s discretion if
the patient has side effects or does not tolerate.

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Corticosteroids 
(Long-acting 
or 
Intermediate- 
acting) 
Administer 20 mg dexamethasone (or equivalent) prior to
daratumumab injection during Cycle 1 (first 4 doses of daratumumab).
Beginning in Cycle 2, corticosteroids may be tapered over 3
consecutive daratumumab injections to discontinuation at the
investigator’s discretion. The following dexamethasone taper should
be used: 12, 8, and 4 mg over 3 daratumumab injections (for example,
12 mg on C2D1, 8 mg on C2D8, and 4 mg on C2D15, with no
dexamethasone being given on C2D22 and beyond).
Dexamethasone is given orally or intravenously prior to the first
daratumumab injection and oral administration may be considered prior
to subsequent injections.
An equivalent intermediate-acting or long-acting corticosteroid may be
substituted as shown below.
Glucocorticoid 
Approximate 
Equivalent Dose (mg) 
Half-life (Biologic)
hours
Intermediate 
Methylprednisolone 
4 
18-36
Prednisolone 
5 
18-36
Prednisone 
5 
18-36
Triamcinolone 
4 
18-36
Long-acting 
Betamethasone 
0.6 –0.75 
36-54
Dexamethasone 
0.75 
36-54
Leukotriene 
inhibitor 
Predose administration of a leukotriene inhibitor (Montelukast 10 mg
PO or equivalent) is optional on C1D1 and can be administered up to
24 hours before daratumumab injection as per investigator discretion.
If necessary, due to timing constraints, all oral pre-medications may be administered outside of the
clinic on the day daratumumab is to be administered, provided they are taken within 3 hours prior
to daratumumab injection.
6.2.2.2. 
Post-administration Medications
Consider administering low-dose oral methylprednisolone (≤20 mg) or equivalent on the day after
daratumumab injection.
For patients with a higher risk of respiratory complications (eg, patients with mild asthma or
patients with COPD who have an FEV1 <80% during screening or developed FEV1 <80% during
the study without any medical history), the following medications should be considered following
SC daratumumab injection:
Antihistamine (diphenhydramine or equivalent)
Leukotriene inhibitor (montelukast or equivalent)
Short-acting β2-adrenergic receptor agonist such as salbutamol aerosol
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2-adrenergic
receptor agonists for patients with asthma; long-acting bronchodilators such as tiotropium or
salmeterol ± inhaled corticosteroids for patients with COPD).

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In addition, these at-risk patients may be hospitalized for monitoring for up to 2 nights after an
injection of daratumumab.
If hospitalized, FEV1 should be measured and documented before discharge.
If not hospitalized, then a follow up telephone call should be made to monitor the patient’s
condition within 48 hours after daratumumab injection.
Note: If the patient does not experience a significant medical event but is hospitalized overnight
only for observation, then the hospitalization should notbe reported as a serious adverse event.
Investigators may prescribe bronchodilators, H1-antihistamines, and corticosteroids that are
deemed necessary to provide adequate supportive care if bronchospasm occurs after a patient is
released from the hospital/clinic. If an at-risk patient experiences no major injection-related
reactions, then these post-injection medications may be waived after 4 doses at the investigator’s
discretion.
Any post-injection medication will be administered after the injection has completed.
6.2.3. 
Management of Injection-site and Injection-related Reactions
6.2.3.1. 
Local Injection-site Reactions
Injection-site Reactions
In clinical studies, SC administration of daratumumab was associated with local injection site
reactions, such as induration and erythema, in some patients. The reactions usually resolved within
60 minutes. Local ISRs should be managed per institutional standards.
6.2.3.2. 
Daratumumab Injection-related Reactions
Patients should be carefully observed during daratumumab administration. Trained study staff at
the clinic should be prepared to intervene in case of any injection-related reactions, and resources
necessary for resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, also
medical equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be
available at the bedside. Attention to staffing should be considered when multiple patients will be
dosed at the same time.
Patients who experience AEs during daratumumab administration must be treated for their
symptoms:
Treatment with acetaminophen, antihistamine, or corticosteroids, may be administered as
needed.
IV saline may be indicated.
For bronchospasm, urticaria, or dyspnea, patients may require antihistamines, oxygen,
corticosteroids, or bronchodilators.
For hypotension, patients may require vasopressors.

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In the event of a life-threatening reaction (which may include pulmonary or cardiac events) or
anaphylactic reaction, daratumumab-SC should be discontinued, and no additional daratumumab
should be administered to the patient; and the patient must be permanently withdrawn from
daratumumab treatment.
6.2.3.2.1. 
Injection-related Reactions of Grade 1 or Grade 2
If the investigator assesses a Grade 1-2 IRR to be related to administration of study intervention,
then the daratumumab SC administration should be interrupted. When the patient's condition is
stable, daratumumab SC administration may be restarted at the investigator's discretion. Refer to
the SIPPM for further details regarding continuation of daratumumab SC administration.
If the patient experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 or higher
event of bronchospasm that does not respond to systemic therapy and does not resolve within
6 hours from onset, then the patient must be permanently  withdrawn from daratumumab SC
treatment.
6.2.3.2.2. 
Injection-related Reactions of Grade 3 or Higher
For injection-related reactions (other than laryngeal edema or bronchospasm) that are Grade 3, the
daratumumab SC administration must be stopped, and the patient must be observed carefully until
resolution of the adverse event or until the intensity of the event decreases to Grade 1, at which
point the daratumumab SC administration may be restarted at the investigator’s discretion. Refer
to the SIPPM for further details regarding continuation of daratumumab SC administration.
If the intensity of the event returns to Grade 3 after restart of the daratumumab SC administration,
then the patient must be permanently discontinued from daratumumab SC treatment.
For injection-related AEs that are Grade 4, the daratumumab SC administration must be stopped,
and the patient permanently discontinued from daratumumab SC treatment.
6.2.3.2.3. 
Recurrent Injection-related Reactions
If a Grade 3 injection-related reaction (or Grade 2 or higher event of laryngeal edema or a Grade 2
or higher event of bronchospasm) recurs during or within 24 hours after a subsequent
daratumumab administration, the patient must be permanently discontinued from daratumumab
treatment.
6.3. 
Dose Delays and Dose Modifications
Dose modification of 1800 mg SC daratumumab  (increase or decrease) is not permitted. Dose
delay is recommended as the only method for managing daratumumab-related toxicities.
Lenalidomide dose may be reduced, or the treatment schedule may be modified for the
management of drug-related toxicities, per the investigator’s discretion, according to lenalidomide
prescribing guidelines.
Toxicities should be attributed, whenever possible, to a specific study drug so that treatment
modifications can be made rationally. If multiple toxicities are attributed to an individual study

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drug, dose adjustment (for lenalidomide only) should be made according to the guidelines for the
most severe toxicity.
Modifications to the planned dosing regimen  (lenalidomide only) should be overseen by
medically-qualified study-site personnel (principal or sub-investigator unless an immediate safety
risk appears to be present).
Study drug administration must be captured in the source documents and the eCRF.
6.3.1. 
Cycle Delay
Day 1 of a cycle should never be skipped, instead it should be considered a cycle delay. A
minimum of 4 days between daratumumab doses must be observed.
On the first day of each new treatment cycle and before each daratumumab dose, the patient will
be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities
are to be assessed according to National Cancer Institute-Common  Terminology  Criteria for
Adverse Events (NCI-CTCAE), Version  5. Dose modifications (for lenalidomide only) or delays
will be made based on the toxicity experienced during the previous cycle of therapy or newly
encountered on Day 1 of a cycle.
The study treatment must be held if any of the following criteria below are met, to allow for
recovery from toxicity, regardless of relationship to daratumumab or lenalidomide.
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 2 or
baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be fully
recovered.
The parameters in Table 3 must be met on the first day of a new cycle (ie, the following represent
baseline inclusion criteria levels).
Table 3: 
Re-treatment Criteria Before the Start of Each Cycle
Laboratory Parameter 
Requirements Before Each Study Drug Administration
Absolute neutrophil count 
≥1.0×109/L
Platelet count 
≥75×109/L
Hemoglobin  
≥7.5 g/dL (≥4.96 mmol/L)
Any dose holds of more than 28 days due to toxicity will result in permanent discontinuation of
daratumumab. If a patient permanently discontinues study treatment(s), procedures should be
performed as outlined in Section 10.2.1.
If the above parameters are not met, the start of the next cycle will be held for a minimum of
1 week and a maximum of 28 days until recovery to the specified levels. During the cycle delay,
daratumumab and lenalidomide must be held. Dose holds of more than 28 days for other reasons
should be discussed with the sponsor. If a dose delay occurs, then pharmacokinetic and

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pharmacodynamic assessments should be performed on the actual day of study drug
administration, not on the original scheduled administration day.
A study drug dose held for more than 3 days from the per-protocol administration date for any
reason other than toxicities suspected to be related to daratumumab should be brought to the
attention of the sponsor at the earliest possible time. Patients missing ≥3 consecutive planned doses
of study drug for reasons other than toxicity should be withdrawn from treatment, unless, upon
consultation with the sponsor and the review of safety and efficacy, continuation is agreed upon.
6.3.2. 
Daratumumab
6.3.2.1. 
Daratumumab Dose Modification
Individual dose modification of daratumumab is not permitted, but dose delay is recommended as
the primary method for managing daratumumab-related toxicities, as described in Sections 6.2.3
and 6.3.2.2.
6.3.2.2. 
Daratumumab-related Toxicity Management
Refer to Section 6.2.3 for details on management of daratumumab injection-related reactions.
Ifany of the following criteria are met and the toxicity is more than expected for lenalidomide
or underlying multiple myeloma, daratumumab injection must be held to allow for recovery
from toxicity. If attribution is unclear, then daratumumab should be held until recovery
from toxicity as noted below.
The criteria for a dose delay are:
Grade 4 hematologic toxicity, except for Grade 4 lymphopenia
Grade 3 thrombocytopenia with bleeding
Febrile neutropenia
Neutropenia with infection, of any grade
Grade 3 or higher non-hematologic toxicities with the following exceptions:
Grade 3 nausea that responds to antiemetic treatment within 7 days
Grade 3 vomiting that responds to antiemetic treatment within 7 days
Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last
administration of daratumumab
Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last
administration of daratumumab
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 2 or
baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be fully
recovered. Other than on Day 1 of a cycle, if any “within-cycle” daratumumab administration does

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not commence within the prespecified window of the scheduled administration date (Table 4), then
the dose will be considered a missed dose. Administration may resume at the next planned dosing
date.
Table 4: 
Daratumumab-related Toxicity Management
Daratumumab Dosing 
Frequency
Dose Missed
Dosing Resumption
Weekly  
>3 days 
Next planned weekly dosing date
Every 2 weeks 
>7 days 
Next planned every-2-weeks dosing date
Every 4 weeks 
>21 days 
Next planned every-4-weeks dosing date
A missed dose will not be made up. Delay of Day 1 drug dosing in any given cycle should not
result in a skipped dose but should lead to a delay of the entire cycle instead. A minimum of 4 days
between daratumumab doses must be observed.
If a dose is delayed, then the dates of all subsequent doses must be adjusted. If a dose delay occurs,
then blood samples should be collected on the actual day of study drug administration, not on the
original scheduled drug administration day. Any adverse event deemed to be related to
daratumumab that requires a dose hold of more than 28 days will result in permanent
discontinuation of daratumumab, unless, upon consultation with the sponsor and the review of
safety and efficacy, continuation is agreed upon.
6.3.2.3. 
Daratumumab Interruption or Missed Doses
A daratumumab dose that is held for more than the permitted time (Table 4) from the per-protocol
administration date for any reason other than toxicities suspected to be related to daratumumab
should be brought to the attention of the sponsor at the earliest possible time. Patients whose dose
is delayed or missed for 3 or more consecutive doses should be withdrawn from study treatment,
unless, upon consultation with the sponsor and the review of safety and efficacy, continued
treatment is agreed upon.
6.3.3. 
Lenalidomide
The lenalidomide dose may be reduced, or the treatment schedule may be modified for the
management of study drug-related toxicities. For example, if a patient develops a drug-related
toxicity that requires a dose or schedule modification while receiving lenalidomide 10 mg on D1
to D28 (continuously) of each 28-day cycle, the dose of lenalidomide may be reduced to ≤10 mg
on D1 to D28 of each 28-day cycle. Alternatively, the dose and treatment schedule may be
modified to ≤10 mg on D1 to D21 of each 28-day cycle, per institutional standard.
6.4. 
Overdose
6.4.1. 
Daratumumab
The maximum tolerated dose has not been established for daratumumab. However, if the dose
exceeds the maximum tested dose of 2000 mg, then it will be considered as an overdose in this
study. In the event of an overdose, the investigator or treating physician should:

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Contact the Medical Monitor immediately.
Closely monitor the patient for adverse event/serious adverse event and laboratory
abnormalities until daratumumab can no longer be detected systemically (at least 3 months).
Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
Decisions regarding dose interruptions will be made by the investigator in consultation with the
Medical Monitor based on the clinical evaluation of the patient.
6.4.2. 
Lenalidomide
According to the latest prescribing information for lenalidomide at the time of this protocol
(October 2019), “There is no specific experience in the management of lenalidomide overdose in
patients with MM, MDS, MCL, FL, or MZL. In dose-ranging studies in healthy patients, some
were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some patients
were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the
primary reported AEs. In clinical studies, the dose-limiting toxicity was neutropenia and
thrombocytopenia.”
Please refer to the most current product label for lenalidomide overdose information.
7. 
STUDY TREATMENT(S) COMPLIANCE
Study drug (daratumumab) will be administered by qualified staff, and the details of each
administration will be recorded in the eCRF. Refer to the Commercial Prescribing Instructions for
drug preparation and administration.
Patients will be provided with a diary to record intake of lenalidomide as well as pre- and post-
daratumumab administration medications, if required; sites will use information to complete
exposure information in the eCRF.
8. 
PRE-STUDY AND CONCOMITANT THERAPY
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens) different from the study treatments must be recorded in the eCRF.
Recorded information will include the type of therapy, duration of use, dosing regimen, route of
administration, and indication.
Pre-study therapies administered up to 30 days (± 7 days) before first dose of study treatment(s)
must be recorded. Modification of an effective preexisting therapy should not be made for the
explicit purpose of entering a patient into the study.
Concomitant therapies will be collected in the eCRF and source documents beginning with signing
of the ICF to 30 days (± 7 days)after the last dose of study treatment or until the start of subsequent
anticancer treatment, if earlier.

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Throughout the study, investigators may prescribe any concomitant medications or treatments
deemed necessary to provide adequate supportive care except for those listed in Section 8.3. The
sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which
prohibited therapies are administered. Concomitant medications to manage adverse events and
serious adverse events will be recorded as per guidelines provided in Section 12.3.2.
The following subsections provide guidelines on recommended, permitted, and prohibited
concomitant therapies during administration of study treatments (Sections 8.1, 8.2, and 8.3,
respectively), as well as guidelines on therapies to be administered after the end of study treatments
(Section 8.4).
8.1. 
Recommended Therapies
All prior oncologic therapies, including those since diagnosis, must be recorded at screening.
Throughout the study, investigators may prescribe any concomitant medications or treatments
deemed necessary to provide adequate supportive care except for those listed in Section 8. The
sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which
prohibited therapies are administered.
Routine systemic use of concomitant medications will be collected in the eCRF and recorded in
the source documents beginning with signing of the ICF up to 30 days after the last dose of the
last study treatment or until the start of subsequent anticancer treatment, if earlier.
8.1.1. 
Prevention of Deep Venous Thrombosisand Pulmonary Embolism
Lenalidomide has been associated with an increased risk of deep vein thrombosis and pulmonary
embolism. Therefore, prophylaxis of venous thromboembolism  (VTE) for all patients is
recommended according to IMWG criteria as shown in (Figure 3).37

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Figure 3: 
Individual and Myeloma-related Risk Factors
In summary:
Both individual and myeloma related risks of VTE should be taken into account in determining
the type of thromboprophylaxis. In summary:
If no risk factor, or any one risk factor is present, aspirin 81 to 325 mg once daily is
recommended or dose per institutional standards.
If 2 or more risk factors are present, low molecular weight heparin (LMWH) (equivalent of
enoxaparin 40 mg once daily) or full-dose warfarin, international normalized ratio (INR) 2-3,
is recommended.
If any myeloma therapy-related risk factor is present, then LMWH (equivalent of 40 mg
enoxaparin once daily) or full-dose warfarin (target INR 2-3) is recommended.

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8.1.2. 
Therapy for Tumor Lysis Syndrome
Patients should be monitored for symptoms of tumor lysis syndrome. Management of tumor lysis
syndrome, including increasing hydration and treating hyperkalemia, hyperuricemia, and
hypocalcemia, is highly recommended. It is also recommended that high-risk patients, ie, those
with a high tumor burden, be treated prophylactically in accordance with local standards (eg,
increased hydration; diuretics, allopurinol 300 mg daily; and medication to increase urate
excretion).
8.1.3. 
Prophylaxis Against Pneumocystis carinii Pneumonia
Pneumocystis carinii pneumonia prophylaxis should be considered, as per institutional guidelines.
8.1.4. 
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation is recommended during treatment as per institutional
guidelines. Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after
starting study treatment and continue for 3 months following study treatment.
Acceptable antiviral therapy includes:
Acyclovir (eg, 400 mg given orally 3 times a day, or 800 mg given orally 2 times a day or per
institutional standards),
Famciclovir (eg, 125 mg given, twice a day or per institutional standards), or
Valacyclovir (eg, 500 mg given orally, twice a day or per institutional standards).
8.1.5. 
Prevention of Hepatitis B Virus Reactivation
Primary antiviral prophylaxis is permitted as per local standard of care. Per protocol, HBV DNA
testing by PCR is mandatory for patients at risk for HBV reactivation.
In patients who develop reactivation of HBV while on study treatment, suspend treatment with
study treatment and any concomitant steroids, chemotherapy, and institute appropriate treatment.
Resumption of study treatment in patients whose HBV reactivation is adequately controlled should
be discussed with physicians with expertise in managing HBV.
8.1.6. 
Prevention of Steroid-induced Gastritis
Dexamethasone and other corticosteroids may induce gastritis. Medications to prevent gastritis are
permitted per institutional guidelines. For example, proton pump inhibitors (omeprazole or
equivalent) or sucralfate, or H2 blockers (ranitidine or equivalent) may be used.
8.1.7. 
Drugs Affecting Bone Structure and Mineralization
Drugs affecting bone structure and mineralization like bisphosphonate therapy or monoclonal
antibodies are strongly recommended for all patients with evidence of lytic destruction of bone or
with osteopenia. Therapy is recommended to be continued per treatment guidelines.29,31
Commercially available IV bisphosphonates (pamidronate and zoledronic acid) are preferred when
available, and should be used according to the manufacturer’s recommendations, as described in

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the prescribing information, for patients with osteolytic or osteopenic myeloma associated bone
disease. Oral bisphosphonates may be used as alternatives if IV bisphosphonates are not available
at the study site. It is preferred that investigators use the same route of bisphosphonate therapy for
all patients at their sites.
Patients who are using bisphosphonate therapy when they enter the study should continue the same
treatment. Patients with evidence of lytic destruction of bone or with osteopenia who are not using
a bisphosphonate at the time of randomization should start a bisphosphonate as soon as possible
during Cycle 1 or 2 oftreatment. Investigators should not start bisphosphonate therapy during the
study, unless it has been agreed with the sponsor that there is no sign of disease progression.
8.2. 
Permitted Therapies
Patients are to receive full supportive care during the study. The following medications and
supportive therapies are examples of support therapies that may be used during the study:
Antivirals.
Colony stimulating factors, erythropoietin, and transfusion of platelets and red blood cells.
Loperamide is recommended for the treatment of diarrhea, starting at the time of the first
watery stool. The loperamide dose and regimen are according to institutional guidelines.
Prophylactic loperamide is not recommended.
Prevention of constipation (eg, adequate hydration, high-fiber diet, and stool softeners, if
needed).
Adequate hydration is recommended for prevention of myeloma-related kidney disease.
Prophylactic antiemetics, except for corticosteroids.
An emergency short course of corticosteroid (equivalent of dexamethasone 40 mg/day for a
maximum 4 days) is permitted before treatment.
Other symptoms may be managed according to institutional guidelines provided prohibited
therapies are not administered as described in the following section (see Section 8.3).
8.3. 
Prohibited Therapies
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered. Use of the treatments listed below is prohibited
during the study:
Other agents that target CD38.
Medications used for other indications that have anti-myeloma properties (for example,
interferon and clarithromycin).14,32,39
Approved or investigational treatments for multiple myeloma (including but not limited to
conventional chemotherapies, immunomodulatory drugs, or proteasome inhibitors).
Concomitant administration of other investigational agents is prohibited, including
administration of commercially available agents with activity against or under investigation

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for multiple myeloma.
Systemic corticosteroids (>10 mg dexamethasone per day or equivalent; other than those
given as pre-/post-medication for the study treatment regimen and for daratumumab injection-
related reactions as described in Section 6.2).
Vaccination with live attenuated vaccines.
In the absence of PD, should a patient require emergency orthopedic surgery or radiotherapy,
upon recovery, the patient may continue treatment after consultation with, and approval by
the sponsor’s medical monitor. Such emergency radiotherapy may consist of localized
radiotherapy for pain control or for stabilization of an extensive bone lesion at high risk of
pathologic fracture or damage to surrounding tissues in a patient in whom delay of systemic
therapy is not appropriate. Such radiotherapy is to occur within the first 2 cycles of treatment,
and the absence of evidence of PD is to be reviewed and approved by the sponsor.
8.4. 
Subsequent Therapies
Administration of any other anti-myeloma therapy to patients who discontinue study treatment for
reasons other than PD should be monitored for PD according to the Time and Events Schedule –
Part 1. It is not permissible to start other anti-myeloma therapy until PD is confirmed by IMWG
criteria.
After confirmation of PD, subsequent therapy is left to the investigator’s discretion. Subsequent
therapy for multiple myeloma (including start and end date and best response) should be
documented in the appropriate section of the eCRF.
9. 
STUDY EVALUATIONS
9.1. 
Study Procedures
The Time and Events Schedules – Parts 1 and 2 summarize the frequency  and timing of
measurements applicable to this study. The signed ICF must be obtained before any study-specific
procedures are performed.
Every effort should be made to keep patients on the study schedule as planned from C1D1. At each
visit, whether in-person or via telemedicine, study assessments should be completed before the
administration of study  treatment. Daratumumab administration and study-specific
tests/procedures must be completed by study staff. Any  missed visits, tests not performed, or
examinations that are not conducted must be reported as such in the appropriate section of the
eCRF.
For study assessments that require sample collection, the actual dates and times of sample
collection must be recorded on the laboratory requisition form. Instructions for the collection,
handling, storage, and shipment of samples can be found in study reference materials. Urine and
blood collections should be kept as close to the specified time as possible. Repeat or unscheduled
samples may be taken for safety reasons or for technical issues with the samples. In addition,
pregnancy tests may be performed as determined necessary by the investigator or required by local

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regulation, to establish the absence of pregnancy at any time during the patient’s participation in
the study.
The total blood volume for the study is estimated at approximately 45 mL during screening,
approximately 180 mL in Year 1 of the Maintenance Phase, and approximately 90 mL annually in
Year 2 and beyond of the Maintenance Phase. This includes laboratory assessments associated
with safety, efficacy, as well as scientific research samples. At the EOT visit, approximately 10
mL of blood will be collected. Unscheduled samples may be taken for safety reasons (eg,
daratumumab injection-related reactions) or repeat samples may be taken due to technical issues
with the samples.
9.2. 
EvaluationsSpecific to Entry Criteria and/or Other Study Measures
Additional information required to evaluate entry criteria and/or efficacy and safety evaluations
are provided in the following subsections.
9.2.1. 
ECOG Performance Status
The ECOG performance status score is assessed as shown in Table 5.33
Table 5: 
ECOG Performance Status Scale
Grade 
ECOG performance status
0 
Fully active, able to carry on all pre-disease performance without restriction
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary
nature, eg, light house work and 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 and confined to bed or chair more than 50% of waking hours
4 
Completely disabled, cannot carry on any self-care, and totally confined to bed or chair
5 
Dead
Key: 
ECOG = Eastern Cooperative Oncology Group.
9.2.2. 
Calculated Creatinine Clearance
Calculated creatinine clearance may be done using the Cockcroft-Gault formula10 or the MDRD
or the CKD-EPI formula22,23 as described below.
Cockcroft-Gault formula
To calculate the patient’s creatinine clearance (CrCl), use the following Cockcroft-Gault formula:
CrCl =
(140 - age [in years]) × weight (kg) 
(× 0.85 for females)
(72 × serum creatinine [mg/dL])
If the serum creatinine is obtained using the SI units (ie, µmol/L), use the following formula to
convert SI units to conventional (mg/dL) units (Manual of Laboratory & Diagnostic Tests, 2004):
serum creatinine (µmol/L) divided by 88.4=serum creatinine (mg/dL).

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MDRD or CKD-EPI
For online calculators, please go to https://www.kidney.org/professionals/KDOQI/gfr_calculator.
9.2.3. 
Serum Calcium Corrected for Albumin
Please use the following formulas for serum calcium corrected for albumin6:
Table 6: 
Serum Calcium Corrected for Albumin
If calcium is in mg/dL and 
albumin is in g/dL: 
Corrected calcium (mg/dL) =
serum calcium (mg/dL) + 0.8× (4 - serum albumin [g/dL])
If calcium is in mmol/L and 
albumin is in g/L: 
Corrected calcium (mmol/L) =
serum calcium (mmol/L) + 0.02 × (40 - serum albumin [g/L])
9.2.4. 
Asthma Guidelines
Please use the guidelines in Attachment 1 for patients with asthma.
9.3. 
Efficacy Evaluations
Assessment of response will be assessed in accordance with the IMWG 2016 response criteria.
Efficacy evaluations will include measurements of residual disease, myeloma proteins, bone
marrow examinations, skeletal surveys, and extramedullary soft tissue plasmacytomas.
As applicable, procedures for sample collection, preparation, identification, storage, and shipment
will be provided in study reference materials.
9.3.1. 
Response
Disease evaluations must be performed on the scheduled assessment day (±7 days). Disease
evaluations scheduled for treatment days should be carried out before study drug is administered.
Testing of specimens used for disease evaluation will be performed by a central laboratory (unless
otherwise specified).
This study will use the IMWG consensus recommendations for multiple myeloma treatment
response criteria presented in Table 7.19 For M-protein and immunofixation measurements in
serum and 24-hour urine and FLC measurements, the investigator will use results provided by the
central laboratory. After completion of study treatment (36 cycles) or premature discontinuation
of study treatment (due to reasons other than progressive disease), disease evaluations will no
longer be performed by the central laboratory, and local laboratory results of blood and urine
M-protein measurements should be used by investigators to determine response and progression.
IMWG assessments can stop after confirmation of Progressive Disease by the investigator. Criteria
for loss of responses is presented in Table 8. Determination of progressive disease, as well as other
response assessments (VGPR, CR, or sCR) per investigator assessments are to follow the IMWG
criteria for assessment of progressive disease and disease response, as outlined in Table 7.

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Table 7: 
IMWG Consensus Recommendations for Multiple Myeloma Treatment Response Criteria
Response 
Response criteria
sCR  
CR as defined below, plus
Normal FLC ratioa, and
Absence of clonal cells in bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ
patients, respectively, after counting ≥100 plasma cells)b
CR  
Negative immunofixation on the serum and urine, and
Disappearance of any soft tissue plasmacytomas, and
<5% PCs in bone marrow aspirates
VGPR  
Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or
≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours
PR 
≥50% reduction of serum M-protein plus reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours
If the serum and urine M-protein are not measurable, a decrease of ≥50% in the difference between involved and
uninvolved FLC levels is required in place of the M-protein criteria
If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, ≥50%
reduction in PCs is required in place of M-protein, provided baseline bone marrow plasma cell percentage was
≥30%
In addition to the above criteria, if present at baseline, a ≥50% reduction in the size (SPD)c of soft tissue
plasmacytomas is also required
MR  
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, a 25% to 49% reduction in the size (SPD)c of soft tissue
plasmacytomas also is required
SD 
Not meeting criteria for CR, VGPR, PR, MR, or PD
PDd,e 
Any 1 or more of the following criteria:
Increase of 25% from lowest response value in any one of the following:
Serum M-protein (absolute increase must be ≥0.5 g/dL)
Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL
Urine M-protein (absolute increase must be ≥200 mg/24 hours)
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 involved FLC
levels, bone marrow PC percentage irrespective of baseline status (absolute increase must be ≥10%)
Appearance of a new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or ≥50% increase in the longest
diameter of a previous lesion >1 cm in short axis; ≥50% increase in circulating PCs (minimum of 200 cells/μL) if
this is the only measure of disease
Notes: 
(1) 
When the only method to measure disease is by serum FLC levels: CR can be defined as a normal FLC ratio of
0.26 to 1.65 in addition to the complete response criteria listed above. Very good PR in such patients requires a ≥90%
decrease in the difference between involved and uninvolved FLC levels. All response categories (CR, sCR, VGPR, PR,
and PD) require 2 consecutive assessments made at any time before the institution of any new therapy; CR, sCR, VGPR,
PR, and SD categories also require no known evidence of progressive, new bone lesions, or extramedullary soft tissue
plasmacytomas if radiographic studies were performed.
(2) 
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments do not
need to be confirmed. Each category, except for stable disease, will be considered unconfirmed until the confirmatory test
is performed. The date of the initial test is considered as the date of response for evaluation of time dependent outcomes
such as duration of response.
a. 
All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on results obtained with
the validated Freelite test.
b. 
Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio. An abnormal κ/λ ratio by
immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an
abnormal clone is κ/λ of >4:1 or <1:2.
c. 
Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT scans
where applicable. For patients with only skin involvement, skin lesions should be measured with a ruler. Measurement of
tumor size will be determined by the SPD.
d. 
Positive immunofixation alone in a patient previously classified as achieving a complete response will not be considered
progression. For purposes of calculating time to progression and progression-free survival, patients who have achieved a
CR and are MRD-negative should be evaluated using the criteria listed for progressive disease. Criteria for relapse from a
complete response or relapse from MRD should be used only when calculating disease-free survival.

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Table 7: 
IMWG Consensus Recommendations for Multiple Myeloma Treatment Response Criteria
Response 
Response criteria
e. 
In the case where a value is felt to be a spurious result per physician discretion (eg, a possible laboratory error), that value
will not be considered when determining the lowest value.
Key: 
Response categories: CR = complete response; MR = minimal response; sCR = stringent complete response; SD = stable
disease; PD = progressive disease; PR = partial response; VGPR = very good partial response.
Other abbreviations: CT = computed tomography; FLC = free light chain; IMWG = International Myeloma Working
Group; M-protein = monoclonal paraprotein; MRD = minimal residual disease; MRI = magnetic resonance imaging; PC =
plasma cell; PET = positron emission tomography; SPD = sum of the products of the maximal perpendicular diameters of
measured lesions.
Table 8: 
Criteria for Loss of Complete Response Without Disease Progression
Loss of complete 
response 
One or more of the following criteria:
Reappearance of serum M-protein by immunofixation or electrophoresis
Reappearance of urine M-protein by immunofixation or electrophoresis
Development of ≥5% plasma cells in the bone marrow
Key: 
M-protein = monoclonal paraprotein.
9.3.2. 
β2-microglobulin and Lactic Acid Dehydrogenase
Blood samples for β2-microglobulin and lactic acid dehydrogenase, indicators of prognosis with
high levels associated with more advanced disease and a potentially worse prognosis, will be
collected and analyzed by a central laboratory.
9.3.3. 
Myeloma Protein Measurements in Serum and Urine
Blood and 24-hour urine samples will be collected and sent to the central laboratory for myeloma
protein measurements. Urine and blood collections should be kept as close to the specified time as
possible. Note, urine sample collected and refrigerated up to 3 days prior to visit are acceptable for
disease evaluation.
Disease progression based on 1 of the laboratory tests alone must be confirmed by at least 1 repeat
investigation performed at least 1 day later. Disease evaluations will continue beyond loss of CR
until PD is confirmed.
Serum and urine immunofixation tests will be performed during screening and thereafter when
serum or 24-hour urine M-protein electrophoresis (serum M-protein quantitation by
electrophoresis or urine M-protein quantitation by electrophoresis) is negative or non-quantifiable,
at suspected CR, stringent complete response (sCR), and at suspected progression (clinical or
biochemical). For patients with light chain multiple myeloma, both serum and urine
immunofixation tests will be performed at on D1 of every 3rd cycle in year 1 and thereafter on D1
of every 6th cycle in year 2 and year 3 of maintenance treatment.
As an IgG1κ  immunoglobulin, daratumumab has been shown to interfere with serum protein
electrophoresis (SPE) and immunofixation electrophoresis (IFE).28 This interference can be
mitigated through a reflex assay using the anti-idiotype antibody to bind daratumumab, shift it on
SPE and IFE, and confirm interference. This reflex assay will be implemented as part of response
criteria. Patients who meet all other clinical criteria for CR/sCR, with confirmed daratumumab
interference on SPE/IFE, will be considered CR/sCR, respectively.

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Note: All attempts should be made to determine eligibility of the patient based on the central
laboratory results of screening blood and urine M-protein measurements. In exceptional
circumstances, the local laboratory results of blood and urine M-protein measurements may
be used to determine eligibility, but only if the results are clearly (eg, 25% or more) above
the thresholds for measurability. In such cases, central laboratory results are still required
to be obtained to establish baseline values and confirm the results from the local laboratory.
9.3.4. 
Bone Marrow Examination and Minimal Residual Disease
Assessment
Bone marrow aspirate and/or biopsy will be performed at screening and bone marrow sample will
be sent to central laboratory for MRD assessment by Adaptive Biotechnologies’ NGS-based MRD
assay, central fluorescence in situ hybridization evaluation of high-risk cytogenetic anomalies,
plasma cell clonality assessment and morphology, in the order of priority. First draw of bone
marrow aspirate should be collected to ensure quality of sample for MRD assessment. High risk
cytogenetics will be defined as presence of del17p, t(4;14), or t(14;16). Please refer to Time and
Events Schedule – Part 2: Details for Bone Marrow Testing. If cytogenetic evaluation was
conducted any time from the time of multiple myeloma diagnosis to randomization, cytogenetic
assessment by central laboratory is not required, however, the results of the local cytogenetic
evaluation should be recorded in the eCRF.
During screening, MRD will be assessed (Adaptive Biotechnologies’ NGS-based MRD assay) at
12, 18, 24, and 36 months after the start of study treatment(s) (ie, after C1D1). Two sequential
NGS assays will be conducted during screening. The first assay will be conducted on archived
bone marrow sample for calibration of index myeloma clone. If an existing result on index
myeloma clone is available from Adaptive Biotechnologies’ NGS-based MRD assay, conducted
as part of institutional procedures, then archived bone marrow sample is not required as long as
Adaptive Biotechnologies is able to retrieve historical results on the index myeloma clone from
the clinical database. Following index clone calibration (or verification of index clone results from
a previously conducted NGS assay), MRD will be assessed by Adaptive Biotechnologies’
NGS-based assay, using fresh bone marrow aspirate sample collected during screening. Residual
bone marrow samples obtained during screening will be banked for future tests. Note that if
post-transplant NGS results, based on Adaptive Biotechnologies’ NGS-based MRD assay
conducted as per institutional standards, are available at the time of screening and the patient is
positive for MRD (at 10-5 based on the existing NGS test result), the patient may be eligible for
study participation. Such patients will not be required to undergo MRD testing by NGS, again, at
the time of screening.
During the bone marrow aspirate procedure, at screening and during maintenance treatment, the
first aspirate sample that is drawn will be sent to the central laboratory to determine MRD (by
Adaptive Biotechnologies’ NGS-based MRD assay). The second aspirate sample will be sent to
the central laboratory to determine cytogenetics (at screening only, if local cytogenetic evaluation
was not conducted at any time from multiple myeloma diagnosis to randomization), plasma cell
clonality and morphology. Additional bone marrow aspirate samples may be taken and used for
local laboratory testing.

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9.3.5. 
Assessment of Lytic Disease
A complete skeletal survey (including the skull, entire vertebral column, pelvis, chest, humeri,
femora, and any other bones for which the investigator suspects involvement by disease) is to be
performed and evaluated by the local radiologist. An alternative (eg, low-dose CT) may be used
in accordance with local standard of care. Please note that the same methodology used during
screening should be used throughout the study for comparison purposes.
During the Maintenance Phase and before PD is confirmed, imaging should be performed
whenever clinically indicated based on symptoms, to document response or progression. Magnetic
resonance imaging (MRI) or low-dose CT scan is an acceptable method for evaluation of bone
disease and may be included at the discretion of the investigator (see the disease response criteria
in Table 7). If a radionucleotide bone scan was used during screening in addition to the complete
skeletal survey, then both methods must be used to document disease status. These tests must be
performed at the same time. However, a radionucleotide bone scan does not replace a complete
skeletal survey.
Some patients present with disease progression manifested by symptoms of pain due to bone
changes. In these cases, PD  may be documented by skeletal survey or other imaging tests,
depending on the symptoms that the patient experiences. If the diagnosis of PD is obvious by
imaging investigations, then no repeat confirmatory x-rays are necessary. In instances when
changes are subtler, a repeat x-ray should be performed in 1 to 3 weeks.
9.3.6. 
Documentation of Extramedullary Plasmacytomas
Sites of known extramedullary soft tissue plasmacytomas must be documented during screening.
Clinical examination or MRI may be used to document extramedullary sites of disease. CT and/or
PET/CT scan evaluations are an acceptable alternative if there is no contraindication to the use of
IV contrast. Positron emission tomography scan or ultrasound tests are not acceptable to document
the size of extramedullary plasmacytomas. Post-screening assessments are to continue to be
performed until confirmed CR or PD, during the maintenance phases. The methodology used for
evaluation of each disease site should be consistent across all visits. Irradiated or excised lesions
will be considered not measurable and will be monitored only for PD.
To qualify for PD (see Table 7), either the sum of products of the perpendicular diameters of the
existing extramedullary plasmacytomas must have increased by at least 50% or a new
plasmacytoma must have developed. In the cases where not all existing extramedullary
plasmacytomas are reported, but the sum of products of the perpendicular diameters of the reported
plasmacytomas have increased by at least 50%, this will also qualify as PD.
9.4. 
Patient-Reported Outcomes
The PRO measures will be completed by the patient at the clinical site. All visit-specific PRO
assessments should be completed before any tests, procedures, or other consultations for that visit
to prevent influencing patient perceptions. If the patient is unable to complete the PRO
assessments, the reason for not completing the questionnaires will be documented in the eCRF (ie,
too ill, patient refused, etc).

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The PRO measures will be provided in the local language. If a patient requires assistance
completing the PRO, a study coordinator may assist but should not prompt the patient in selecting
their response. At completion, the study coordination should check that the questionnaires are
completed or document why they are missing. Full training documentation will be provided to site
coordinators before the start of data collection.
Three PRO measures will be utilized in this study: the EORTC QLQ-C30, EORTC QLQ-MY20
module, and the EQ-5D-5L. These measures will be administered according to the Time and
Events Schedule –Part 1 to understand how patients self-reported health state changes over time
and the difference between-treatment arms during maintenance treatment and post-progression.
EORTC QLQ-C30 Version 3 includes 30 items resulting in 5 functional scales (physical
functioning, role functioning, emotional functioning, cognitive functioning, and social
functioning), 1 Global Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and
pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial
difficulties). The recall period is 1 week (“past week item”) and responses are reported using a
verbal rating scale. The item and scale scores are transformed to a 0 to 100 scale. A higher score
represents greater health-related quality of life (HRQoL), better functioning, and more (worse)
symptoms. The EORTC QLQ-C30 has been widely used among patients with multiple myeloma.
Reliability, validity, and clinically meaningful change have been demonstrated.45,46
The EORTC QLQ-MY20 has been designed to be usedalongside the EORTC QLQ-C30 to address
issues of more relevance to myeloma patients.11 The 20 items make up 4 scales: disease symptoms,
side effects of treatment, future perspective, and body image. Recall, response options, and
interpretation are similar to the EORTC QLQ-C30. Together the EORTC QLQ-C30 and the
EORTC QLQ-MY20 administration time is less than 30 minutes. Key PRO endpoints include the
Global Health Status, physical functioning, fatigue, and pain scales from the EORTC QLQ-C30
and the Disease Symptoms scale from the EORTC QLQ-MY20.
The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that
assesses 5 domains including mobility, self-care, usual activities, pain/discomfort, and
anxiety/depression plus a visual analog scale rating “health today” with anchors ranging from 0
(worst imaginable health state) to 100 (best imaginable health state).15 The scores for the 5 separate
questions are categorical and cannot be analyzed as cardinal numbers. However, the scores for the
5 dimensions are used to compute a single utility score ranging from zero (0.0) to 1 (1.0)
representing the general health status ofthe individual. The EQ-5D-5L asks respondents to select
their response based on their current health (“today”) and takes less than 5 minutes to complete.
9.5. 
Safety Evaluations
Screening and ongoing measurements of safety in this study include adverse event monitoring,
clinical laboratory tests (hematology, chemistry, pregnancy, HCV viral load, HBV infection [HBV
serology and/or HBV-DNA testing], and indirect antiglobulin tests), electrocardiograms (ECGs),
chest x-ray  or full chest CT scan, physical examination, spirometry (FEV1), vital sign
measurements including weight, and ECOG performance status as details in the Time and Events
Schedule –Part 1.

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All toxicities will be graded according to the NCI-CTCAE Version 5. Clinically relevant changes
that occur during the study must be recorded in the Adverse Event eCRF page. Clinically
significant abnormalities persisting at the end of the study/early withdrawal will be followed by
the investigator until resolution or until a clinically stable endpoint is reached.
Based on previous experience with daratumumab in humans, in vitro studies, and animal
toxicological findings, injection-related reactions/allergic reactions, and hemolysis will be closely
monitored. Any of the safety monitoring assessments may be performed more frequently  as
clinically indicated, and adverse events should be evaluated by the investigator according to the
standard practice.
9.5.1. 
Adverse Events
Adverse events (excluding progression of multiple myeloma) will be reported by the patient (or,
when appropriate, by a caregiver, surrogate, or the patient’s legallyacceptable representative) from
the time a signed and dated informed consent is obtained until 30 days (± 7 days) following the
last dose of any component of study treatment(s). Adverse events will be followed by the
investigator as specified in Section 11.1.
9.5.2. 
Clinical Laboratory Tests
9.5.2.1. 
Hematology, Chemistry, Pregnancy, HCV, and HBV Tests
Hematology, serum chemistry, and pregnancy tests (for women of childbearing potential) will be
conducted by an on-site accredited local laboratory. The specific tests and the timing of these tests
are detailed in the Time and Events Schedule –Part 1 (refer to the rows for hematology, serum
chemistry, and pregnancy testing).
Note: For women of childbearing potential only: lenalidomide is a thalidomide analogue and is
contraindicated for use during pregnancy. Birth defects have been observed in preclinical studies
of lenalidomide similar to thalidomide in humans. Therefore, strict monitoring for pregnancy must
be conducted during screening and throughout the Treatment Phase, as specified in the Time and
Events Schedules. Where lenalidomide is supplied locally, patients must adhere to the local
lenalidomide REMS program. Where lenalidomide is supplied centrally and no local lenalidomide
REMS program exists, then patients must adhere to the lenalidomide Global Pregnancy Prevention
Plan  in Attachment 3. If pregnancy does occur, then study treatment should be discontinued
immediately, and the patient should be referred to an obstetrician experienced in reproductive
toxicity for further evaluation and counselling.
In patients with a prior history of HCV, HCV viral load will be tested in  a local laboratory
throughout the study as specified in the Time and Events Schedule –Part 1 rows for HCV viral
load testing.
All patients will be tested for HBsAg, anti-HBs, and anti-HBc assessments performed locally prior
to the first dose. For patients (in all treatment arms) with serologic evidence of prior HBV
infection, HBV-DNA testing will be performed locally at screening, every 12 weeks during
treatment, at EOT, and every 12 weeks for up to 6 months after last dose of study treatment. HBV-

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DNA is not required at C1D1 if performed at screening. Patients with serologic findings suggestive
of HBV vaccination (anti-HBs positivity as the only serologic marker) and a known history of
prior HBV vaccination do not need to be tested for HBV-DNA by PCR. See Time and Events
Schedule –Part 1 rows for HBV testing.
The investigator must review the laboratory results, document this review, and record any
clinically relevant changes occurring during the study in the Adverse Event section of the eCRF.
The laboratory reports must be filed with the source documents.
9.5.2.2. 
Indirect Antiglobulin Test
Blood type, Rh, and indirect antiglobulin test (IAT) should be done for all patients. Patient RBC
phenotyping (standard or extended) is an alternative option to the IAT test, if locally required.
Either method must be completed prior to first daratumumab injection.
Daratumumab interferes with the IAT, which is a routine pre-transfusion test performed to identify
a patient’s antibodies to minor antigens so that suitable donor blood can be given for transfusion.
Daratumumab does not interfere with ABO/RhD typing. CD38 is expressed at very low levels on
erythrocytes. Daratumumab binds to the CD38 on erythrocytes, which results in a positive IAT
(Indirect Coombs Test). This positive result masks the detection of antibodies to minor antigens
and may prevent or delay blood banks from issuing donor blood for transfusion. This effect occurs
during daratumumab treatment and for up to 6 months after treatment ends.
Patients receiving daratumumab  will receive an  identification wallet card for the study that
includes the blood profile (ABO, Rh, and IAT or phenotyping) determined before the first injection
of daratumumab along with information on the IAT interference for healthcare providers/blood
banks.
Patients are to carry this card throughout the treatment period and for at least 6 months after
treatment ends. Blood banks can eliminate the daratumumab interference with IAT by treating
reagent RBCs with dithiothreitol (DTT).7,8
Possible methods for blood banks to provide safe RBCs for transfusion to patients receiving
daratumumab include the following:
a) Providing ABO/RhD-compatible, phenotypically (standard or extended phenotyping) or
genotypically matched units
b) Providing ABO/RhD-compatible, K-negative units after ruling out or identifying
alloantibodies using DTT-treated reagent RBCs
Uncrossmatched, ABO/RhD-compatible RBC units should be administered if transfusion is
needed emergently as per local blood bank practice.
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 and addenda, as applicable.

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9.5.3. 
ECGs, Chest Imaging, Physical Examination, and Spirometry
A 12-lead ECG is required during screening and may be performed during the study as clinically
indicated. During the collection of 12-lead ECGs, patients should be in a quiet setting without
distractions (eg, television and cell phones). Patients should rest in a supine position for at least
5 minutes before ECG collection and should refrain from talking or moving arms or legs. If blood
sampling or vital sign measurement is scheduled for the same time point as ECG recording, the
procedures should be performed in the following order: ECG(s), vital signs, blood draw.
A chest x-ray or full chest CT scan is required during screening if not conducted within 30 days
prior to screening.
A complete physical examination with measurement of height will be required during screening.
Thereafter, only a symptom- and disease-directed physical examination is required as clinically
indicated.
Patients with known or suspected COPD or asthma must have an FEV1 test during screening if
not performed as part of standard of care anytime from 60 days prior to transplant up to
randomization; refer to Section 6.2.2.2 for details on patients with higher risk of respiratory
complications.
9.5.4. 
Vital Signs Including Weight
Vital signs and weight will be measured regularly as specified in the Time and Events Schedule –
Part 1; abnormalities will be recorded as adverse events (refer to Section 12).
9.5.5. 
Eastern Cooperative Oncology Group Performance Status
The ECOG performance status will be conducted to evaluate the effect of the disease status on the
activities of daily living (see Table 5). When scheduled, ECOG performance status assessments
should be obtained prior to any other study procedures planned for the same day whenever possible.
9.6. 
Benefit-risk Evaluation
The benefit-risk assessment of daratumumab  in combination with lenalidomide relative to
lenalidomide alone will be conducted by comparing between-treatment differences of key efficacy
and safety endpoints. Additional details on the benefit-risk assessment will be provided in a
separate analysis plan. Please refer to Section 3.2.1 for additional information on anticipated
benefit-risk profile.
10. 
PATIENT COMPLETION/DISCONTINUATION OF TREATMENT(S)/
WITHDRAWAL FROM THE STUDY
10.1. 
Study Completion
A patient will be considered to have completed the study if he or she has finished all
protocol-specified procedures, including 36 cycles of maintenance treatment, or, if he or she has
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follow-up, and has not withdrawn consent for study participation before the end of the study or
has transitioned to commercial drug product.
10.2. 
Discontinuation of Study Treatment/Withdrawal from the Study
10.2.1. 
Discontinuation of Study Treatment
A patient will not be automatically withdrawn from the study if he or she must discontinue study
treatment before the end of the treatment regimen; instead, the patient will enter the Follow-up
Phase. The EOT  Visits and Follow-up visit assessments should continue as specified in the
Time and Events Schedules.
A patient’s study treatment must be discontinued ifthe following occurs:
The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it
is in the best interest of the patient to discontinue study treatment.
The patient becomes pregnant.
The patient (or the patient’s legally acceptable representative) withdraws consent for
administration of study drug.
The patient experiences unacceptable toxicity, including daratumumab injection-related
reactions described in Section 6.2.3.
If 3 consecutive planned doses of daratumumab are missed for reasons other than toxicity
unless, upon consultation with the sponsor and the review of safety and efficacy, continuation
is agreed upon.
The patient experiences PD (please see below); loss of CR is not considered as PD.
The patient experiences a malignancy other than multiple myeloma that cannot be treated by
surgery alone (however, a patient who develops a malignancy that can be cured surgically
may continue to receive the assigned study treatment and should continue to be followed for
subsequent progression of multiple myeloma).
The primary reason for discontinuation of study treatment will be recorded in the eCRF.
Study treatment will continue until PD/unacceptable toxicity or until the end of study treatment,
whichever occurs first. Before patients are discontinued from study treatment because of suspected
PD:
1. The investigator (or designee) will provide documentation of PD (eg, by completing a PD
form or by contacting the IWRS) as soon as possible and within 48 hours of confirmation of
PD.
2. The sponsor’s medical monitor will review the provided documentation and confirm that PD
has occurred per IMWG criteria (see Section 9.3.1) and that study treatment should be
discontinued.
3. After confirmation of PD by the sponsor, the patient will discontinue study treatment and enter
the Follow-up Phase.

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10.2.2. 
Withdrawal From the Study
A patient will be withdrawn from the study for any of the following reasons:
Lost to follow-up
Withdrawal of consent for study participation
Death
Sponsor terminates the study
If a patient is lost to follow-up, every reasonable effort must be made by the study-site personnel
to contact the patient and determine the reason for discontinuation/withdrawal. The measures taken
to follow-up must be documented.
When a patient withdraws consent before completing the study, the reason for withdrawal is to be
documented in the eCRF and in the source document. Study treatment assigned to the withdrawn
patient may not be assigned to another patient. Patients who withdraw will not be replaced. If a
patient discontinues study treatment and withdraws from the study before the EOT Phase, EOT
assessments should be obtained. If the reason for withdrawal from the study is withdrawal of
consent, then no additional assessments are allowed.
10.3. 
Withdrawal From the Use of SamplesIn Future Research
The patient may withdraw consent for use of samples for research (refer to Section 16.2.5). In such
a case, samples will be destroyed after they are no longer needed for the clinical study. Details of
the sample retention for research are presented in the main ICF.
11. 
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
11.1. 
Patient Information
The primary and secondary efficacy analysis will be performed based on the intent-to-treat
population, which will include all randomized patients.
Safety will be evaluated for the safety population, which includes all treated patients who receive
at least 1 dose of randomized therapy. Subgroup analyses will be performed as appropriate, and
details will be specified in the SAP.
Continuous variables will be summarized using descriptive statistics such as mean, standard
deviation, and range. Categorical variables will be summarized using frequency tables. For time-
to-event variables, the Kaplan-Meier method will be used for descriptive summaries.
The primary analysis will be conducted at 2-sided alpha level of 0.05.

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11.2. 
Sample Size Determination
Based on previous reports of MRD negativity rate in lenalidomide-treated myeloma patients, as
discussed in Section 3.2.1, the anticipated MRD (at 10-5) negativity conversion rate is estimated to
be 20% for patients treated by lenalidomide alone following post ASCT. Assuming a20% absolute
increase in MRD negativity rate (40% daratumumab plus lenalidomide versus 20% lenalidomide
alone) by the end of 12-month maintenance treatment, a sample size of 214 patients
(ie, 107 patients per treatment group at a 1:1 randomization) will be needed to achieve at least 85%
power to detect such a treatment difference at a 2-sided alpha of 0.05 using continuity corrected
chi-squared test.
Disease assessments for each patient will continue until 36 months from the date ofrandomization
of last patient. It is anticipated that this will yield 64 PFS events and provide approximately 79%
power to detect a 50% reduction in the risk of progression or death (HR=0.50, translating to an
improvement in median PFS from 60 months to 120 months) with a log-rank test at a 2-sided alpha
of 0.05 with an accrual period of 1 year. One interim analysis using Obrien-Fleming alpha
spending function is planned at the time of primary endpoint analysis when approximately
32 events are anticipated.
11.3. 
Efficacy Analyses
Response to study treatment and PD will be evaluated by a validated computer algorithm based on
IMWG 2016 criteria. There is no imputation planned for missing efficacy endpoint values.
11.3.1. 
Primary Endpoint and Analysis
The primary endpoint is the MRD conversion rate from baseline to 12 months after maintenance
treatment as determined by NGS, which is the proportion of patients who have achieved MRD
negative status [at 10-5] by 12 months after maintenance treatment prior to progressive disease
(PD) or subsequent anti-myeloma therapy. Patients who have achieved MRD negative status on or
after PD or switch to subsequent anti-myeloma therapy before PD, will not be considered MRD
negative in the primary endpoint analysis.
The MRD conversion rate will be compared between the 2 treatment groups based on the intent-
to-treat population using the stratified Cochran Mantel-Haenszel test with baseline cytogenetic
risk (high versus standard/unknown) as stratification factor. A Mantel-Haenszel odds ratio along
with its 2-sided 95% CIs will be calculated.
11.3.2. 
Secondary Endpoints and Analysis
11.3.2.1. 
Progression-free Survival, Overall Survival, and Minimal Residual
Disease
Time-to-event secondary endpoints including PFS and OS will be analyzed through a stratified
log-rank test for the comparison of the distribution between the 2 treatment groups. The
Kaplan-Meier method will be used to estimate the distribution for each treatment. The treatment
effect (HR) and its 2-sided 95% CIs are to be estimated using a stratified Cox regression model

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with treatment as the sole explanatory variable stratified by baseline cytogenetic risk (high versus
standard/unknown).
The overall MRD negativity rate at any time after randomization and MRD durability will be
analyzed.
The binary secondary endpoints including rate of CR and sCR will be analyzed similarly to MRD
negativity rate.
A descriptive summary for duration of response will be provided. No statistical comparison will
be made.
11.3.2.2. 
Patient-reported Outcomes
The EORTC QLQ-C30 and EORTC QLQ-MY20 scale scores and EQ-5D-5L utility and visual
analog scores will be descriptively summarized by treatment group at each time point. Within-
group and between-group treatment effects of the PRO endpoints will be assessed by change from
baseline using mixed models for repeated measures. Full details on meaningful change thresholds
and statistical analyses will be provided in the SAP.
11.4. Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events are
AEs with onset during the Treatment Phase or that are a consequence of a pre-existing condition
that has worsened since baseline. All reported AEs will be included in the analysis. For each AE,
the percentage of patients who experience at least 1 occurrence of the given event will be
summarized by treatment group.
Summaries, listings, datasets, or patient narratives may be provided, as appropriate, for those
patients who die, who discontinue study drug due to an AE, or who experience a severe or a serious
AE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the SAP) will be used in the summary of laboratory data. Descriptive
statistics will be calculated for each laboratory analyte at baseline and for observed values and
changes from baseline at each scheduled time point. Changes from baseline results will be
presented in pre- versus post-treatment cross-tabulations (with classes for below, within, and above
normal ranges). A listing of patients with any laboratory results outside the reference ranges will
be provided. A listing of patients with any markedly abnormal laboratory results will also be
provided.

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Vital Signs
Descriptive statistics of pulse, temperature, and blood pressure (systolic and diastolic) values and
changes from baseline will be summarized at each scheduled time point. The percentage of patients
with values beyond clinically important limits will be summarized.
11.5. Benefit-risk Analyses
For benefit risk analyses, between-treatment differences will be shown with absolute rate or other
difference measures and corresponding 95% CIs. Both continuous and dichotomized versions of
continuous endpoints will be shown. Results will be displayed in tabular and forest plot form.
Additional details will be provided in the separate benefit-risk SAP.
11.6. Interim Analyses
No interim analysis is planned for the primary endpoint of the study. The primary analysis will be
performed after all randomized patients have completed 12 months of maintenance treatment, have
disease progression, died, or have been discontinued/withdrawn from study treatment by this time
point. Afterwards, an annual analysis will be performed to update secondary endpoints and safety.
A final analysis will occur at the end of study 36 months from the date of randomization of last
patient.
An interim  analysis, at the time of primary endpoint analysis, and a final analysis will be
conducted for PFS. Obrien-Fleming alpha spending function will be used to control overall alpha
at 0.05.
11.7. 
Independent Data Monitoring Committee
An Independent Data Monitoring Committee, consisting of at least 2 clinicians and 1 statistician,
will be established to review safety data before the primary analysis of the MRD negativity rate,
which will be conducted by the sponsor. The Independent Data Monitoring Committee will start
their review after the first 100 patients have been treated for at least 4 cycles or discontinued and
subsequently perform their review every 6 months. Details will be provided in a separate
Independent Data Monitoring Committee charter. Emerging data from all ongoing SC
daratumumab studies will be communicated to the Independent Data Monitoring Committee,
where applicable.
12. 
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of patients, investigators, and the sponsor and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.

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Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or serious adverse events.
Open-ended and nonleading verbal questioning of the patient is the preferred method to inquire
about adverse event occurrence.
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the patient is
specifically questioned.
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the patient is specifically not
questioned.
12.1. 
Definitions
12.1.1. 
Adverse Event Definitions and Classifications
12.1.1.1. 
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study patient administered a
medicinal (investigational or non-investigational) product. An adverse event does not necessarily
have a causal relationship with the intervention. An adverse event can therefore be any unfavorable
and unintended sign (including an abnormal finding), symptom, or disease temporally associated
with the use of a medicinal (investigational or non-investigational) product, whether or not related
to that medicinal (investigational or non-investigational) product. (Definition per International
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF  (refer to
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
12.1.1.2. 
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal
Products for Human Use is any untoward medical occurrence that at any dose:
Results in death
Is life-threatening (the patient 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

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Is a suspected transmission ofany 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 patient or may require
intervention to prevent one of the other outcomes listed in the definition above. These should
usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal
relationship between the study treatment(s) and the event (eg, death from anaphylaxis), the event
must be reported as a serious and unexpected suspected adverse reaction even if it is a component
of the study endpoint (eg, all-cause mortality).
12.1.1.3. 
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 or package insert.
12.1.1.4. 
Adverse Event Associated With the Use of the Intervention
An adverse event is considered associated with the use of the study treatment(s) if the attribution
is possible, probable, or very likely by the definitions listed in Section 12.1.2, Attribution
Definitions.
12.1.1.5. 
Adverse Event Associated With Progression of Disease
Expected progression of disease should not be considered an adverse event (or serious adverse
event). However, if determined by the investigator to be more likely related to the study treatment
than the underlying disease, the clinical signs or symptoms of progression and the possibility that
the study treatment is enhancing disease progression should be reported per the usual reporting
requirements.
12.1.2. 
Attribution Definitions
Each adverse event is to be assigned an attribution definition, as shown below.
Not Related
An adverse event that is not related to the use of the intervention.
Doubtful
An adverse event for which an alternative explanation is more likely, for example, concomitant
drug(s) and concomitant disease(s), or the relationship in time, suggests that a causal relationship
is unlikely.

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Possible
An adverse event that might be due to the use of study treatment(s). An alternative explanation,
eg, concomitant drug(s) and concomitant disease(s), is inconclusive. The relationship in time is
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of study treatment(s). The relationship in time is
suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely,
eg, concomitant drug(s) and 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) and concomitant disease(s). The
relationship in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3. 
Severity Criteria
The severity assessment for an adverse event or serious adverse event should be completed using
NCI-CTCAE Version 5. Any adverse event or serious adverse event not listed in the NCI-CTCAE
will be graded according to investigator clinical judgment by using general guideline in the
introduction of CTCAE Version 5:
Grade 1 (Mild): 
Asymptomatic or mild symptoms; clinical or diagnostic observations
only; intervention not indicated.
Grade 2 (Moderate): Moderate; minimal, local or noninvasive intervention indicated; limiting
age appropriate instrumental ADL*.
Grade 3 (Severe): 
Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling;
limiting self-care ADL**.
Grade 4: 
Life-threatening consequences; urgent intervention indicated.
Grade 5: 
Death related to AE.
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone,
managing money, etc.
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking
medications, and not bedridden
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the patient (eg, laboratory abnormalities).

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12.2. 
Special Reporting Situations
Safety events of interest on a sponsor study treatment that may require expedited reporting or
safety evaluation include, but are not limited to, the following:
Overdose of sponsor study treatment. No maximum tolerated dose has been reached for
daratumumab. However, if the dose exceeds the maximum tested dose of 2000 mg, then it
will be considered as an overdose in this study.
Suspected abuse/misuse sponsor study treatment
Accidental or occupational exposure to sponsor study treatment
Any failure of expected pharmacologic action (ie, lack of effect) of sponsor study treatment
Unexpected therapeutic or clinical benefit from use of a sponsor study treatment
Medication error involving a sponsor product (with or without patient/patient exposure to the
sponsor study intervention, eg, name confusion)
Exposure to sponsor study treatment from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation
that meets the criteria of a serious adverse event should be recorded on the serious adverse
event page of the eCRF.
12.3. 
Procedures
12.3.1. 
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported
from the time a signed and dated ICF is obtained until 30 days (± 7 days) after the last dose of
study treatment(s). The only exceptions are as follows (whichever occurs first):
Patients who have withdrawn informed consent for study participation
Patients who have received additional treatment with therapeutic intent for multiple myeloma
within 30 days (± 7 days) after the lastdose studytreatment(s). For these patients, only adverse
events that are considered to be possibly, probably, or definitely related to the study drug must
be reported (unless the patient has been withdrawn from the study).
Serious adverse events, including those spontaneously reported to the investigator within 30 days
(± 7 days) after the last dose of study treatment(s), 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.
Death and PD should not be recorded as an adverse event or serious adverse event but as the
outcome of an adverse event. The event that resulted in the death should be reported as a serious
adverse event.

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All events that meet the definition of a serious adverse event will be reported as serious adverse
events, regardless of whether they are protocol-specific assessments. Anticipated events will be
recorded and reported as described in Attachment 2.
All adverse events, regardless of seriousness, severity, or presumed relationship to study
treatment(s), must be recorded using medical terminology in the source document and the eCRF.
Whenever possible, diagnoses should be given when signs and symptoms are due to a common
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as
“upper respiratory infection”). Investigators must record in the eCRF their opinion concerning the
relationship of the adverse event to study therapy. All measures required for adverse event
management must be recorded in the source document and reported according to sponsor
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory
authorities. The sponsor will also report to the investigator (and the head of the investigational
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For
anticipated events reported as individual serious adverse events, the sponsor will make a
determination of relatedness in addition to and independent of the investigator’s assessment. The
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence
and the sponsor has determined that there is a reasonable possibility that the intervention caused a
serious anticipated event, they will submit a safety report in narrative format to the investigators
(and the head of the investigational institute where required). The sponsor assumes responsibility
for appropriate reporting of anticipated events to the regulatory authorities. The investigator (or
sponsor, where required) must report SUSARs to the appropriate Institutional Review Board (IRB)
that approved the protocol unless otherwise required and documented by the IRB.
For all studies with an outpatient phase, including open-label studies, the patient must be provided
with a “wallet (study) card”and instructed to carry this card with them for the duration of the study
indicating the following:
Study number
Statement, in the local language(s), that the patient 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
Patient number
Any other information that is required to do an emergency breaking of the blind
12.3.2. 
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor
contact person by study-site personnel within 24 hours of their knowledge of the event.

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Information regarding serious adverse events will be transmitted to the sponsor using the Serious
Adverse Event Form and Safety Report Form of the eCRF, which must be completed and reviewed
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 transmitted electronically or by facsimile
(fax).
All serious adverse events that have not resolved by the end of the study, or that have not resolved
upon discontinuation of the patient’s participation in the study, must be followed until any of the
following occurs:
The event resolves
The event stabilizes
The event returns to baseline, if a baseline value/status is available
The event can be attributed to agents other than the study treatment(s) or to factors unrelated
to study conduct
It becomes unlikely that any additional information can be obtained (patient or health care
practitioner refusal to provide additional information or 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 patient’s participation in a study must be reported as a serious adverse event,
except hospitalizations for the following:
If the patient has not experienced a significant medical event but is hospitalized overnight
only for observation following administration of daratumumab, then the hospitalization
should not be reported as a serious adverse event.
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.
For convenience, the investigator may choose to hospitalize the patient for the duration of the
treatment period.
As previously described, disease progression should not be recorded as an adverse event or serious
adverse event term; instead, signs and symptoms of clinical sequelae resulting from disease
progression/lack of efficacy will be reported if they fulfill the serious adverse event definition
(refer to Section 12.1.1).

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12.3.3. 
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel within
24 hours of their knowledge of the event using the appropriate pregnancy notification form.
Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, and congenital anomaly) are
considered serious adverse events and must be reported using the Serious Adverse Event Form.
Any patient who becomes pregnant during the study must discontinue further study treatment. The
patient should be referred to a physician experienced in teratology for evaluation and advice.
Investigators should follow the local label for guidance on patient education and ensure that all
patients adhere to the local lenalidomide REMS program (when lenalidomide is supplied locally),
or the lenalidomide Global Pregnancy Prevention Plan provided in Attachment 3
(when lenalidomide is supplied centrally and no local lenalidomide REMS program exists).
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required. Because the effect of the study drug on sperm is unknown, pregnancies in
partners of male patients included in the study will be reported by the study-site personnel within
24 hours of their knowledge of the event using the appropriate pregnancy notification form.
12.4. Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
13. 
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, that is, 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 patients, investigators,
and the sponsor and are mandated by regulatory agencies worldwide. The sponsor has established
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting
of PQC information; all studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
13.1. 
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the
PQC to the sponsor according to the serious adverse event reporting timelines (refer to
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be maintained
for further investigation if requested by the sponsor.
13.2. 
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.

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14. 
STUDY TREATMENT INFORMATION
For the purposes of this study, study drug refers to daratumumab.
14.1. Physical Description and Packaging of Daratumumab
Daratumumab, supplied in glass vials, is a colorless to yellow liquid and sterile concentrate of
120 mg/mL in a vial. It will be manufactured and provided under the responsibility of the sponsor.
Refer to the Investigator’s Brochure for a list of excipients.
14.2. Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each
vial will contain a study-specific label with a unique identification number.
14.3. Preparation, Handling, and Storage
All study drug vials must be stored in the original carton in a refrigerator ranging from 2°C to 8°C
and must not be utilized after the expiry date printed on the label. The product must be protected
from light and must not be frozen. Daratumumab does not contain preservatives; therefore, any
unused portion remaining in the vial must be discarded.
Refer to the Commercial Prescribing Instructions for drug preparation and administration  and
Pharmacy Manual for details regarding dose preparation, storage, and handling of diluted solutions.
14.4. Study Treatment Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried
and accounted for throughout the study. The study drug administered to the patient must be
documented on the drug accountability form. All study drug will be stored and disposed of
according to the sponsor's instructions. Study-site personnel must not combine contents of the
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label and must
be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study drug must be available for verification by the sponsor’s
study site monitor during on-site monitoring visits. The return to the sponsor of unused study drug
will be documented on the drug return form. When the study site is an authorized destruction unit
and study drug supplies are destroyed on-site, this must also be documented on the drug return
form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing
hazardous liquids should be disposed of immediately in a safe manner and therefore will not be
retained for drug accountability purposes.

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Study drug should be dispensed under the supervision of the investigator or a qualified member of
the study-site personnel or by a hospital/clinic pharmacist. Study drug will be supplied only to
patients participating in the study. Returned study drug must not be dispensed again, even to the
same patient. Study drug may not be relabeled or reassigned for use by other patients. The
investigator agrees neither to dispense the study drug from nor store it at any site other than the
study sites agreed upon with the sponsor.
15. 
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
Study protocol
Investigator’s Brochure for daratumumab
Investigational Product Manual
Laboratory manual and laboratory kits
Electronic data capture (eDC) manual
Sample ICF Trial Center file and corresponding site-specific documentation
Patient study tools (patient diaries) and emergency ID card
Investigator study tools and quick reference cards, as required
NCI-CTCAE Version 5
PRO questionnaires and user manuals: PRO questionnaires will include the EORTC QLQ-
C30, EQ-5D-5L, and EORTC QLQ-MY20
IWRS manual and codes
16. 
ETHICAL ASPECTS
16.1. Study-specific Design Considerations
The safety profile of daratumumab, primarily consists ofinfusion-related reactions. Based on the
mode of action of daratumumab, a potential risk could be infection; therefore, review of
hematological laboratory results prior to daratumumab administration  is required per protocol.
CD38 is distributed in erythrocytes and platelets. A significant reduction of platelets was reported
in an animal study. In addition, in a human clinical study (Study GEN501), thrombocytopenia was
also reported. However, safety laboratory monitoring has not shown  a clinically meaningful
reduction of platelets. No bleeding events were observed. Anemia was also reported in Study
GEN501. Free hemoglobin was mildly elevated, but other parameters did not support hemolysis.
Routine safety laboratory measurement of RBCs and platelets will be closely monitored in this
study. In addition, an Independent Data Monitoring Committee will be established to review safety
data on a regular basis throughout the duration of the study.

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Potential patients will be fully informed of the risks and requirements of the study and, during the
study, patients will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only patients who are fully able to understand the risks, benefits, and
potential adverse events of the study and provide their consent voluntarily will be enrolled. Note that
as specified in Section 16.2.3, a legally acceptable representative may provide consent on behalf of
the patient.
The total blood volume to be collected during the course of the study is considered to be acceptable
for patients participating in a cancer clinical study and reasonable over the time frame of the study.
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 patients.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study patients are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
16.2.2. 
Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide 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 patients)
Investigator’s 
Brochure 
for 
daratumumab  
(or 
equivalent 
information) 
and
amendments/addenda
Sponsor-approved patient recruiting materials
Information on compensation for study-related injuries or payment to patients for participation
in the study, if applicable
Investigator’s curriculum vitae or equivalent information (unless not required, as documented
by the IRB)
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for patients
Any other documents that the IRB requests to fulfill its obligation

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This study will be undertaken only after the IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
patients, data, or study conduct, unless required locally), the ICF, applicable recruiting materials,
and patient compensation programs and the sponsor has received a copy of this approval. This
approval letter must be dated and must clearly identify the IRB and the documents being approved.
During the study, the investigator (or sponsor where required) will send the following documents
and updates to the IRB for their review and approval, where appropriate:
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for patients, data, or study conduct)
Revision(s) to ICF and any other written materials to be provided to patients
If applicable, new or revised patient recruiting materials approved by the sponsor
Revisions to compensation for study-related injuries or payment to patients 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 IRB (at least
annually)
Reports of adverse events that are serious, unlisted/unexpected, and associated with the study
intervention
New information that may adversely affect the safety of the patients or the conduct of the
study
Deviations from or changes to the protocol to eliminate immediate hazards to the patients
Report of deaths of patients 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 IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for patients, data, or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IRB for review and approval before implementation of the
change(s).
At least once a year, the IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IRB about the
study completion  (if applicable, the notification will be submitted through the head of
investigational institution).

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16.2.3. 
Informed Consent
Each patient (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 IRB and be in a language that the patient can read and
understand. The informed consent should be in accordance with principles that originated in the
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and
sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential patients or their legally acceptable representatives the aims,
methods, reasonably anticipated benefits, potential hazards of the study, and any discomfort
participation in the study may entail. Patients will be informed that their participation is voluntary
and that they may withdraw consent to participate at anytime. They will be informed that choosing
not to participate will not affect the care the patient will receive for the treatment of his or her
disease. Patients 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 patient 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 patient, to the extent permitted by the applicable law(s) or
regulations. By signing the ICF, the patient or legally acceptable representative is authorizing such
access, which includes permission to obtain information about his or her survival status. It also
denotes that the patient agrees to allow his or her study physician to recontact the patient for the
purpose of obtaining consent for additional safety evaluations and subsequent disease-related
treatments, if needed. The physician may also recontact the patient for the purpose of obtaining
consent to collect information about his or her survival status.
The patient 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 the patient’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 patient.
If the patient or legally acceptable representative is unable to read or write, an impartial witness
should be present for the entire informed consent process (which includes reading and explaining
all written information) and should personally date and sign the ICF after the oral consent of the
patient or legally acceptable representative is obtained.
When prior consent of the patient is not possible and the patient’s legally acceptable representative
is not available, enrollment procedures should be described in the protocol with documented
approval/favorable opinion by the IRB to protect the rights, safety, and well-being of the patient
and to ensure compliance with applicable regulatory requirements. The patient or legally
acceptable representative must be informed about the study as soon as possible and give consent
to continue.

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16.2.4. 
Privacy of Personal Data
The collection and processing of personal data from patients 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 patients confidential.
The informed consent obtained from the patient (or his or her legally acceptable representative)
includes explicit consent for the processing of personal data and for the investigator/institution to
allow direct access to his or her original medical records (source data/documents) for study-related
monitoring, audit, IRB review, and regulatory inspection. This consent also addresses the transfer
of the data to other entities and to other countries.
The patient 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.
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 patients 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 till the end of the study (or according to local
regulations) for additional research. Samples will only be used to understand daratumumab, to
understand multiple myeloma, to understand differential intervention 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. Patients may withdraw their consent for their samples to be stored
for research (refer to Section 10.3, Withdrawal From the Use of Samples in Future Research).

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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 IRB approval or when
the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the patients, in which case the amendment must be
promptly submitted to the IRB and relevant competent authority. Documentation of amendment
approval by the investigator and IRB must be provided to the sponsor. When the change(s)
involves only logistic or administrative aspects of the study, the IRB (where required) only needs
to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
listed in the Contact Information page(s), which will be provided as a separate document. Except
in emergency situations, this contact should be made before implementing any departure from the
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the
situation and agree on an appropriate course of action. The data recorded in the eCRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
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 Pre-study Documentation
The following documents must be provided to the sponsor before shipment of daratumumab to the
study site:
Protocol and amendment(s), if any, signed and dated by the principal investigator
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IRB approval of the protocol, amendments, ICF, any recruiting materials, and, if applicable,
patient compensation programs. This approval must clearly identify the specific protocol by
title and number and must be signed (or sealed, where appropriate per local regulations) by
the chairman or authorized designee
Name and address of the IRB, including a current list of the IRB members and their function,
with a statement that it is organized and operates according to GCP and the applicable laws
and regulations. If accompanied by a letter of explanation, or equivalent, from the IRB, a
general statement may be substituted for this list. If an investigator or a member of the study-

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site personnel is a member of the IRB, documentation must be obtained to state that this person
did not participate in the deliberations or in the vote/opinion of the study
Regulatory authority approval or notification, if applicable
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
Documentation of investigator qualifications (eg, curriculum vitae)
Completed investigator financial disclosure form from the principal investigator, where
required
Signed and dated clinical trial agreement, which includes the financial agreement
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first patient:
Completed investigator financial disclosure forms from all sub-investigators
Documentation of sub-investigator qualifications (eg, curriculum vitae)
Name and address of any local laboratory conducting tests for the study and a dated copy of
current laboratory normal ranges for these tests, if applicable
Local laboratory documentation  demonstrating competence and test reliability
(eg, accreditation/license), if applicable
17.3. Patient Identification, Enrollment, and Screening Logs
The investigator agrees to complete a patient identification and enrollment log to permit easy
identification of each patient during and after the study. This document will be reviewed by the
sponsor study-site contact for completeness.
The patient identification and enrollment log will be treated as confidential and will be filed by the
investigator in the study file. To ensure patient confidentiality, no copy will be made. All reports
and communications relating to the study will identify patients by patient identification and date
of birth (as allowed by local regulations). In cases where the patient is not enrolled into the study,
the date seen and date of birth (as allowed by local regulations) will be used.
The investigator must also complete a patient screening log, which reports on all patients who
were seen to determine eligibility for inclusion in the study.
17.4. Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
patient 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;
intervention receipt/dispensing/return records; study treatment(s) administration information; and
date of study completion and reason for early discontinuation of study treatment(s) or withdrawal
from the study, if applicable.

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The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent documents). The minimum source documentation requirements for
Section 4.1, Inclusion Criteria and Section 4.2, Exclusion Criteria that specify a need for
documented medical history are as follows:
Referral letter from treating physician
Complete history of medical notes at the site
Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by patient interview or other protocol required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
An electronic source system may be utilized, which contains data traditionally maintained in a
hospital or clinic record to document medical care (eg, electronic source documents) as well as the
clinical study-specific data fields as determined by the protocol. These data are electronically
extracted for use by the sponsor. If the electronic source system is utilized, references made to the
eCRF in the protocol include the electronic source system, but information collected through the
electronic source system may not be limited to that found in the eCRF. Data in this system may be
considered source documentation.
17.5. Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each patient in electronic format.
All eCRF entries, corrections, and alterations must be made by the investigator or authorized
study-site personnel. The investigator must verify that all data entries in the eCRF are accurate and
correct.
The study data will be transcribed by study-site personnel from the source documents onto an
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets (eg, cytogenetic worksheet) may be used for the capture of some data to facilitate
completion of the eCRF. Any such worksheets will become part of the patient’s source documents.
Data must be entered into eCRF in English. The eCRF must be completed as soon as possible after
a patient visit and the forms should be available for review at the next scheduled monitoring visit.
All patientive measurements (eg, pain scale information or other questionnaires) will be completed
by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after
the initial entry into the eCRF, this can be done in either of the following ways:

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Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
17.6. Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor’s database.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before
the start of the study. The sponsor will review eCRF for accuracy and completeness during on-site
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with the
investigator or designee, as appropriate. After upload of the data into the study database they will
be verified for accuracy and consistency with the data sources.
17.7. Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each patient, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custodymust be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.

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17.8. Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, or on-site
monitoring) to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study-site visit log that will be kept at the study site. The first post-
initiation visit be scheduled within two to three weeks of the first patient’s screening visit.
Subsequent on-site monitoring visits will be scheduled as established in the monitoring frequency
for the study and will be communicated by the site manager. At these visits, the monitor will
compare the data entered into the eCRF with the source documents (eg, hospital/clinic/physician’s
office medical records). The nature and location of all source documents will be identified to
ensure that all sources of original data required to complete the eCRF are known to the sponsor
and study-site personnel and are accessible for verification by the sponsor study-site contact. If
electronic records are maintained at the study site, the method of verification must be discussed
with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the
relevant study-site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts will occur on a regular basis. It is expected
that during these remote contacts, study-site personnel will be available to provide an update on
the progress of the study at the site. Central monitoring will take place for data identified by the
sponsor as requiring central review.
17.9. Study Completion/Termination
17.9.1. 
Study Completion/End of Study
The end of the study is defined as 36 months from the date of randomization of last patient. If a
patient has died, the date and cause of deathwill be collected and documented in the eCRF. Patients
benefiting from treatment with daratumumab and/or lenalidomide may  continue receiving
treatment after the end of the study treatment period of 36 months and after the end of the study,
per the investigator’s discretion. However, because the study specified treatment is for 36 months,
the sponsor will not provide daratumumab and/or lenalidomide after the end of the study, unless
required by local health regulatory authorities. The final data from the study site will be sent to the
sponsor (or designee) after completion of the final patient assessment at that study site, in the time
frame specified in the Clinical Trial Agreement.

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17.9.2. 
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
studysite is considered closed when all required documents and study supplies have been collected
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided that 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 the following:
Failure of the investigator to comply with the protocol, the requirements of the IRB or local
health authorities, the sponsor’s procedures, or GCP guidelines
Inadequate recruitment of patients by the investigator
Discontinuation of further daratumumab development
17.10. On-site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Patient privacy must, however, be respected.
The investigator and study-site personnel are responsible for being present and available for
consultation during routinely scheduled study-site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding daratumumab or the sponsor’s
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, and formulation information) supplied by the sponsor to the investigator and not
previously published and any data generated as a result ofthis 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.

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The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development ofdaratumumab and thus may be disclosed
as required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report (CSR) generated by the sponsor
and will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. As applicable, results of
analyses performed after the CSR has been issued will be reported in a separate report and will not
require a revision of the CSR. Study patient identifiers will not be used in publication of results.
Any work created in connection with performance of the study and contained in the data that can
benefit from copyright protection (except any publication by the investigator as provided for
below) shall be the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and substudy approaches, secondary results generally should not be
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 18months after study end date, or the sponsor confirms that there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on guidelines such as those described in the ICMJE Recommendations for the Conduct,
Reporting, Editing, and Publication of Scholarly Work in Medical Journals, which state that the
named authors must have made a significant contribution to the conception or design of the work
or the acquisition, analysis, or interpretation of the data for the work; drafted the work or revised
it critically for important intellectual content; given final approval of the version to be published;
and agreed to be accountable for all aspects of the work in ensuring that questions related to the
accuracy or integrity of any part of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law.

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teasing out monoclonal antibody interference. Clin Chem Lab Med. 2016;54(6):1095-1104.
29. Moreau P, Attal M, Hulin, C, et al. Bortezomib, thalidomide, and dexamethasone with or without
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36. Owen RG, Rawstron AC. Minimal residual disease monitoring in multiple myeloma: flow cytometry is the
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survival in multiple myeloma. Nordic Myeloma Study Group. Br J Haematol. 1997;97:29-37.

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Attachment 1: Asthma Guidelines
Components of
Severity
Classification ofAsthma Severity
Intermittent
Persistent
Mild 
Moderate 
Severe
0-4
yrs
5-11 yrs 
12 + yrs 
0-4yrs 
5-11 yrs 12 + yrs 
0-4yrs 
5-11 yrs 12 + yrs 
0-4yrs 
5-11 yrs 12 + yrs
Impairment
Normal
FEV1/FVC :
8-19yr 85%
20-39yr 80%
40-59yr 75%
60-80yr 70%
Symptoms
≤2 days/week  
≥2 days/week but not daily  
Daily 
Throughout the day
Nighttime
awakenings
0
≤2×/month
1-2×/
month  
3-4x/month  
3-4×/month
>1×/week but not
nightly
>1×/month  
Often 7×/week
SABA use for
symptom control
(not prevention
of EIB)
≤2 days/week  
≤2 days/week but not daily 
>2 days/
week but
not daily, 
and
not more
than 1×
on
any day
Daily 
Several times per day
Interference with
normal activity
None 
Minor limitation  
Some limitation  
Extremely limited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1
between
exacerbations
>80%
>85%
Normal FEV1
between
exacerbations
>80%
Normal
N/A  
>80%
>80%
>80%
Normal
N/A  
60-80%
75-80%
60-80%
Reduced
5%
N/A
<60%
<75%
<60%
Reduced
5%
Risk
Exacerbations
requiring oral
systemic
corticosteroids
0-1/year
≥2 exacerbations in 6
months requiring oral
steroids or >4 wheezing
episodes/1 year lasting
>1 day and risk factors
for persistent asthma
≥2/year 
Relative 
annual risk 
may be 
related to 
FEV1. 
≥2/year
Relative
annual risk
may be
related to
FEV1.
≥2 exacerbations in 6
months requiring oral
steroids or >4
wheezing
episodes/1 year
lasting >1 day and
risk factors for
persistent asthma
≥2/year
Relative
annual risk
may be
related to
FEV1.
≥2/year
Relative
annual risk
may be
related to
FEV1.
≥2 exacerbations in
6 months requiring
oral steroids or >4
wheezing
episodes/1 year
lasting >1 day and
risk factors for
persistent asthma
≥2/year
Relative
annual risk
may be
related to
FEV1.
≥2/year
Relative
annual risk
may be
related
to FEV1.
Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category.

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Recommended 
Step for 
Initiating 
Treatment 
Step 1 
Step 2 
Step 3 and consider 
short course of oral 
steroids 
Step 3: 
medium  
dose ICS  
and 
consider 
short 
course of 
oral
steroids
Step 3 and 
consider 
short course 
of oral 
steroids 
Step 3 and 
consider short 
course of oral 
steroids 
Step 3: 
medium dose 
ICS or Step 4 
and consider 
short course of
oral steroids
Step 4or 5
and
consider
short
course
of oral
steroids
In 2-6 weeks, evaluate level of asthma control that is achieved.
0-4years: If no clear benefit is observed in 4-6 weeks, stop treatment and consider alternate diagnosis or adjusting
therapy. 5-11 and 12+ years: adjust therapy accordingly.
Components of
Control
Classification of Asthma Control
Well Controlled 
Not Well Controlled 
Very Poorly Controlled
0-4 yrs 
5-11 yrs 
12 + yrs 
0-4 yrs 
5-11 yrs 
12 + yrs 
0-4 yrs 
5-11 yrs 
12 + yrs
Symptoms 
≤2 days/week but not 
more than once on 
each day 
≤2 days/ 
week  
>2 days/week or
multiple times on 
≤2 days/week  
>2 days/ 
week
Throughout the day
Impairment
Nighttime
awakenings 
≤1×/month  
≤2×/month  >1×/month  ≥2×/month  1-3×/week 
>1×/week ≥2×/week ≥4×/week
Interference with
normal activity  
None 
Some limitation 
Extremely limited
SABA use for symptom
control (not prevention of
EIB) 
≤2 days/week  
>2 days/week  
Several times per day
Lung function
FEV1 or peak flow  
FEV1/FVC
N/A  
>80% 
>80% 
>80% 
N/A  
60-80% 
75-80% 
60-80% 
N/A  
<60%
<75%
<60%
Validated questionnaires 
ATAQ  
ACQ
ACT
0 
≤0.75  
≥20 
1-2 
≥1.5  
16-19 
3-4
N/A
≤15
Risk  
Exacerbations requiring 
oral systemic
corticosteroids 
0-1/year 
≥2/year
Consider severity and interval since last exacerbation
Reduction in lung growth/
Progressive loss of lung 
function
Evaluation requires long-term follow-up
• Maintain current step  
Step up 1 
step  
Step up at 
least 1 
step  
• Step up 1 
step  
• Re-evaluate 
• Consider short 
course of oral 
steroids
• Consider
short

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Recommended Action for
Treatment
• Regular follow-up every 1
to 6 months
• Consider step down if well
controlled for at least 3
months
in 2-6 
weeks 
• For side
effects,
consider
alternative
treatment
options
• Step up 1 to 2 steps 
course of
oral steroids
• Step up 1
to 2 steps
• Re-
evaluate in
2 weeks
• For side
effects,
consider
alternative
treatment
options
• Before step up: 
Review adherence to 
medication, inhaler 
technique, and 
environmental control. 
If alternative treatment 
was used, discontinue 
it and use preferred 
treatment for that step. 
• Re-evaluate the 
level of asthma 
control in 2 to 6  
weeksto achieve 
control. 
0to 4 years: If no clear 
benefit is observed in  
4to 6 weeks, consider 
alternative diagnoses or 
adjusting therapy. 
5 to 11 years: Adjust 
therapy accordingly. 
• For side effects, 
consider alternative 
treatment options. 
• Before step up:
Review adherence to
medication, inhaler
technique, and
environmental control.
If alternative treatment
was used, discontinue
it and use preferred
treatment for that step.
• Re-evaluate the
level of asthma
control in 2 to 6
weeksto achieve
control.
0to 4 years: If no clear
benefit is observed in
4to 6 weeks, consider
alternative diagnoses
or adjusting therapy.
5 to 11 years: Adjust
therapy accordingly.
• For side effects,
consider
alternative
treatment options.
ACQ = asthma control questionnaire; ACT = asthma control test; ATAQ = asthma therapy assessment questionnaire; EIB = exercise-induced bronchoconstriction; FEV1 = forced
expiratory volume (in 1 second); FVC = forced vital capacity; ICS = inhaled corticosteroids; N/A = not applicable; SABA = short-acting beta agonist.

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Attachment 2: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a
consequence of the underlying disease or condition under investigation (disease-related) or
background regimen.
For the purposes of this study, the following events will be considered anticipated events:
Bleeding
Bone diseases
Hypercalcemia
Hyperuricemia
Hyperviscosity syndrome
Infection
Renal failure or insufficiency
Reporting of Anticipated Events
All AEs will be recorded in the eCRF regardless of whether considered to be anticipated events
and will be reported to the sponsor as described in Section 12.3.1, All Adverse Events. Any
anticipated event that meets serious adverse event criteria will be reported to the sponsor as
described in Section 12.3.2, Serious Adverse Events. Each anticipated event will be assessed by
the investigator at the individual case level and if considered to be drug-related will undergo
expedited reporting (if appropriate) as per applicable clinical trial legislation to Health Authorities
and IRB/ECs. If an anticipated event is considered disease-related or not related to study drug the
event will be exempt from expedited reporting.
To meet US  regulatory clinical trial legislation, the sponsor will perform aggregate review of
anticipated events as outlined below, and if determined to be drug-related will implement
expedited reporting of these events to Health Authorities and IRBs/ECs. If an interim analysis of
trial results leads to an unblinded, aggregate review of safety data by the study team, the sponsor
may terminate the review of pre-specified anticipated events outlined above.
Safety Assessment Committee
A Safety Assessment Committee (SAC) will be established to perform reviews of pre-specified
anticipated events at an aggregate level. The SAC is a safety committee within the sponsor’s
organization that is independent of the sponsor’s study team. The SAC will meet to aid in the
recommendation to the sponsor’s study team as to whether there is a reasonable possibility that an
anticipated event is related to the study drug based on a review of the aggregate data by arm.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold
to trigger an aggregate analysis of anticipated events, will be provided in a separate Anticipated
Events Safety Monitoring Plan.

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Attachment 3: Contraceptive (and Barrier) Guidance and Collection of Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 4.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 12.3.3, Pregnancy and
Section 12.1.1 Adverse Events: Definitions and Classifications.
Refer to Guidance for Contraceptive and Barrier Use below.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required to
use one of the non-estrogen-containing hormonal highly effective contraceptive methods if she
wishes to continue HRT during the study.
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal
occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should
be consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
For Lenalidomide studies
Lena website: http://www.revlimidrems.com/
Further information about the REMS programs is available at: www.celgeneriskmanagement.com
1. 
For women of childbearing potential, adequate contraception, without interruption, must
begin 28 days before starting lenalidomide and continue during the Treatment Phase,
during any dose interruptions, and for at least 4 weeks after the last dose of lenalidomide.
All women must not donate ova during the study and for at least 4 weeks after the last
dose of lenalidomide. All women must not breastfeed while taking lenalidomide and for
at least 28 days after the last dose of lenalidomide.
2 
Prior to starting lenalidomide, two negative pregnancy tests are required. The first
pregnancy test must be performed within 10 to 14 days prior to the start of lenalidomide

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and the second pregnancy test must be performed within 24 hours prior to the start of
lenalidomide.
3 
During the Treatment Phase, pregnancy tests are required weekly during Cycle 1 and then
monthly in subsequent cycles in women with regular menstrual cycles or every 2 weeks
in women with irregular menstrual cycles. A pregnancy test is also required at the End of
Treatment Visit and 28 days following the last dose of lenalidomide for women with
regular menstrual cycles or 14 and 28 days following the last dose of lenalidomide for
women with irregular menstrual cycles. Additional pregnancy tests may be required, as
specified in the local lenalidomide REMS (where lenalidomide is supplied locally) or the
Lenalidomide Global Pregnancy Prevention Plan in Attachment 3 (where lenalidomide is
supplied centrally and no local lenalidomide REMS program exists).
4 
A man who is sexually active with a pregnant woman or a woman of childbearing
potential must always use a latex or synthetic condom during the study and for at least 4
weeks after discontinuing lenalidomide (even if he has undergone a successful
vasectomy). All men must not donate semen or sperm during the study, during dose
interruptions, or for at least 4 weeks after the last dose of lenalidomide.
5 
Because of the embryo-fetal risk of lenalidomide, all patients must adhere to the local
lenalidomide REMS program (when lenalidomide is supplied locally), or the
lenalidomide Global Pregnancy Prevention Plan provided in Attachment 3 (when
lenalidomide is supplied centrally and no local lenalidomide REMS program exists).
6 
Patients must not donate blood during therapy, during dose interruptions, and for at least
4 weeks following discontinuation of lenalidomide.

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Lenalidomide Global Pregnancy Prevention Plan
Where lenalidomide is supplied locally, patients must adhere to the local lenalidomide REMS
program. Where lenalidomide is supplied centrally and no local lenalidomide REMS program
exists, then patients must adhere to the lenalidomide Global Pregnancy Prevention Plan provided
in this attachment.
Within this attachment only, use of the phrase “study drug” refers to lenalidomide.
1.1 Pregnancy Prevention Risk Management Plans
1.1.1 Lenalidomide Pregnancy Prevention Risk Management Plan
1.1.1.1 Lenalidomide Pregnancy Risk Minimisation Plan for Celgene Clinical Trials
This attachment applies to all patients receiving lenalidomide therapy. The following Pregnancy
Risk Minimisation Plan documents are included:
1) Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable
Birth Control Methods (Section 1.1.1.2);
2) Lenalidomide Education and Counseling Guidance Document (Section 1.1.1.3);
3) Lenalidomide Information Sheet (Section 1.1.1.4).
1. The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and
Acceptable Birth Control Methods document (Section 1.1.1.2) provides the
following information:
Potential risks to the fetus associated with lenalidomide exposure
Definition of Female ofChildbearing Potential
Pregnancy testing requirements for patients receiving Lenalidomide who are
females ofchildbearing potential
Acceptable birth control methods for both female of childbearing potential and male
patients receiving Lenalidomide in the study
Requirements for counseling of all study patients receiving Lenalidomide about
pregnancy precautions and the potential risks of fetal exposure to lenalidomide
2. The Lenalidomide Education and Counseling Guidance Document
(Section 1.1.1.3) must be completed and signed by either a trained counselor or
the Investigator at the participating clinical center prior to each dispensing of
lenalidomide study treatment. A copy of this document must be maintained in the
patient records.
3. The Lenalidomide Information Sheet (Section 1.1.1.4) will be given to each
patient receiving lenalidomide study therapy. The patient must read this document
prior to starting lenalidomide study treatment and each time they receive a new
supply of study drug.

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1.1.1.2 Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and
Acceptable Birth Control Methods)
Risks Associated with Pregnancy
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic
active substance that causes severe life-threatening birth defects. An embryofetal development
study in animals indicates that lenalidomide produced malformations in the offspring of female
monkeys who received the drug during pregnancy. The teratogenic effect of lenalidomide in
humans cannot be ruled out. Therefore, a risk minimization plan to prevent pregnancy must be
observed.
Criteria for females of childbearing potential (FCBP)
This protocol defines a female of childbearing potential as a sexually mature woman who: 1) has
not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential)
for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive
months).
Counseling
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following
are met (ie, all females of childbearing potential must be counseled concerning the following risks
and requirements prior to the start of lenalidomide study therapy):
She understands the potential teratogenic risk to the unborn child
She understands the need for effective contraception, without interruption, 4 weeks before
starting study treatment, throughout the entire duration of study treatment, dose interruption
and 28 days after the end of study treatment
She should be capable of complying with effective contraceptive measures
She is informed and understands the potential consequences of pregnancy and the need to
notify her study doctor immediately if there is a risk of pregnancy
She understands the need to commence the study treatment as soon as study drug is
dispensed following a negative pregnancy test
She understands the need and accepts to undergo pregnancy testing based on the frequency
outlined in this protocol (Section 1.1.1.2)
She acknowledges that she understands the hazards and necessary precautions associated
with the use of lenalidomide
The investigator must ensure that for females of childbearing potential:
Complies with the conditions for pregnancy risk minimization, including confirmation that
she has an adequate level of understanding
Acknowledge the aforementioned requirements
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the
following are met (i.e., all females NOT of childbearing potential must be counseled concerning
the following risks and requirements prior to the start of lenalidomide study therapy):

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She acknowledges that she understands the hazards and necessary precautions associated with
the use of lenalidomide
Traces of lenalidomide have been found in semen. Male patients taking lenalidomide must meet
the following conditions (ie, all males must be counseled concerning the following risks and
requirements prior to the start of lenalidomide study therapy):
Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female
or a female of childbearing potential
Understand the need for the use of a condom even if he has had a vasectomy, if engaged in
sexual activity with a pregnant female or a female of childbearing potential.
Contraception
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable
forms of contraception simultaneously or to practice complete abstinence from heterosexual
contact during the following time periods related to this study: 1) for at least 28 days before starting
study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 28 days
after study treatment discontinuation.
The two methods of reliable contraception must include one highly effective method and one
additional effective (barrier) method. FCBP must be referred to a qualified provider of
contraceptive methods if needed. The following are examples of highly effective and additional
effective methods of contraception:
Highly effective methods:
- Intrauterine device (IUD)
- Hormonal (birth control pills, injections, implants)
- Tubal ligation
- Partner’s vasectomy
Additional effective methods:
- Male condom
- Diaphragm
- Cervical Cap
Because of the increased risk of venous thromboembolism in patients with multiple myeloma
taking lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended.
If a patient is currently using combined oral contraception, the patient should switch to one of the
effective methods listed above. The risk of venous thromboembolism continues for 4 to 6 weeks
after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be
reduced during co-treatment with dexamethasone.
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be
considered particularly in patients with neutropenia.

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Pregnancy testing
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be
performed for females of childbearing potential, including females of childbearing potential who
commit to complete abstinence, as outlined below.
Before starting study drug
Female Patients:
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting
study drug. The first pregnancy test must be performed within 10 to 14 days prior to the start of
study drug and the second pregnancy test must be performed within 24 hours prior to the start of
study drug. The patient may not receive study drug until the study doctor has verified that the
results of these pregnancy tests are negative.
Male Patients:
Must practice complete abstinence or agree to use a condom during sexual contact with a pregnant
female or a female of childbearing potential while participating in the study, during dose
interruptions and for at least 28 days following study drug discontinuation, even if he has
undergone a successful vasectomy.
During study participation and for 28 days following study drug discontinuation
Female Patients:
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the
first 28 days of study participation and then every 28 days while on study, at study
discontinuation, and at day 28 following study drug discontinuation. If menstrual cycles are
irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days
while on study, at study discontinuation, and at days 14 and 28 following study drug
discontinuation.
At each visit, the Investigator must confirm with the FCBP that she is continuing to use two
reliable methods of birth control.
Counseling about pregnancy precautions and the potential risks of fetal exposure must be
conducted at a minimum of every 28 days.
If pregnancy or a positive pregnancy test does occur in a study patient, study drug must be
immediately discontinued.
Pregnancy testing and counseling must be performed if a patient misses her period or if her
pregnancy test or her menstrual bleeding is abnormal. Study drug treatment must be
discontinued during this evaluation.
Females must agree to abstain from breastfeeding during study participation and for at least
28 days after study drug discontinuation.

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Male Patients:
Counseling about the requirement for complete abstinence or condom use during sexual
contact with a pregnant female or a female of childbearing potential and the potential risks of
fetal exposure to lenalidomide must be conducted at a minimum of every 28days.
If pregnancy or a positive pregnancy test does occur in the partner of a male study patient
during study participation, the investigator must be notified immediately.
Additional precautions
Patients should be instructed never to give this medicinal product to another person and to
return any unused capsules to the study doctor at the end of treatment.
Female patients should not donate blood during therapy, during dose interruptions and for at
least 28 days following discontinuation of study drug.
Male patients should not donate blood, semen or sperm during therapy, during dose
interruptions and for at least 28 days following discontinuation of study drug.
Only enough study drug for one cycle of therapy may be dispensed with each cycle oftherapy.
1.1.1.3 Lenalidomide Education and Counseling Guidance Document
To be completed prior to each dispensing of study drug.
Protocol Number: ____________________________________________
Patient Name (Print): __________________ DOB: _____/_____/_____ (mm/dd/yyyy)
(Check the appropriate box to indicate risk category)
Female: □
If female, check one:
□ FCBP (Female ofchildbearing potential): sexually mature female who: 1) has not
undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy
(the surgical removal of both ovaries) or 2) has not been naturally postmenopausal
(amenorrhea following cancer therapy does not rule out childbearing potential) for at
least 24 consecutive months (i.e., has had menses at any time during the preceding 24
consecutive months)
□ NOT FCBP
Male: □
Do Not Dispense study drug if:
The patient is pregnant.
No pregnancy tests were conducted for a FCBP.
The patient states she did not use TWO reliable methods of birth control (unless
practicing complete abstinence of heterosexual contact) [at least 28 days prior to
therapy, during therapy and during dose interruption].
FCBP:
1. I verified that the required pregnancy tests performed are negative.
2. I counseled FCBP regarding the following:

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Potential risk of fetal exposure to lenalidomide: If lenalidomide is taken during pregnancy, it
may cause birth defects or death to any unborn baby. Females are advised to avoid pregnancy
while taking lenalidomide. The teratogenic potential of lenalidomide in humans cannot be
ruled out. FCBP must agree not to become pregnant while taking lenalidomide.
Using TWO reliable methods of birth control at the same time or complete abstinence from
heterosexual contact [at least 28 days prior to therapy, during therapy, during dose interruption
and 28 days after discontinuation of study drug].
That even if she has amenorrhea, she must comply with advice on contraception
Use of one highly effective method and one additional method of birth control AT THE SAME
TIME. The following are examples of highly effective and additional effective methods of
contraception:
o Highly effective methods:
- Intrauterine device (IUD)
- Hormonal (birth control pills, injections, implants)
- Tubal ligation
- Partner’s vasectomy
o Additional effective methods:
- Male condom
- Diaphragm
- Cervical Cap
Pregnancy tests before and during treatment, even if the patient agrees not to have
reproductive heterosexual contact. Two pregnancy tests will be performed prior to receiving
study drug, one within 10 to 14 days and the second within 24 hours of the start of study drug.
Frequency of pregnancy tests to be done:
- Every week during the first 28 days of this study and a pregnancy test every 28 days
during the patient’s participation in this study if menstrual cycles are regular or every
14 days if cycles are irregular.
- If the patient missed a period or has unusual menstrual bleeding.
- When the patient is discontinued from the study and at day 28 after study drug
discontinuation if menstrual cycles are regular. If menstrual cycles are irregular,
pregnancy tests will be done at discontinuation from the study and at days 14 and 28
after study drug discontinuation.
Stop taking study drug immediately in the event of becoming pregnant and to call their study
doctor as soon as possible.
NEVER share study drug with anyone else.
Do not donate blood while taking study drug, during dose interruptions and for 28 days after
stopping study drug.
Do not breastfeed a baby while participating in this study and for at least 28 days after study
drug discontinuation.
Do not break, chew, or open study drug capsules.
Return unused study drug to the study doctor.

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3. Provide Lenalidomide Information Sheet to the patient.
FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR AT
LEAST 24 CONSECUTIVE MONTHS, A HYSTERECTOMY, OR BILATERAL
OOPHORECTOMY):
1. I counseled the female NOT of childbearing potential regarding the following:
Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP)
NEVER share study drug with anyone else.
Do not donate blood while taking study drug, during dose interruptions and for 28 days after
stopping study drug.
Do not break, chew, or open study drug capsules
Return unused study drug capsules to the study doctor.
2. Provide Lenalidomide Information Sheet to the patient.
MALE:
1. I counseled the Male patient regarding the following:
Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP).
To engage in complete abstinence or use a condom when engaging in sexual contact
(including those who have had a vasectomy) with a pregnant female or a female of
childbearing potential, while taking study drug, during dose interruptions and for 28 days
after stopping study drug.
Males should notify their study doctor when their female partner becomes pregnant and
female partners of males taking study drug should be advised to call their healthcare provider
immediately if they get pregnant.
NEVER share study drug with anyone else.
Do not donate blood, semen or sperm while taking study drug, during dose interruptions and
for 28 days after stopping study drug.
Do not break, chew, or open study drug capsules.
Return unused study drug capsules to the study doctor.
2. Provide Lenalidomide Information Sheet to the patient.
Investigator/Counselor Name (Print): ____________________
(circle applicable)
Investigator/Counselor Signature: _______________________ Date: _____/_____/_____
(circle applicable)
**Maintain a copy of the Education and Counseling Guidance Document in the patient
records.**

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1.1.1.4 Lenalidomide Information Sheet
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES
Please read this Lenalidomide Information Sheet before you start taking study drug and each
time you get a new supply. This Lenalidomide Information Sheet does not take the place of an
informed consent to participate in clinical research or talking to your study doctor or healthcare
provider about your medical condition or your treatment.
What is the most important information I should know about lenalidomide?
1. Lenalidomide may cause birth defects (deformed babies) or death of an unborn
baby.
Lenalidomide is similar to the medicine thalidomide. It is known that thalidomide causes
life-threatening birth defects. Lenalidomide has not been tested in pregnant women but
may also cause birth defects. Findings from a monkey study indicate that lenalidomide
caused birth defects in the offspring of female monkeys who received the drug during
pregnancy.
If you are a female who is able to become pregnant:
Do not take study drug if you are pregnant or plan to become pregnant
You must practice complete abstinence or use two reliable, separate forms of
effective birth control at the same time:
- for 28 days before starting study drug
- while taking study drug
- during dose interruptions of study drug
- for 28 days after stopping study drug
You must have pregnancy testing done at the following times:
- within 10 to 14 days and again 24 hours prior to the first dose of study drug
- weekly for the first 28 days
- every 28 days after the first month or every 14 days if you have irregular
menstrual periods
- if you miss your period or have unusual menstrual bleeding
- 28 days after the last dose of study drug (14 and 28 days after the last dose if
menstrual periods are irregular)
Stop taking study drug if you become pregnant during treatment
- If you suspect you are pregnant at any time during the study, you must stop study
drug immediately and immediately inform your study doctor. Your study doctor
will report all cases of pregnancy to Celgene Corporation
Do not breastfeed while taking study drug
- The study doctor will be able to advise you where to get additional advice on
contraception.
If you are a female not of childbearing potential:
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor
will confirm that you are not able to become pregnant.

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If you are a male:
Lenalidomide is detected in trace quantities in human semen. The risk to the foetus in
females ofchildbearing potential whose male partner is receiving lenalidomide is
unknown at this time.
Male patients (including those who have had a vasectomy) must practice complete
abstinence or must use a condom during sexual contact with a pregnant female or a
female that can become pregnant:
- While you are taking study drug
- During dose interruptions of study drug
- For 28 days after you stop taking study drug
Male patients should not donate sperm or semen while taking study drug and for
28 days after stopping study drug.
If you suspect that your partner is pregnant any time during the study, you must
immediately inform your study doctor. The study doctor will report all cases of
pregnancy to Celgene Corporation. Your partner should call their healthcare
provider immediately if they get pregnant.
2. Restrictions in sharing study drug and donating blood:
Do not share study drug with other people. It must be kept out of the reach of
children and should never be given to any other person.
Do not donate blood while you take study drug, during dose interruptions and for 28
days after stopping study drug.
Do not break, chew, or open study drug capsules.
You will get no more than a 28-day supply of study drug at one time.
Return unused study drug capsules to your study doctor.
Additional information is provided in the informed consent form and you can ask your studydoctor
for more information.

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Attachment 4: Protocol Amendment History
Amendment 3 (24 June 2021)
Overall Rationale for the Amendment: Administrative protocol clarifications and updates to allow for
Canadian sites to join the study, and clarify the discrepancy in inclusion/exclusion criteria.
Section number and Name 
Description of Change 
Brief Rationale
SYNOPSIS: OVERVIEW OF 
STUDY DESIGN; 3.1 
Overview of Study Design  
Revised study design and overview to include the 
addition of Canada. “Phase 3, randomized, open- 
label, active-controlled, multicenter study to be 
conducted at sites in the United States (US) and
Canada…”
Added language to allow
for the addition of
Canadian sites to the study
4.1 Inclusion Criteria 
Revised language to remove the below bullet 
points from Inclusion Criterion #2. 
a. For patients who have not 
received consolidation therapy,
the patient must be within
180 days post-transplant at the
time of randomization.
b. For patients treated with
consolidation therapy, the
patient must be within 90 days
of the last dose of consolidation
therapy at the time of
randomization.
Removed bullets a) and b)
from Inclusion Criterion 2
to align with changes made
during Amendment 2.
6.1 Daratumumab and 
Lenalidomide Dosing and 
Supply  
Revised the language within Daratumumab and 
Lenalidomide dosing to include the following 
statement. “… or the lenalidomide Global 
Pregnancy Prevention Plan (when lenalidomide is 
supplied centrally and no local lenalidomide
REMS program exists) in Attachment 3.”
Added language to align
with lenalidomide
reporting requirements for
Canadian sites.
6.2.2.1 Pre-administration
Medications
Revised the language to indicate correct cycle for
dexamethasone step down dosing. “(for example,
12 mg on C2D1, 8 mg on C2D8, and 4 mg on
C2D15, with no dexamethasone being given on
C2D22 and beyond).”
Updated language to align
with Time and Events
Schedule for step down
dosing of dexamethasone.
14. STUDY TREATMENT
INFORMATION
Revised the language to remove “Daratumumab
will be supplied by the sponsor. Lenalidomide is
commercially available.” The following language
was added in its place, “For the purposes of this
study, study drug refers to daratumumab”.
Removed prior language to
align protocol with
Canadian drug provision
requirements.
17.9.1 Study Completion/End
of Study
Revised the language to include the bolded
language, “… daratumumab and/or
lenalidomide may continue receiving treatment
after the end of the study treatment period of
36 months and after the end of the study, per the
Added language to align
protocol with Canadian
drug provision
requirements.

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Section number and Name 
Description of Change 
Brief Rationale
investigator’s discretion. However, because the
study specified treatment is for 36 months, the
sponsor will not provide daratumumab and/or
lenalidomide after the end of the study, unless
required by local health regulatory
authorities.”
Attachment 3 
Revised the language to include the Lenalidomide 
Global Pregnancy Prevention Plan. 
Added the Lenalidomide
Global Pregnancy
Prevention Plan for
Canadian sites joining the
study.
Amendment 2 (08 July 2020)
Overall Rationale for the Amendment: Protocol clarification and revision of inclusion/exclusion
criteria, including removal of the 8-cycle upper limit, and extension of screening window to 60 days.
Section number 
and Name
Description ofChange 
BriefRationale
SYNOPSIS: 
HYPOTHESIS; 
OBJECTIVES AND
ENDPOINTS – Primary
Objective, OVERVIEW
OF STUDY DESIGN,
PATIENT
POPULATION; 1
Introduction; Table 1.
Objectives and Endpoints
– Primary Objective; 2.2
Hypothesis; 3.1 Overview
of Study Design; 3.2.1
Overall Rationale for
Study Design; 3.2.3
Subcutaneous
Daratumumab Dosing and
rHuPH20 Concentration
Chosen for This Study;
4.1 Inclusion Criteria;
Figure 1. Schematic
Overview of the Study
Revised language to remove “with or without 
consolidation therapy.” 
To align with changes
in inclusion criteria.
SYNOPSIS: 
OBJECTIVES AND 
ENDPOINTS – Primary 
Objective, OVERVIEW 
OF STUDY DESIGN; 1 
Introduction; Table 1. 
Objectives and Endpoints
– Primary Objective; 3.1
Overview of Study
Design; 3.2.1 Overall
Revised study objectives and inclusion criterion 
#5 to require that enrolled patients have MRD 
positivity, as determined by NGS, at the time of 
screening (revised from “post-transplant” in 
some sections). 
To clarify that MRD
positivity must be
documented no earlier
than 30 days before the
start of the screening
period.

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Section number
and Name
Description ofChange 
BriefRationale
Rationale for Study
Design; Figure 1.
Schematic Overview of
the Study
SYNOPSIS: OVERVIEW
OF STUDY DESIGN; 3.1
Overview of Study Design
Strikethrough text was removed:
“This is a Phase 3, randomized, open-label,
active-controlled, multicenter study to be
conducted at approximately 50 to 60 sites in the
United States (US)…”
To remove language
specifying approximate
number of study sites.
SYNOPSIS: OVERVIEW
OF STUDY DESIGN,
PATIENT
POPULATION; 1
Introduction; 3.1
Overview of Study
Design; 3.2.1. Overall
Rationale for Study
Design; 4.1 Inclusion
Criteria; Figure 1.
Schematic Overview of
the Study
Revised study design and inclusion criterion #2
to replace “4 to 8 cycles of induction” with “a
minimum of4 to 8cycles of induction
therapy.”
To remove the 8-cycle
upper limit to allow for
additional therapy prior
to transplant for
patients whose
transplant is delayed
due to COVID-19
pandemic.
SYNOPSIS: OVERVIEW
OF STUDY DESIGN,
PATIENT
POPULATION; TIME
AND EVENT
SCHEDULE – PART 1:
OVERALL STUDY
PROCEDURES; 1
Introduction; 3.1
Overview of Study
Design; 3.2.1. Overall
Rationale for Study
Design; 4.1 Inclusion
Criteria; Figure 1.
Schematic Overview of
the Study
Revised study design and inclusion criterion
#2 to replace the description of the interval
between transplant and randomization—“within
180 days post-transplant”—with “within 6
months of ASCT” on the date of randomization.
To make this eligibility
criterion easier for sites
to accurately determine
eligibility window
between transplant date
and randomization.
Revised study design and inclusion criterion
#2 to include that patients must “have undergone
HDT and ASCT within 12 months of the start of
induction therapy.”
To limit the amount of
time elapsed between
induction and
HDT/ASCT in light of
removal of 8-cycle
upper limit for
induction therapy.
SYNOPSIS: PATIENT
POPULATION; 3.1
Overview of Study
Design; 4.1 Inclusion
Criteria
Revised inclusion criterion #4 sub-bullets to
reflect the following changes (bolded text was
added; strikethrough text was removed):
o Non-decalcified diagnostic bone marrow
aspirate clot sections (block or slides) for
MRD assessment:
A Formalin fixed paraffin embedded
(FFPE) block of bone marrow aspirate
clot, or 5 slides (preferably 5 slides, if
available), 5 µm each, of non-decalcified
bone marrow, or
5 sSlides (preferably 5 slides, if
available), bone marrow aspirate smear.
Please note, bone marrow core sections
are not acceptable samples for analysis.
In exceptional circumstances when
For clarification
purposes and to allow
option of post-
transplant archived
bone marrow sample
for MRD analysis for
patients whose pre-
induction or pre-
transplant bone marrow
samples do not provide
an informative clone
due to poor specimen
quality.

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Section number
and Name
Description ofChange 
BriefRationale
index myeloma clone cannot be
identified from the archived bone
marrow sample, a post-transplant
sample can be used to identify
myeloma clone with permission from
the Sponsor.
SYNOPSIS:
OVERVIEW OF STUDY
DESIGN; TIME AND
EVENT SCHEDULE –
PART 1:
OVERALL STUDY
PROCEDURES; 4 Patient
Population
Expanded screening window from “42 days” to 
“60 days” prior to randomization. 
To expand the
timeframe for screening
window necessitated by
the switch to NGS
method for MRD
screening and the
COVID-19 pandemic.
TIME AND EVENT
SCHEDULE – PART 1:
OVERALL STUDY
PROCEDURES
Revised Screening Phase footnote to include the
following language:
“Tandem transplants are not allowed.”
For clarification
purposes.
Revised Notes for chest x-ray or full chest CT
scan to indicate that scan is not required if
performed as part of standard of care within 30
days prior to screening.
For clarification
purposes and to
simplify screening
procedure.
Revised Study Phases/Visits (Maintenance) for
ECOG performance status to include the
following language (bold text has been added):
“D1 of odd cycles (ie, C1, C3, C5, C7, and so on).”
To provide further
clarification around
“D1 of odd cycles”
schedule.
Revised Notes for 12-lead ECG to remove the
following language:
“Not required if an ECG was performed as part
of standard of care within 42 days prior to
randomization.”
For clarification
purposes and to
simplify screening
procedure.
Revised Study Phases/Visits (Maintenance) for
weight to remove the following language:
On C1D1, immediately before daratumumab SC
administration
To clarify a definitive
timeframe (C1D1).
Revised Study Phases/Visits (Maintenance) for
vital signs (bolded text was added; strikethrough
text was removed):
Daratumumab + lenalidomide arm:
- C1D1: ImmediatelyUp to 30
minutes before administration; at
end of administration; and at 0.5
and 1 hour (+/-5 minutes) after
end of administration.
To clarify definitive
timeframes.
Revised Study Phases/Visits (Maintenance) for 
hematology and serum chemistry to include the 
following language (bold text has been added):
On C1D1 and D1 of subsequent cycles, there is
no need to repeat the tests if performed within
the past 3 days.
For clarification
purposes.
Revised Notes for randomization to replace “72 
To clarify that

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Section number
and Name
Description ofChange 
BriefRationale
hours” with “3 business days” in describing the 
interval between randomization and first dose of 
study treatment on C1D1. 
randomization
timeframe refers to
business, and not
calendar, days in case
randomization occurs
after a weekend.
TIME AND EVENT
SCHEDULE –PART 1:
OVERALL STUDY
PROCEDURES (BONE
MARROW
ASPIRATE/BIOPSY)—
Procedure: Assessment of
lytic bone disease,
Extramedullary soft tissue
plasmacytomas
(in patients with history of
extramedullary soft tissue
plasmacytoma, physical or
radiologic examination to be
done as applicable)
Revised Notes as follows (bolded text was 
added; strikethrough text was removed): 
Not required during screening if performed as 
part of standard of care within 4230 days before
randomization screening.
For clarification
purposes and to
simplify screening
procedure.
Revised Procedures as follows (bolded text was 
added): 
Extramedullary soft tissue plasmacytomas
(in patients with history of extramedullary soft
tissue plasmacytoma, physical or radiologic
examination to be done as applicable)
For clarification
purposes.
TIME AND EVENT
SCHEDULE –PART 1:
OVERALL STUDY
PROCEDURES (BONE
MARROW
ASPIRATE/BIOPSY)—
Procedure: Cytogenetics -
FISH aspirate (performed
centrally)
Revised Notes as follows (bolded text was
added; strikethrough text was removed):
If central and local cytogenetic results are unnot
available, the patient will be assumed to have
normal stratified with patients with standard
cytogenetics.
To clarify language
regarding cytogenetic
risk stratification.
TIME AND EVENT
SCHEDULE – PART 1:
OVERALL STUDY
PROCEDURES—
Procedure: Blood and 24-
hour urine samples
Revised Screening and Notes for SPEP, UPEP,
Serum IFE, Urine IFE (bolded text was added;
strikethrough text was removed):
“Note that screening SPEP, UPEP, serum IFE,
and urine IFE must be done within 14 21 days
before C1D1randomization.”
To allow greater
flexibility in collecting
laboratory samples in
light of COVID-19
pandemic.
Revised Study Phases/Visits (Maintenance) for
Urine IFE (bolded text was added; strikethrough
text was removed):
Note: *Please note: SPEP, UPEP, serum IFE, and
urine IFE assays must be done during screening
(1421 days before C1D1) as well as on C1D1.
To allow greater
flexibility in collecting
laboratory samples in
light of COVID-19
pandemic.
Revised Notes to include the following language:
“During the COVID-19 pandemic, local
laboratory results can be used to determine
eligibility of the patient on a temporary basis and
with Sponsor approval before laboratory results
are collected. Local laboratory results should be
reported in eCRF as an unscheduled visit. After
the COVID-19 situation improves, all attempts
should be made to determine eligibility of the
patient based on the central laboratory results.”
To provide clarification
regarding local vs.
central laboratory
results use in relation to
COVID-19 situation.

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Section number
and Name
Description ofChange 
BriefRationale
Revised Notes to include the following language: 
On C1D1 and D1 of subsequent cycles, there is
no need to repeat the tests if performed within
the past 3 days of scheduled visit. In addition,
tests may be repeated as clinically indicated.
Results must be evaluated before each
daratumumab administration or beginning of new
cycle of lenalidomide administration.
For clarification
purposes.
TIME AND EVENT
SCHEDULE – PART 1:
OVERALL STUDY
PROCEDURES—
Footnote
Revised footnote to include language in relation 
to central laboratory tests: 
Local and central laboratory tests should be
conducted within 3 days of Day 1 of each
lenalidomide cycle (control arm) OR within 3
days of each daratumumab administration.
To provide clarification
regarding local vs.
central laboratory tests.
TIME AND EVENTS
SCHEDULE – Part 2,
Cytogenetics
Revised Lab column text (strikethrough text has
been removed):
Central and Local
3.2.2.2. Rationale for
Subcutaneous
Daratumumab
Administration
Revised text to include the following details 
related to subcutaneous daratumumab 
administration: 
“DARZALEX FasproTM (daratumumab and 
hyaluronidase-fihj) injection, for subcutaneous 
use, received FDA approval on 01 May 2020 to 
be administered at a dose of 1800 mg of 
daratumumab and 30,000 units hyaluronidase per
15 mL (120 mg and 2000 units/mL) solution in a
single-dose vial.”
To provide further
detail and clarification
on subcutaneous
daratumumab
administration
following US FDA
approval on 01 May
2020.
TIME AND EVENT
SCHEDULE – PART 1:
OVERALL STUDY
PROCEDURES (BONE
MARROW
ASPIRATE/BIOPSY);
3.2.5. MRD Assessment
Using NGS
Revised text to add the following language: 
“If a bone marrow biopsy was conducted up to 
30 days prior to the start of screening AND a 
positive MRD result based on Adaptive 
Biotechnologies’ NGS-based MRD assay is 
available, a repeat biopsy during screening is not 
required. In this situation, local PC clonality and
morphology may be used.”
To clarify interval
between bone marrow
biopsy and screening
that allows for
avoidance of repeat
biopsy during
screening.
3.2.3. Subcutaneous
Daratumumab Dosing and
rHuPH20 Concentration
Chosen for This Study
Strikethrough text was removed: 
In the proposed study, daratumumab 1800 mg SC 
will be administered in 28-day cycles using the 
standard dosing schedule for daratumumab 
monotherapy (ie, weekly during Cycles 1 and 2,
every 2 weeks during Cycles 3 through 6, and
every 4 weeks from Cycle 7 onward for a
maximum of 36 cycles) to quickly achieve and
maintain effective daratumumab concentrations.
Newly diagnosed multiple myeloma pPatients
treated with induction with or without
consolidation will be randomized after transplant
in a 1:1 ratio to maintenance therapy with SC
daratumumab and lenalidomide or lenalidomide
To align with changes
in inclusion criteria and
other language changes
in reference to
consolidation therapy.

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Section number 
and Name
Description ofChange 
BriefRationale
alone.
4.2 Exclusion Criteria 
Added new exclusion criterion #2 and 
renumbered exclusion criteria accordingly. 
Exclusion criterion #2 (bolded text was added):
Must not have progressed on MM therapy at
any time prior to screening.
For clarification
purposes.
6.2.2.1. Pre-administration 
Medications 
Expanded language on pre-administration 
corticosteroid dosing (bolded text was added; 
strikethrough text was removed): 
Corticosteroids (Long-acting or Intermediate- 
acting): Administer 20 mg dexamethasone (or 
equivalent) prior to every daratumumab injection
during Cycle 1 (first 4 doses of
daratumumab). Beginning in Cycle 2,
corticosteroids may be tapered over 3
consecutive daratumumab injections to
discontinuation at the investigator’s
discretion. The following dexamethasone
taper should be used: 12, 8, and 4 mg over 3
daratumumab injections (for example, 12 mg
on C1D1, 8 mg on C1D8, and 4 mg on C1D15,
with no dexamethasone being given on C1D22
and beyond).
To change pre-
administration steroid
requirement in light of
emerging data on safety
of discontinuing
steroids.
Expanded language on pre-administration 
antihistamine administration to include the 
following: 
“Antihistamine may be discontinued after Cycle 
2 at the investigator’s discretion if the patient has 
side effects or does not tolerate.”
To modify pre-
administration
antihistamine
requirement to allow
for discontinuation after
Cycle 2.
6.3.1. Cycle Delay  
Revised language as follows (strikethrough text 
was removed): 
On the first day of each new treatment cycle and 
before each daratumumab dose, the patient will 
be evaluated by the treating physician for
possible toxicities that may have occurred after
the previous dose(s).
To expand language on
evaluation for possible
toxicities such that this
can be done by
chemotherapy nurses.
6.3. Dose Delays and 
Dose Modifications; 
17.2.2 Required Pre-study 
Documentation  
Replaced all uses of “subinvestigator” with “sub- 
investigator.” 
Minor errors, editorial
issues, or changes for
clarity/consistency
noted in the protocol
were corrected.
6.4.2. Lenalidomide 
Updated the date provided for most recent 
prescribing information for lenalidomide from
“January 2019” to “October 2019.”
TIME AND EVENTS 
SCHEDULE – PART 2: 
DETAILS FOR BONE 
MARROW TESTING –
MRD (aspirate) by NGS  
Revised “During Screening: Collect bone
marrow aspirate and/or biopsy” language (bolded
text was added; strikethrough text was removed):
Note that archived samples collected prior to
induction therapy or prior to after transplant will
also be obtained as described in Inclusion
Criterion #4 for calibration of MRD by NGS.

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Section number
and Name
Description ofChange 
BriefRationale
ABBREVIATIONS;
Throughout the protocol
Updated all uses of “CRF” to “eCRF” and
removed “CRF” and its definition from the
abbreviations list.
9.3.6. Documentation of
Extramedullary
Plasmacytomas
Revised language as follows (bolded text was 
added): 
CT and/or PET/CT scan evaluations are an
acceptable alternative if there is no
contraindication to the use of IV contrast.
To clarify option for
use of PET/CT scan
evaluations.
9.5.3. ECGs, Chest
Imaging, Physical
Examination, and
Spirometry
Revised as follows (bolded text was added; 
strikethrough text was removed): 
A 12-lead ECG is required during screening and 
if not conducted within the previous 42 days and
may be performed during the study as clinically
indicated.
A chest x-ray or full chest CT scan is required
during screening if not conducted within the
previous 42 30 days prior to screening.
For clarification
purposes and to
simplify screening
procedure.

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Amendment 1 (09 December 2019)
Overall Rationale for the Amendment:Protocol clarification and revision of inclusion/exclusion criteria,
including MRD assessment by NGS assay during screening and to align with standard clinical practice for
multiple myeloma patients receiving maintenance treatment.
Section number 
and Name
Description of Change 
Brief Rationale
SYNOPSIS
TIME AND EVENT
SCHEDULE –PART 1:
OVERALL STUDY
PROCEDURES
Revised screening window in Synopsis and
footnote in T&E Schedule Part 1 Table from
’28 days’ to ’42 days’.
To allow time for 2 sequential
NGS assays (MM index clone
calibration and MRD
assessment) during screening.
SYNOPSIS
TIME AND EVENT
SCHEDULE –PART 1:
OVERALL STUDY
PROCEDURES
3.1. Overview of Study
Design
4.1 Inclusion Criteria
Revised Screening Phase footnote in T&E
Schedule Part 1 Table and inclusion criterion
#2a to extend the interval between transplant
and randomization from ‘60 to 100 days’ to
‘within 180 days’ post-transplant in patients
who have not received consolidation therapy.
To align with institutional best
practice to avoid the need for
multiple bone marrow sample
collection and to align the time
at which screening activities,
including MRD assessment of
the screening bone marrow
biopsy, must start with
institutional clinical practice
timelines
Revised inclusion criterion #2b to extend the
interval between last dose of consolidation
therapy post-autologous stem cell transplant
(ASCT) and randomization from ‘60 days’ to
‘within 90 days’ of the last dose of
consolidation therapy.
Revised inclusion criterion #4 to indicate that
existing results from Adaptive
Biotechnologies’ NGS-based MRD assay,
conducted post-ASCT may be used for
identification of index myeloma clone and in
that case, an archived sample is not required.
Revised inclusion criterion #4b and #4b(i) to
clarify acceptable archived samples (eg,
aspirate clot).
To align with the clot collection
and dispatch of whole block
(formalin fixed paraffin
embedded bone marrow
aspirate clot) at US sites.
Revised inclusion criterion #5 to conduct
screening of MRD status by NGS assay.
Since Adaptive
Biotechnologies’ NGS-based
MRD assay has received FDA
clearance, it will be used for
MRD assessment during
screening.
Revised inclusion criterion#7c (adequate bone
marrow function) to clarify platelet count
criteria from ‘≥50×109/L’ to ‘≥75×109/L’.
To align with other
daratumumab protocols.
Revised inclusion criterion#7c (adequate liver
function) total and direct bilirubin criteria from
‘≥1.5 folds of ULN to ‘≥2.0 folds of ULN.
Revised inclusion criterion#7b (adequate renal
function) serum calcium from ‘≤13.5 mg/dL
(≤3.4 mmol/L)’ to ‘≤14 mg/dL (≤3.5 mmol/L)’.

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Section number 
and Name
Description of Change 
Brief Rationale
SYNOPSIS  
TIME AND EVENT 
SCHEDULE –PART 1: 
OVERALL STUDY
PROCEDURES
11.6. Interim Analyses
17.9.1. Study
Completion/End of Study
Added ‘confirmed progression of disease’ and 
‘changed treatment due to study drug toxicity’ 
to the end of study definition.
To be consistent with the rest of
the protocol.
SYNOPSIS  
TIME AND EVENT 
SCHEDULE –PART 1: 
OVERALL STUDY
PROCEDURES
3.2.5. MRD Assessment
Using NG
9.3.4. Bone Marrow
Examination and Minimal
Residual Disease
Assessment
Deleted the MRD assessment by NGS at 
6 months during maintenance treatment. 
To reduce the frequency of
bone marrow collection for
patient’s convenience.
TIME AND EVENT 
SCHEDULE –PART 1: 
OVERALL STUDY 
PROCEDURES  
Revised timeline for an acceptable spirometry 
test from ‘42 days prior to screening’ to ‘up to 
‘60 days prior to transplant’. 
To accept spirometry test
conducted up to 60 days prior
to transplant as these results are
unlikely to change significantly
during screening.
TIME AND EVENT 
SCHEDULE –PART 1: 
OVERALL STUDY 
PROCEDURES  
Added details for the timing and assessment of 
vital signs, hematology, serum chemistry, HCV 
viral load, blood and 24-hour urine samples,
PC clonality assay, and morphology.
To clarify the timing and
assessment of the evaluations.
Specified that PROs should be completed at
EOT visit if the patient discontinues early and
at other specified timepoints even after the
patient discontinues the study treatment.
TIME AND EVENT 
SCHEDULE –PART 1: 
OVERALL STUDY 
PROCEDURES  
TIME AND EVENT 
SCHEDULE –PART 2: 
DETAILS FOR BONE
MARROW TESTING
9.3.4. Bone Marrow
Examination and Minimal
Residual Disease
Assessment
Revised the time of cytogenetics assessment 
from ‘within 42 days of randomization’ to ‘at 
any time from the time of multiple myeloma 
diagnosis to randomization’. 
To allow for the utilization of
historical cytogenetics data and
ensure that patients’
cytogenetics profiles are
captured as accurately as
possible.
SYNOPSIS  
TIME AND EVENT 
SCHEDULE –PART 1:
OVERALL STUDY
PROCEDURE
1.INTRODUCTION
3.2 Study Design Rationale
Added details of 3rd study CASSIOPEIA. 
To add new study data in the
context of PFS.
3.1. Overview of Study 
Design
Updated ’40 sites’ to ‘50 to 60 sites’. 
To facilitate enrollment.
4.2 Exclusion Criteria 
Deleted exclusion criterion#1 regarding 
peripheral neuropathy or neuropathic pain. 
Because study treatment does
not contain medications that

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Section number 
and Name
Description of Change 
Brief Rationale
may exacerbate neuropathy,
and patients may have residual
neuropathy from their
induction/consolidation
regimen that requires additional
time to recover should not be
excluded from the study.
Revised exclusion criterion#2 to further clarify 
on history of any concurrent malignancy. 
To align with other
daratumumab protocols.
Revised exclusion criterion#7a from 
‘seropositivity for HIV’ to ‘have no known 
history of seropositivity for HIV’.
To modify the language for
clarification.
Revised exclusion criterion#8 to add current or 
history of CNS. 
To align with other
daratumumab protocols.
Revised exclusion criterion#9b and deleted
exclusion criteria#9c and #9d.
Added sorbitol to exclusion criterion#10.
Revised exclusion criteria#12, #14, #15.
6.2 Daratumumab  
Revised instructions on preparation, dosing 
schedule, administration, and storage of 
daratumumab.
To align with other
daratumumab protocols.
Revised text on pre-and post-administration
medications.
Revised text on injection-related reactions.
6.3.1 Cycle Delay  
Revised text on delay of any treatment cycles 
and re-treatment criteria. 
To align with other
daratumumab protocols.
8 Pre-study and 
Concomitant Therapy  
Revised text on recommended, permitted, and 
prohibited therapies. 
To align with other
daratumumab protocols.
9.5.2 Clinical Laboratory 
Tests 
Revised text on effect of lenalidomide on 
WOCBP and pregnancy. 
To align with other
daratumumab protocols.
Revised text on indirect antiglobulin tests.
10 Patient 
Completion/Discontinuation 
of Treatment/Withdrawal
From the Study
Revised text to be more specific per latest 
daratumumab protocol template requirements. 
To align with other
daratumumab protocols.
11.2 Sample Size 
Determination  
Revised power from ‘80%’ to ‘at least 85%’. 
Since NGS assay will be used
for screening MRD status,
assumption of 15%
non-evaluable archived bone
marrow samples will be applied
for estimation of screening
population, and not for
estimation of final sample size.
Despite this change, the original
sample size of 214 was
retained, which increased
power from 80% to 85% for
this Phase 3 study.
11.3 Efficacy Analysis 
Added text on missing data and clarification on 
patients with MRD negative status. 
To clarify handling of missing
data and sensitivity analyses.
11.6 Interim Analyses 
Added a paragraph on interim and final 
analysis of PFS.
To address PFS analysis.
12.3.3 Pregnancy  
Revised text to be more specific on reporting of 
pregnancy. 
To align with other
daratumumab protocols.

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Section number 
and Name
Description of Change 
Brief Rationale
Attachment 2 
Deleted anemia, neutropenia, and 
thrombocytopenia from the list of anticipated 
events; revised conditions of their reporting 
period; and renamed review committee from
‘Anticipated Event Review Committee’ to
‘Safety Assessment Committee’ with its
purpose to review aggregate data by treatment
arm.
To update the language on
anticipated events as provided
by R&D.
Attachment 3 
Added details on local lenalidomide REMS  
program or the lenalidomide Global Pregnancy 
Prevention Plan.
To align with other
daratumumab protocols.

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

Signature
User 
Date 
Reason
 
23-Aug-2024
17:19:25
(GMT)
Document Approval
PPD