Clinical trial NCT03201965
Conditions: Amyloidosis
Sponsor: Janssen Research & Development, LLC
Start date: 2017-10-05; Completion date: 2024-11-19
Enrollment: 416 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of daratumumab plus cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared with CyBorD alone in treatment of newly diagnosed amyloid light chain (AL) amyloidosis participants.

Detailed description:
Participant involved in study for approx. 8 years duration includes Screening Phase (complete clinical evaluation will be done), Treatment Phase (monitoring of adverse events (AEs), laboratory abnormalities and clinical response), Post-Treatment Observation Phase (disease evaluations will be done) and a Long-term Follow-up Phase (Subsequent anticancer treatment, response to subsequent treatment, date of progression and survival status will be obtained every 16 weeks).The primary hypothesis is that daratumumab in combination with CyBorD will improve the overall complete hematological response rate compared to CyBorD alone in AL amyloidosis participants. Safety will be assessed by AEs, laboratory test results, electrocardiogram, vital sign measurements, physical examination, and Eastern Cooperative Oncology Group (ECOG) performance status.

Arms: arm 1: Participants will receive dexamethasone (40 milligrams \[mg\] orally or intravenous \[IV\] dose), followed by cyclophosphamide (300 milligram per meter square \[mg/m\^2\] orally or IV dose), then bortezomib (1.3 mg/m\^2 subcutaneous injection) weekly on Days 1, 8, 15, 22 in every 28-day cycle for a maximum of 6 cycles. arm 2: Participants will receive dexamethasone (20 mg orally or IV dose as premedication and 20 mg on the day after daratumumab dosing) followed by 1800 mg of daratumumab subcutaneously followed by cyclophosphamide (300 mg/m\^2 orally or IV dose weekly) and bortezomib (1.3 mg/m\^2 subcutaneous injection weekly) on Days 1, 8, 15, 22 in every 28-day cycle for a maximum of 6 cycles. Daratumumab will be administered weekly for the first 8 weeks (2 cycles), then every 2 weeks for 4 cycles (cycles 3-6), and then every 4 weeks until progression of disease or subsequent therapy for a maximum of 2 years.
Interventions: intervention 1: Cyclophosphamide intervention 2: Bortezomib intervention 3: Dexamethasone, 40 mg intervention 4: Daratumumab
Intervention descriptions: intervention 1: Participants will receive 300 mg/m\^2 of cyclophosphamide as an oral or IV dose. intervention 2: Participants will receive 1.3 mg/m\^2 of bortezomib as an subcutaneous (SC) injection. intervention 3: Participants of CyBorD alone arm will receive 40 mg dexamethasone orally or IV dose. Participants of CyBorD plus daratumumab arm will receive dexamethasone 20 mg orally or IV dose as premedication and 20 mg on the day after daratumumab dosing to make a total of 40 mg. intervention 4: Participants will receive 1800 mg of daratumumab subcutaneously.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved, Date: 10 October 2019
Janssen Research & Development *
Clinical Protocol
A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in 
Combination with Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) 
Compared With CyBorD Alone in Newly Diagnosed Systemic AL Amyloidosis
Protocol 54767414AMY3001; Phase 3
AMENDMENT 3
JNJ-54767414 daratumumab
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information
page that accompanies the protocol.
This compound is approved for marketing in multiple myeloma.
US sites of this study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER: 2016-001737-27
Status:
Approved
Date:
10 October 2019
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-125497413, 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 22
TIME AND EVENTS SCHEDULES ............................................................................................................ 26
ABBREVIATIONS ...................................................................................................................................... 33
1.
INTRODUCTION................................................................................................................................ 35
1.1.
Amyloidosis .................................................................................................................................... 35
1.1.1.
Bortezomib-based Treatment Options for Amyloidosis .............................................................. 36
1.1.2.
Background on Bortezomib in Combination with Cyclophosphamide and 
Dexamethasone (CyBorD regimen) ........................................................................................... 36
1.2.
Daratumumab ................................................................................................................................ 37
1.2.1.
Daratumumab in AL Amyloidosis ............................................................................................... 38
1.3.
Overall Rationale for the Study...................................................................................................... 39
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 40
2.1.
Objectives ...................................................................................................................................... 40
2.2.
Endpoints ....................................................................................................................................... 41
2.3.
Hypothesis ..................................................................................................................................... 43
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 43
3.1.
Overview of Study Design.............................................................................................................. 43
3.2.
Study Design Rationale.................................................................................................................. 45
3.2.1.
Rationale for Dose and Subcutaneous Administration............................................................... 45
3.2.2.
Rationale for Study Treatment Regimen .................................................................................... 47
3.2.3.
Rationale for Run-in Phase ........................................................................................................ 48
3.2.4.
Rationale for Biomarker Collection ............................................................................................. 49
3.2.5.
Rationale for Patient-Reported Outcome Measures .................................................................. 49
4.
SUBJECT POPULATION.................................................................................................................. 49
4.1.
Inclusion Criteria ............................................................................................................................ 50
4.2.
Exclusion Criteria ........................................................................................................................... 52
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 55
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 55
6.1.
Treatment Cycles ........................................................................................................................... 55
6.2.
Daratumumab ................................................................................................................................ 56
6.2.1.
Treatment Schedule and Administration .................................................................................... 56
6.2.2.
Dose Delays and Dose Modification........................................................................................... 57
6.2.2.1.
Dose Modification .................................................................................................................... 57
6.2.2.2.
Toxicity Management .............................................................................................................. 57
6.2.2.3.
Interruption or Missed Doses................................................................................................... 58
6.2.3.
Guidelines for Prevention and Management of Daratumumab Infusion-related 
Reactions.................................................................................................................................... 58
6.2.3.1.
Preinfusion Medication ............................................................................................................ 58
6.2.3.2.
Postinfusion Medication........................................................................................................... 58
6.2.3.3.
Management of Infusion-Related Reactions ........................................................................... 59
6.2.3.3.1.
Infusion-Related Reactions of Grade 1 or Grade 2.............................................................. 60
6.2.3.3.2.
Infusion-Related Reactions of Grade 3 or Higher................................................................ 60
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6.2.3.3.3.
Recurrent Infusion-Related Reactions ................................................................................. 60
6.2.4.
Guidelines for Management of Daratumumab Administration-related Reactions ...................... 60
6.3.
Cyclophosphamide......................................................................................................................... 61
6.3.1.
Dose Adjustments for Cyclophosphamide.................................................................................. 61
6.3.2.
Urinary Tract and Renal Toxicity ................................................................................................ 62
6.4.
Bortezomib ..................................................................................................................................... 62
6.4.1.
Dose Adjustments of Bortezomib ............................................................................................... 62
6.4.2.
Neurologic Toxicity ..................................................................................................................... 63
6.4.3.
Other Grade 3 or 4 Adverse Events ........................................................................................... 63
6.5.
Dexamethasone............................................................................................................................. 63
7.
TREATMENT COMPLIANCE............................................................................................................ 64
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 65
8.1.
Recommended Therapies.............................................................................................................. 65
8.1.1.
Prophylaxis for Pneumocystis carinii (jirovicii)............................................................................ 65
8.1.2.
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 65
8.1.3.
Prophylaxis or Management of Hemorrhagic Cystitis ................................................................ 65
8.1.4.
Management of Hepatitis B Virus Reactivation .......................................................................... 65
8.1.5.
Management of Peripheral Edema, Pulmonary Edema, Congestive Heart Failure................... 66
8.2.
Permitted Therapies....................................................................................................................... 66
8.3.
Prohibited Therapies During the First 6 Cycles of Therapy........................................................... 66
9.
STUDY EVALUATIONS .................................................................................................................... 67
9.1.
Study Procedures........................................................................................................................... 67
9.1.1.
Overview..................................................................................................................................... 67
9.1.1.1.
Bone Marrow Biopsy/Aspirate Considerations........................................................................ 67
9.1.2.
Screening Phase ........................................................................................................................ 68
9.1.2.1.
Histopathological Diagnosis of Amyloidosis ............................................................................ 68
9.1.2.2.
Factor X Deficiency ................................................................................................................. 69
9.1.3.
Treatment Phase ........................................................................................................................ 69
9.1.3.1.
Safety Run-In........................................................................................................................... 69
9.1.3.2.
Randomized Study .................................................................................................................. 70
9.1.3.3.
Autologous Stem Cell Collection Considerations.................................................................... 70
9.1.4.
End-of-Treatment........................................................................................................................ 71
9.1.4.1.
Subsequent Therapy ............................................................................................................... 71
9.1.4.2.
End-of-Treatment Visits........................................................................................................... 72
9.1.5.
Post-Treatment Observation Phase and Long-Term Follow-up................................................. 72
9.2.
Efficacy Evaluations....................................................................................................................... 72
9.2.1.
Hematologic Response Categories ............................................................................................ 73
9.2.2.
Monoclonal Protein (M-protein) Measurements in Serum and Urine ......................................... 74
9.2.3.
Determination of Organ Response............................................................................................. 75
9.2.4.
Bone Marrow Assessment.......................................................................................................... 76
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 76
9.3.1.
Evaluations ................................................................................................................................. 76
9.3.2.
Analytical Procedures................................................................................................................. 76
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 77
9.3.4.
Immunogenicity Assessments .................................................................................................... 77
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 77
9.5.
Biomarkers ..................................................................................................................................... 78
9.6.
Sample Collection and Handling.................................................................................................... 78
9.7.
Medical Resource Utilization.......................................................................................................... 78
9.8.
Patient-Reported Outcomes .......................................................................................................... 79
9.9.
Safety Evaluations ......................................................................................................................... 80
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 84
10.1.
Completion ..................................................................................................................................... 84
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10.2.
Discontinuation of Study Treatment/Withdrawal from the Study ................................................... 84
11.
STATISTICAL METHODS................................................................................................................. 85
11.1.
Subject Information ........................................................................................................................ 86
11.2.
Sample Size Determination ........................................................................................................... 86
11.3.
Efficacy Analyses ........................................................................................................................... 86
11.4.
Pharmacokinetic Analyses............................................................................................................. 87
11.5.
Immunogenicity Analyses .............................................................................................................. 87
11.6.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 87
11.7.
Biomarker Analyses ....................................................................................................................... 88
11.8.
Patient-Reported Outcomes .......................................................................................................... 88
11.9.
Safety Analyses ............................................................................................................................. 88
11.10.
Interim Analysis.............................................................................................................................. 89
12.
ADVERSE EVENT REPORTING ...................................................................................................... 89
12.1.
Definitions ...................................................................................................................................... 90
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 90
12.1.2.
Attribution Definitions.................................................................................................................. 91
12.1.3.
Severity Criteria .......................................................................................................................... 91
12.2.
Special Reporting Situations.......................................................................................................... 92
12.3.
Procedures..................................................................................................................................... 92
12.3.1.
All Adverse Events...................................................................................................................... 92
12.3.2.
Serious Adverse Events ............................................................................................................. 94
12.3.3.
Pregnancy................................................................................................................................... 95
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 95
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 95
13.1.
Procedures..................................................................................................................................... 95
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 95
14.
STUDY DRUG INFORMATION......................................................................................................... 96
14.1.
Physical Description of Study Drug(s) ........................................................................................... 96
14.2.
Packaging ...................................................................................................................................... 96
14.3.
Labeling.......................................................................................................................................... 96
14.4.
Preparation, Handling, and Storage............................................................................................... 96
14.5.
Bortezomib, Cyclophosphamide, and Dexamethasone................................................................. 96
14.6.
Drug Accountability ........................................................................................................................ 96
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 97
16.
ETHICAL ASPECTS ......................................................................................................................... 98
16.1.
Study-Specific Design Considerations........................................................................................... 98
16.2.
Regulatory Ethics Compliance....................................................................................................... 99
16.2.1.
Investigator Responsibilities ....................................................................................................... 99
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 99
16.2.3.
Informed Consent ..................................................................................................................... 100
16.2.4.
Privacy of Personal Data .......................................................................................................... 101
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 102
16.2.6.
Country Selection ..................................................................................................................... 102
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 102
17.1.
Protocol Amendments.................................................................................................................. 102
17.2.
Regulatory Documentation .......................................................................................................... 103
17.2.1.
Regulatory Approval/Notification .............................................................................................. 103
17.2.2.
Required Prestudy Documentation........................................................................................... 103
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 104
17.4.
Source Documentation................................................................................................................. 104
17.5.
Case Report Form Completion .................................................................................................... 105
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 106
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17.7.
Record Retention ......................................................................................................................... 106
17.8.
Monitoring .................................................................................................................................... 107
17.9.
Study Completion/Termination..................................................................................................... 107
17.9.1.
Study Completion/End of Study................................................................................................ 107
17.9.2.
Study Termination..................................................................................................................... 107
17.10.
On-Site Audits .............................................................................................................................. 108
17.11.
Use of Information and Publication.............................................................................................. 108
REFERENCES.......................................................................................................................................... 110
ATTACHMENT 1:
ECOG PERFORMANCE STATUS SCALE ............................................................ 113
ATTACHMENT 2:
DEFINITION OF ORGAN INVOLVEMENT BASED ON AMYLOIDOSIS 
CONSENSUS CRITERIA ................................................................................................................ 114
ATTACHMENT 3:
NYHA CLASSIFICATION ....................................................................................... 115
ATTACHMENT 4:
CONVERSION TABLE FOR GLUCOCORTICOID DOSE ..................................... 116
ATTACHMENT 5:
CALCULATED CREATININE CLEARANCE AND ESTIMATED 
GLOMERULAR FILTRATION RATE.............................................................................................. 117
ATTACHMENT 6:
GUIDELINE FOR ASTHMA ELIGIBILITY CRITERIA............................................ 118
ATTACHMENT 7:
BODY SURFACE AREA NOMOGRAM ................................................................. 119
ATTACHMENT 8:
EORTC QLQ-C30.................................................................................................... 120
ATTACHMENT 9:
SUPPLEMENTAL ITEMS TO EORTC QLQ-C30 (FROM EORTC ITEM 
BANK)
................................................................................................................................. 122
ATTACHMENT 10:
EQ-5D-5L............................................................................................................... 123
ATTACHMENT 11:
SF-36V2................................................................................................................. 126
ATTACHMENT 12:
ANTICIPATED EVENTS ....................................................................................... 132
ATTACHMENT 13:
PROTOCOL 54767414AMY3001 STUDY RISK/BENEFIT ASSESSMENT........ 134
ATTACHMENT 14:
MAYO CLINICAL CARDIAC STAGING SYSTEM ............................................... 148
ATTACHMENT 15:
LIST OF CYP3A INDUCERS AND INHIBITORS ................................................. 149
INVESTIGATOR AGREEMENT ............................................................................................................... 150
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Time and Events Schedule....................................................................................................... 26
Table 2:
Time and Events Schedule: Study Treatment Dosing.............................................................. 31
Table 3:
Efficacy of Daratumumab in AL Amyloidosis and Multiple Myeloma with AL 
Amyloidosis............................................................................................................................... 39
Table 4:
Daratumumab-Related Toxicity Management .......................................................................... 57
Table 5:
Cyclophosphamide Dose Adjustment....................................................................................... 61
Table 6:
Recommended Dose Modification for Bortezomib-related Neuropathic Pain or 
Peripheral Sensory or Motor Neuropathy ................................................................................. 63
Table 7:
Dexamethasone Dose Modification Based on Toxicity ............................................................ 64
Table 8:
Recommendations for Subsequent Therapy After Cycle 6 ...................................................... 72
Table 9:
International Amyloidosis Consensus Criteria .......................................................................... 73
Table 10:
Organ Response and Progression Criteriaa ............................................................................. 75
FIGURES
Figure 1:
Schematic Overview of the Safety Run-In................................................................................ 44
Figure 2:
Schematic Overview of the Randomized Study ....................................................................... 45
Figure 3:
Daratumumab Dosing Schedule............................................................................................... 56
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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
6 April 2017
Amendment 1
03 April 2018
Amendment 2
23 January 2019
Amendment 3
10 October 2019
Amendments below are listed beginning with the most recent amendment.
Amendment 3 (10 October 2019)
The overall reason for the amendment: The overall reason for the amendment is to clarify that an aggregated 
(hematologic and organ) progression-free survival (PFS) for this study is now split into a specific hematologic 
progression-free survival (HemPFS) which is moved to an exploratory objective, while retaining organ-specific 
response rate and duration of response as secondary objectives; add a complete hematologic response (CHR) 
analysis at 6 months; revise Severity Criteria for adverse events to align with National Cancer Institute –
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 severity definitions; update anticipated 
events in Attachment 12; and provide other revisions, updates, and clarifications based on increased knowledge 
since the start of protocol development.
Applicable Section(s)
Description of Change(s)
Rationale: Progression in amyloidosis can occur by both hematologic progression and organ progression, and 
there are currently no publications available to assess for clinical meaningfulness of aggregated (hematologic and 
organ) PFS as an endpoint in treatment of AL amyloidosis. A 6-month landmark analysis of organ-specific 
response and progression will be reported. The PFS endpoint in this study will be specific for hematologic 
parameters and renamed HemPFS.
Synopsis (OBJECTIVES
AND HYPOTHESIS);
2.1 Objectives
PFS was removed from the list of secondary objectives and HemPFS was added as 
an exploratory objective.
Synopsis (STATISTICAL 
METHODS);
2.1 Objectives (Secondary 
Objectives);
9.5 Biomarkers;
11.3 Efficacy Analyses
“PFS” was revised to “HemPFS”.
2.2 Endpoints (Secondary 
Endpoints)
The definition of PFS was deleted.
2.2 Endpoints 
(Exploratory Endpoints)
The definition of HemPFS was added.
Rationale: To add a CHR analysis at 6 months.
Synopsis (STATISTICAL 
METHODS);
11.3 Efficacy Analyses
Specified that analysis of CHR rate at 6 months will be performed similarly to the 
primary endpoint CHR rate.
2.2 Endpoints (Secondary 
Endpoints)
The definition of CHR rate at 6 months was added.
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Applicable Section(s)
Description of Change(s)
Rationale: To revise Severity Criteria for adverse events to align with NCI-CTCAE v4.03 severity definitions.
12.1.3 Severity Criteria
Definitions for Grade 1 through Grade 4 severity criteria were revised, and 
definitions were added accordingly for activities of daily living (ADL).
Rationale: An anticipated event is an AE (serious or non-serious) that commonly occurs as a consequence of the 
underlying disease or condition under investigation (disease-related) or background regimen. Some events that 
are already listed as adverse drug reactions for daratumumab can be deleted.
Attachment 12 
(Anticipated Events)
Anemia, neutropenia, and thrombocytopenia were deleted from the anticipated 
events list.
The review and reporting requirements for anticipated events were clarified.
Revised “Anticipated Event Review Committee” (ARC) to “Safety Assessment 
Committee” (SAC).
Rationale: Discordance in organ response within an individual subject can occur. Subjects with involvement in 
more than 1 organ may have discordance in organ response or progression. At baseline, a subject may have 
advanced organ damage in one organ that will progress (ie, the subject cannot overcome the existing level of 
damage). However, the same subject can have improvement in another organ.
Synopsis (STATISTICAL 
METHODS);
11.3 Efficacy Analyses
Specified that organ response/progression analysis will be performed separately for 
each organ involved at baseline, specifically for heart, kidney, and liver, and that 
descriptive statistics will be provided to summarize organ response/progression at 
6 months, time to organ response, and time to organ progression.
2.2 Endpoints (Secondary 
Endpoints)
Revised the definition of time to organ response to individually list time to cardiac 
response, time to renal response, and time to liver response.
Added a definition for time to cardiac progression, time to renal progression, and 
time to liver progression.
Clarified that organ response rate (OrRR) for kidney, heart, liver is defined as the 
proportion of baseline organ involved subjects who achieve confirmed organ 
response in each corresponding organ.
11.3 Efficacy Analyses
Specified that a transient increase in NT-proBNP, troponin T, 24-hour proteinuria, 
and alkaline phosphatase, or a transient decrease in eGFR meeting organ 
progression criteria are not considered for organ progression if it persisted less than 
6 months, and levels returned to baseline level or better.
Rationale: Patients with AL amyloidosis often experience an intolerance to or adverse events with steroid 
treatment. Infusion-related reactions (IRRs) typically occur during initial treatment cycles of daratumumab.
6.2.3.2 Postinfusion 
Medication
Revised the instructions for receiving postinfusion corticosteroids.
Rationale: During the conduct of this study, it became apparent that the Comenzo 20127 guidelines require 
clarifications. Based on a deeper understanding of disease biology and outcomes (Manwani 2018, Muchtar 
2019)27,31 as well as the impact of daratumumab on serum free light chains (Comenzo 2019)6 that affect the 
definition of a complete hematologic response, 
 
Table 9 (International 
Amyloidosis Consensus 
Criteria) 
Clarified that for progression, involved light chain must double.
A footnote was added that if iFLC<ULN and serum and urine IFE are negative, 
then neither a normal uFLC level nor a normal FLC ratio are required for complete 
response (CR).
CCI
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Applicable Section(s)
Description of Change(s)
Rationale: To provide updates to pharmacokinetic, pharmacodynamic, and immunogenicity assessments.
9.3.3 Pharmacokinetic 
Parameters
Revisions were made to align text with the sparse sampling conducted in this study.
9.4 Pharmacokinetic/ 
Pharmacodynamic 
Evaluations;
11.6 Pharmacokinetic/ 
Pharmacodynamic 
Analyses
Clarified that pharmacokinetic/pharmacodynamic modeling may be performed to 
gain understanding of the relationship between serum concentrations of 
daratumumab and endpoints of clinical efficacy or safety.
11.4 Pharmacokinetic 
Analyses
Revisions and clarifications were made to how PK data will be summarized.
11.5 Immunogenicity 
Analyses
Deleted redundant text: Separate listings of subjects who are positive for antibodies 
to daratumumab or positive for antibodies to rHuPH20 will be provided.
Rationale: Laboratory values can fluctuate for a variety of reasons.
9.2.1 Hematologic 
Response Categories
Added text to strongly recommend that hematologic disease progression be 
confirmed in a subsequent disease evaluation visit via central laboratory values 
prior to determining MOD-PFS.
Rationale: Revisions, updates, and clarifications were provided.
Synopsis (DOSAGE AND 
SC-ADMINISTRATION);
6.3 Cyclophosphamide
Clarified that the maximum absolute weekly dose of cyclophosphamide is 500 mg, 
irrespective of body surface area (BSA).
Table 5 
(Cyclophosphamide Dose 
Adjustment)
Text revised to clarify that cyclophosphamide dose could be adjusted or held if 
neutrophil and/or platelet counts or both met values specified in Table 5.
Table 1 (Patient-Reported 
Outcome)
Noted that the first 6-month post-treatment ePRO assessment should occur 
6 months after the EOT visit.
Extended the collection window for PRO in the LTFU phase to ±14 days to provide 
subjects more flexibility and improve compliance.
Table 1 (HBV DNA test);
9.9 Safety Evaluations 
(Hepatitis B Virus (HBV) 
DNA Tests)
Specified that subjects who tested positive for Anti-HBc or Anti-HBs or both will 
undergo testing for hepatitis B DNA by PCR.
9.1.3.2 Randomized Study
Added instructions that if continued treatment is desired after MOD-PFS is met, a 
discussion between the investigator and medical monitor should occur about 
whether further study treatment would benefit a subject, without safety concerns.
If disease progression is confirmed by the sponsor and no benefit is expected 
from further treatment, the subject will discontinue study treatment, complete the 
End-of-Treatment visit, and enter the Long-Term Follow-up Phase.
9.2.3 Determination of 
Organ Response
Modified text to clarify that organ disease that is considered to be quantifiable for 
response be evaluated by the central laboratory.
9.9 Safety Evaluations 
(HBV Serology)
Added text that if the Hepatitis B serologic status of a subject in the daratumumab 
plus CyBorD arm is unknown, HBsAg, Anti-HBs, and Anti-HBc testing is 
recommended if the subject is still receiving daratumumab or is within 6 months of 
the last dose.
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Applicable Section(s)
Description of Change(s)
9.9 Safety Evaluations 
(Hematology Panel)
Specified that Factor X testing is optional, but recommended if a subject will have 
an invasive procedure or experiences a clinically significant bleeding event.
10.2 Discontinuation of 
Study 
Treatment/Withdrawal 
from the Study
A subject’s study treatment must be discontinued if:
8.  The subject meets criteria for MOD-PFS endpoint (See Section 2.2), provided 
no benefit is expected from continuing treatment (see Section 9.1.3.2).
Table 9 (International 
Amyloidosis Consensus 
Criteria);
Table 10 (Organ Response 
and Progression Criteria)
A definition of baseline measurement was added as a footnote, where appropriate.
Table 9 (International 
Amyloidosis Consensus 
Criteria);
References
Three new references were added to footnote “a”.
Citations for 3 new references were added to the list of references.
Synopsis (OVERVIEW 
OF STUDY DESIGN, 
DOSAGE AND 
SC-ADMINISTRATION);
3.1 Overview of Study 
Design;
6.2.1 Treatment Schedule 
and Administration;
9.1.3.2 Randomized 
Study;
9.1.3.3 Autologous Stem 
Cell Collection 
Considerations;
9.1.4 End-of-Treatment
24 cycles is defined as approximately 2 years of daratumumab treatment ; treatment 
duration was provided as cycles from the first dose of study treatment; not years
from the start of the study.
Rationale: Minor errors and inconsistencies were noted.
Throughout the protocol
Minor errors and inconsistencies were revised, and grammatical, formatting, or 
spelling changes were made.
Amendment 2 (23 January 2019)
The overall reason for the amendment: The overall reason for the amendment is in response to identification of 
a new important risk (hepatitis B virus [HBV] reactivation). Additionally, revisions and clarifications were made 
to disease assessment, PK and immunogenicity, and biomarker timings and definitions, as well as other 
parameters throughout the Protocol.
Applicable Section(s)
Description of Change(s)
Rationale: The text for identification of HBV reactivation, testing, and management of subjects with the potential 
for HBV reactivation was added or modified in response to identification of a new important risk (HBV 
reactivation).
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JNJ-54767414 daratumumab
Clinical Protocol 54767414AMY3001 Amendment 3
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Approved, Date: 10 October 2019
Applicable Section(s)
Description of Change(s)
Table 1 Time and 
Events Schedule
Added row for HBV serology, modified text for HBV DNA test, and identified the 
timepoints at which HBV serology and HBV DNA test would be conducted.
4.2 Exclusion Criteria 
(Criterion 9)
Clarified language to exclude subjects who are seropositive for hepatitis B. Modified the 
following sentence: Subjects with resolved infection (ie, subjects who are HBsAg 
negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or 
antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time 
polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels.
8.1.4 Management of 
Hepatitis B Virus 
Reactivation
Added a new section providing information for the management of hepatitis B virus 
reactivation.
9.1.1 Overview; 16.1 
Study-Specific 
Design 
Considerations
Corrected the blood volume to be collected during the Screening Visit to approximately 
25 mL, thus accounting for HBV serology.
9.9 Safety 
Evaluations
Added and revised information detailing the conduct of hepatitis B virus serology and 
DNA tests.
Attachment 13; 
References
Removed original Attachment 13: JSH Guidelines for the Management of Hepatitis B 
Virus Infection. 
Removed Reference: Drafting Committee for Hepatitis Management Guidelines and the 
Japan Society of Hepatology (JSH). Guidelines for the management of hepatitis B virus 
infection. Hepatol Res. 2014;44(Suppl S1):1-58.
Rationale: Clarifications were made to disease assessment, PK and immunogenicity, and biomarker timings and 
definitions.
Table 1 Time and 
Events Schedule
The timing windows for EOT and long-term follow-up were modified to +/-3 days and 
+/-7 days, respectively.
Removed assessment at -28 Days for Clinical Evaluation of MOD-PFS endpoint.
Table 2 Time and 
Events Schedule
Revised measurement of vital signs: Arm A: Vital signs will be measured before study 
drug administration. Arm B: Vital signs will be measured immediately before and after 
daratumumab SC-administration start and end.
Table 1 Time and 
Events Schedule; 9.2 
Efficacy Evaluations; 
Table 9; 9.7 Medical 
Resource Utilization
Moved and clarified the instructions for the Medical Encounters Summary (From Section 
9.2 Efficacy Evaluations to Section 9.7 Medical Resource Utilization); updated notation in 
Table 1.
Clarified the following sentence: To mitigate this interference, the sponsor has developed a 
reflex assay that utilizes anti-idiotype antibody to bind daratumumab and confirm its 
interference on IFE. For all subjects on Arm B (daratumumab plus CyBorD) with 
VGPR, and a negative M-protein by SPEP, reflex IFE testing may be performed by the 
central laboratory to confirm daratumumab interference on IFE.
9.2.1 Hematologic 
Response Categories 
(Table 9)
Added clarification to the definitions of the hematologic response categories.
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JNJ-54767414 daratumumab
Clinical Protocol 54767414AMY3001 Amendment 3
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Approved, Date: 10 October 2019
Applicable Section(s)
Description of Change(s)
Table 1 Time and 
Events Schedule
Indicated that the biomarker FISH may be sent to central lab in China, and certain other 
biomarker samples will not be collected in China.
A window of +/-1 week was added to PK and immunogenicity frequency during the 
Observation Phase for Safety Run-in and Arm B only.
Table 1 Time and 
Events Schedule; 
9.2.3 Determination 
of Organ Response; 
Attachment 14
Added clarification: Note: only HS Troponin T sent to central laboratory in China.
Also made correction to troponin T in Attachment 14.
Rationale: Clarifications were made to the diagnosis of amyloidosis. 
9.1.2 Screening 
Phase; 9.1.2.1 
Histopathological 
Diagnosis of 
Amyloidosis
The clarification was added: Retesting of abnormal screening values that lead to 
exclusion are allowed only once during the screening period (to reassess eligibility). 
The last result known prior to Cycle 1 Day 1 will be used to determine eligibility.
Added clarification that mass spectrometry is not available in China.
Rationale: Clarification was made to the dosing of daratumumab with regard to management of toxicity. 
6.2.2.2 Toxicity 
Management
The clarification was added: Note: there should be at least 4 days between each 
daratumumab administration.
Rationale: Minor changes and clarifications were made throughout.
Table 2 Time and 
Events Schedule
Revised dexamethasone premedication for Treatment Arm B: Dexamethasone 20 mg. May 
be given up 1 to 3 hours before the dose of daratumumab
4.2 Exclusion Criteria 
(Criterion 19)
Added the clarification that strong CYP3A4 inducers must discontinue their use at least 5 
half-lives prior to the first dose of study treatment.
4.1 Inclusion Criteria 
(Criterion 3)
Changed the units of measure for free light chain.
3.1 Overview of 
Study Design
Clarified the treatment cycle: All treatment cycles are 4 weeks (28 days with a +/-5 day 
window) in length. 
9.1.1.1 Bone Marrow 
Biopsy/Aspirate 
Considerations
Modified the timing of sample collection: If a fresh bone marrow aspirate will not be 
performed at Screening because a sample is available within 56 days prior to 
randomization Cycle 1 Day 1.
9.1.4.1 Subsequent 
Therapy
The clarification was added: For Treatment Arm A subjects who continue CyBorD 
post 6-cycles, the continued CyBorD treatment will be considered subsequent 
therapy.
Table 1 Time and 
Events Schedule; 
12.3.1 All Adverse 
Events
The clarification was made: For subjects who have received additional treatment with 
therapeutic intent for AL amyloidosis during the AE reporting period, only AEs that are 
considered to be possibly, probably, or definitely very likely related to study drug must be 
reported.
17.4 Source 
Documentation
The clarification was made: (EORTC QLQ-C30, EQ-5D-5L, SF-36v2 Health Survey.
Rationale: Minor errors were noted.
Attachment 15
The spellings of CYP3A inducers and inhibitors were corrected.
Abbreviations
Added to the Abbreviations Table: Anti-HBc, Anti-HBs
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JNJ-54767414 daratumumab
Clinical Protocol 54767414AMY3001 Amendment 3
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Approved, Date: 10 October 2019
Applicable Section(s)
Description of Change(s)
Throughout the 
Protocol
Other minor corrections/ clarifications were made throughout the document.
Amendment 1 (03 April 2018)
The overall reason for the amendment: The overall reason for the amendment is to align with Health Authority 
requests and to revise the AL Amyloidosis response consensus criteria.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify that the informed consent form must be signed before any study-specific procedures are 
performed. 
9.1.2 Screening Phase; 
16.2.3 Informed 
Consent
Clarified that the signed ICF must be obtained from the subject before any study-specific 
procedures (not Standard of Care procedures) are performed. 
Rationale: To clarify the censoring of data for secondary endpoints of time to complete hematologic response and 
time to organ response. 
2.2 Endpoints
Removed data censoring for time to complete hematologic response and time to organ 
response.
Rationale: Stratification by cardiac stage will be based on the Mayo Clinic Cardiac Staging System. 
Synopsis; 3.1 
Overview of Study 
Design; 5 Treatment 
Allocation and 
Blinding
Stratification of subjects by Mayo Clinical Cardiac Stating (I, II, and IIIa) was specified 
and sources (Dispenzieri 2014 and Palladini 2016) were cited.
Rationale: To clarify the definition of hematologic progressive disease based on the recommendation of the 
AMY3001 Steering Committee that detectable monoclonal protein must be above a pre-defined quantitative level as 
described below, to qualify for progression. 
2.2 Endpoints; 9.2.1 
Table 9 International 
Amyloidosis 
Consensus Criteria
Changed the definition of hematologic progressive disease to the following:
From CHR, any detectable monoclonal protein or abnormal free light chain ratio (light 
chain ratio must double) Note: the development of a IgG Kappa spike on SPEP/IFE will 
not be considered disease progression for subjects who have received daratumumab, 
DIRA testing may be indicated. 
From PR, or from CHR/VGPR/PR, 50% increase in serum M-protein to >0.5 g/dL or
50% increase in urine M-protein to >200 mg/day (a visible peak must be present)
Free light chain increase of 50% to >100 mg/L
Rationale: To provide additional details regarding observation of subjects after the end of study drug administration 
during Cycle 1. 
Synopsis; 3.1 
Overview of Study 
Design; 6.2.1 
Treatment Schedule 
and Administration
Clarified that once the randomized portion of the study begins, subjects in Treatment Arm 
B (CyBorD plus daratumumab) will be observed for at least 6 hours after the end of study 
drug administration during Cycle 1 Day 1 and, if deemed necessary by the investigator, 
after consecutive administrations.
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JNJ-54767414 daratumumab
Clinical Protocol 54767414AMY3001 Amendment 3
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Approved, Date: 10 October 2019
Applicable Section(s)
Description of Change(s)
Rationale: To capture post-progressive disease patient-reported outcome assessment.
Table 1 Time and 
Events Schedule: 
Patient-Reported 
Outcome
Column: Post-treatment Week 8 and after: Q6 months until Start of subsequent therapy. 
Immediately before subsequent therapy is started, and 8 wks after; Q6 mos until 
MOD-PFS
Column: q16 wks: 16 weeks post MOD-PFS; 32 weeks post MOD-PFS
Rationale: To ensure accurate recording of medical encounters.
9.8 Table and Events 
Schedule, Medical 
Encounters Summary
Clarified visits at which a Medical Encounters eCRF page must be completed.
Rationale: “Dizziness” is non-specific and not attributable to amyloidosis. 
9.8 Patient-Reported 
Outcomes; Attachment 
9 Supplemental Items 
to EORTX QLQ-C30
“Dizziness” has been removed from the supplemental EORTC QLQ-C30 item bank. 
Rationale: To update the renal organ response criteria to the criteria as detailed in Palladini 2014.
9.2.3 Determination of 
Organ Response
The Cardiac and liver organ response must be monitored by the International 
Amyloidosis Consensus Criteria (Comenzo 2012)6 shown in. Renal organ response must 
be monitored by Palladini criteria (Palladini 2014). Refer to Table 10.
For kidney response, the recent Palladini criteria response is defined as a 50% decrease 
in 24-hour urine protein (at least proteinuria by ≥30% or below 0.5 g/day when pre-
treatment urine protein is >0.5 g/day) in 24 hours without renal progression; renal 
progression is required. In addition, the creatinine clearance must not worsen by defined 
as a ≥25% over baseline eGFR decrease (Palladini 2014).
9.2.3, Table 10, 
Kidney Response Row
Response column: 50% decrease (at least 0.5 g/day) of 24 h urine protein (urine protein 
must be >0.5 g/day) pre-treatment. Creatinine and creatinine clearance must not worsen 
by 25% over baseline. ≥30% decrease in proteinuria or drop in proteinuria below 0.5 
g/24 hours in the absence of renal progression.
Progression column: 50% increase (at least 1 g/day) of 24 h urine protein to >1 g/day or 
25% worsening of serum creatinine or creatinine clearance ≥25% decrease in eGFR.
Footnotes: Footnote a: Based on Comenzo 2012 consensus criteria (Comenzo 2012)
Footnote b added: Based on Palladini 2014 criteria (Palladini 2014)
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JNJ-54767414 daratumumab
Clinical Protocol 54767414AMY3001 Amendment 3
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Applicable Section(s)
Description of Change(s)
Rationale: Exclusion criteria and safety follow-up for HBV were revised to align with regional guidelines for 
management of HBV infection. 
4.2. Exclusion Criteria 
9.1.a 
Revised exclusion text to define hepatitis B as hepatitis B surface antigen [HBsAg] 
positive, or antibodies to hepatitis B surface or core antigens [antiHBs or anti-HBc] with 
hepatitis B virus [HBV]-DNA quantitation positive). In addition, subjects who are 
positive for anti-HBs or anti-HBc must have a negative polymerase chain reaction (PCR) 
for HBV-DNA quantitation result at screening, PCR positive subjects are to be excluded. 
Subjects with serologic findings suggestive of prior HBV vaccination and known history 
of prior vaccination do not require PCR testing.
Table 1 Time and 
Events Schedule –
HBV DNA Test; 9.9. 
Safety evaluations; 
Attachment 13 JSH 
Guidelines for the 
Management of 
Hepatitis B Virus 
Infection
Added a new section for safety follow-up for subjects who are positive for anti-HBc or 
anti-HBs. During the study, subjects who are positive for anti-HBc or ant-iHBs will 
undergo testing for hepatitis B DNA by PCR every 12 weeks. During and following study 
treatment, subjects who have history of HBV infection will be closely monitored for 
clinical and laboratory signs of reactivation of HBV. Added reference: JSH Guidelines for 
the 
Management 
of 
Hepatitis 
B 
Virus 
Infection 
2014.
Clarified that subjects with serologic findings suggestive of HBV vaccination (anti-HBs 
positivity as the only serologic marker) AND a known history of prior HBV vaccination 
do not need to be tested for HBV DNA by PCR.
Rationale: PH20 is handled as an active agent in Japan
1.2 Daratumumab; 3.1 
Overview of Study 
Design; 3.2.1 rationale 
for Dose and 
Subcutaneous 
Administration; 4.2 
Exclusion Criterion 
#14.1; 
Clarification that daratumumab is co-formulated with rHuPH20 has been added 
throughout the protocol.
Rationale: To clarify that daratumumab monotherapy is approved in the United States, European Union, and other 
countries.
3.2.1 Rationale for 
Dose and 
Subcutaneous 
Administration
Daratumumab monotherapy for subjects with multiple myeloma is approved for the 
treatment of patients with relapsed/refractory multiple myeloma in the United 
States, European Union, and other countries at a dose of 16 mg/kg (weekly for 
8 weeks, then every 2 weeks for 16 weeks, then every 4 weeks thereafter) administered 
via IV infusion until disease progression, start of subsequent therapy, or unacceptable 
toxicity in the United States, European Union, and other countries.
Rationale: To align with Health Authority requirements for increased safety monitoring around treatment with 
bortezomib.
Table 1: Time and 
Events Schedule –
Chest X-Ray
A chest x-ray was added at Screening.
Table 2: Time and 
Events Schedule –
Hematology; Study 
Drug Dosing
Hematology testing was added at Days 8 and 22 for Cycles 1 through 6. 
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JNJ-54767414 daratumumab
Clinical Protocol 54767414AMY3001 Amendment 3
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Approved, Date: 10 October 2019
Applicable Section(s)
Description of Change(s)
Rationale: To align with Health Authority requests for increased contraception duration after discontinuation of 
cyclophosphamide. 
4.1 Inclusion Criteria 
9.1
A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control; eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during and up to 4 
6 months after discontinuation of cyclophosphamide or 3 months after discontinuation of 
daratumumab, whichever is longer. All men must also not donate sperm during the study 
and for 4 6 months after discontinuation of cyclophosphamide or 3 months after 
discontinuation of daratumumab, whichever is longer.
Rationale: To align with Health Authority requests to exclude subjects with hypersensitivity or contraindications to 
cyclophosphamide or any of its metabolites. 
4.2 Exclusion Criteria 
11.1
Criterion 11.1 Known hypersensitivity or contraindications to any of the study drugs
including bortezomib, boron, mannitol, or cyclophosphamide or any of its metabolites.
Rationale: Serum is the preferred sample type for pregnancy testing.
Table 1 Time and 
Events Schedule –
Pregnancy Test; 4.1 
Inclusion Criteria 
Criterion 10.1; 9.1.1 
Overview; 9.1.2 
Screening Phase; 9.9 
Safety Evaluations
(Serum preferred) has been added to every location in which pregnancy testing is 
discussed. 
Rationale: To align with Health Authority requests for the addition of the benefit/risk assessment to be included in 
the protocol.
Attachment 14
Inserted new Attachment 14, which consists of the benefit/risk assessment specific to this 
study. 
Rationale: To provide greater detail surrounding the prevention and management of daratumumab infusion-related 
reactions.
6.2.3.1 Preinfusion 
Medication
In an effort to prevent infusion-related reactions, all subjects will receive the 
following medications 1 to 3 hours prior to each daratumumab administration 
(1 hour prior to daratumumab administration is preferred):
Preinfusion medications include the following:

Dexamethasone 20 mg IV or PO (an equivalent of long-acting corticosteroid may 
substitute [see Attachment 4 for conversion table])

Antipyretic: Paracetamol (acetaminophen) 650 to 1000 mg PO or IV

An antihistamine (diphenhydramine 25 to 50 mg, or equivalent) either given IV or 
PO. Avoid IV use of promethazine.

Montelukast (leukotriene inhibitor): Predose administration of a leukotriene 
inhibitor (montelukast 10 mg PO or equivalent) is optional on Cycle 1 Day 1,
and optional can be administered up to 24 hours before all other doses of 
daratumumab SC-infusion as per investigator discretion.
If necessary, oral preinfusion medications may be administered at outside the subject’s 
home clinic on the day of the daratumumab treatment, provided they are taken within 
3 hours prior to the administration of daratumumab SC infusion.
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JNJ-54767414 daratumumab
Clinical Protocol 54767414AMY3001 Amendment 3
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Approved, Date: 10 October 2019
Applicable Section(s)
Description of Change(s)
6.2.3.2 Postinfusion 
Medication
Consider administering low-dose oral methylprednisolone (≤20 mg) or equivalent, 
the day after the SC-infusion.
However, if a background regimen-specific corticosteroid (eg, dexamethasone) is 
administered the day after the SC-infusion, additional postinfusion steroids are not 
required, but may be considered by the investigator. 
Subjects who continue daratumumab monotherapy after completing 6 cycles in 
Treatment Arm B will receive long or intermediate-acting corticosteroid orally 
(20 mg methylprednisolone or equivalent in accordance with local standards) 
starting in Cycle 7 on the 2 days following daratumumab SC administrations 
(beginning the day after the SC-infusion) for the prevention of delayed IRRs. Note: 
Subjects will continue to receive 20 mg of dexamethasone, or equivalent, as pretreatment 
medication prior to each dose of daratumumab. In the absence of infusion-related AEs 
after 3 cycles of monotherapy (Cycles 7 to 9), postinfusion corticosteroids may be 
administered per investigator discretion.
For subjects with a higher risk of respiratory complications (eg, subjects with mild asthma 
or subjects with COPD who have an FEV1 <80% at Screening or developed FEV1 <80% 
during the study without any medical history), the following postinfusion medications 
should be considered:

Antihistamine (diphenhydramine or equivalent) on the first and second days after all 
daratumumab SC administration

Leukotriene inhibitor (montelukast or equivalent)

Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol

Control medications for lung disease (eg, inhaled corticosteroids plus long-acting β2 
adrenergic receptor agonists for subjects with asthma; long-acting bronchodilators 
such as tiotropium or salmeterol plus + inhaled corticosteroids for subjects with 
chronic obstructive pulmonary disease COPD).
Investigators may prescribe bronchodilators, H1-antihistamines, and corticosteroids that 
are deemed necessary to provide adequate supportive care in the event a bronchospasm 
occurs after subjects are released from the hospital/clinic. If an at-risk subject experiences 
no major infusion-related reactions IRRs, then these postinfusion medications may be 
omitted after 4 doses at the investigator’s discretion.
Subjects who continue daratumumab monotherapy after completing 6 cycles in Treatment 
Arm B will receive long or intermediate-acting corticosteroid orally (20 mg 
methylprednisolone or equivalent in accordance with local standards) starting in Cycle 7 
on the 2 days following all daratumumab SC administrations (beginning the day after the 
infusion) for the prevention of delayed infusion-related reactions. Note: Subjects will 
continue to receive 20mg of dexamethasone, or equivalent, as pre-treatment medication 
prior to each dose of daratumumab. In the absence of infusion-related AEs after 3 cycles 
of monotherapy (Cycles 7 to 9), postinfusion corticosteroids may be administered per 
investigator discretion.
Any postinfusion medication will be administered after the SC-infusion has 
completed.
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JNJ-54767414 daratumumab
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Approved, Date: 10 October 2019
Applicable Section(s)
Description of Change(s)
6.2.3.3 Management of 
Infusion-Related 
Reactions
If an infusion-related reaction IRR develops, then the administration of daratumumab 
should be temporarily interrupted. (see IPPI for further details). Subjects who 
experience adverse events AEs during daratumumab SC administration must be treated 
according to the investigator’s judgment and best clinical practice for their symptoms. 
The following recommendations apply:

In the event of a life-threatening infusion-related reaction IRR (which may include 
pulmonary or cardiac events) or anaphylactic reaction, daratumumab should be 
discontinued and after consultation with the sponsor, no additional daratumumab 
should be administered to the subject. Aggressive symptomatic treatment should be 
applied.
6.2.3.3.1 Infusion-
Related Reactions of 
Grade 1 or Grade 2
If the investigator assesses an adverse event a Grade 1-2 IRR to be related to the 
daratumumab SC administration, then the administration of daratumumab should be 
paused. When the subject’s condition is stable, daratumumab administration may be 
restarted at the investigator’s discretion.
If the subject experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or 
higher event of bronchospasm that does not respond to systemic therapy and does not 
resolve within 6 hours from onset, then the subject must be withdrawn from 
daratumumab treatment.
6.2.3.3.2 Infusion-
Related Reactions of 
Grade 3 or Higher
For SC-infusion-related adverse events
AEs (other than laryngeal edema or 
bronchospasm) that are Grade 3 or higher, the daratumumab SC administration must be 
stopped and the subject must be observed carefully until resolution of the adverse event
AE or until the intensity of any other adverse event remains at Grade 3 or 4 after 2 hours, 
then the subject must be withdrawn from treatment. If the intensity of any other adverse
the event decreases to Grade 1 or 2 within 2 hours, then, at which point daratumumab 
SC-administration may be restarted at the investigator’s discretion. If the intensity of the 
AE returns to Grade 3 after restart of daratumumab administration, then the 
subject must be withdrawn from daratumumab treatment.
If the intensity of the adverse event returns to For IRR AEs that are Grade 3 or 4, after 
restart of the daratumumab administration, then the procedure described in this section 
may be repeated at the investigator’s discretion. Should the intensity of the adverse event 
increase to Grade 3 or 4 for a third time, then must be stopped and the subject must be
withdrawn from daratumumab treatment.
6.2.3.3.3 
Recommendations 
Recurrent Infusion-
Related Reactions
If a Grade 3 IRR (or Grade 2 or higher) event of laryngeal edema or bronchospasm 
recurs during or within 24 hours after a subsequent daratumumab SC-
administration, daratumumab treatment must be discontinued.
6.2.4 Guidelines 
Recommendations for 
Management of 
Daratumumab 
Administration-related 
Reactions
For the purpose of this protocol, “administration-related reactions” are defined as 
localized reactions at the injection site (eg, erythema, local tenderness, swelling, etc).
In Study MMY1004 Part 1, SC-administration-related reactions have been mild (Grade 
1) and consist of daratumumab in abdominal SC tissue was associated with local pain 
or burning at the injection-site, erythema, and reactions such as induration to the
abdomen. Treatment for and erythema in some subjects. The reactions usually resolved 
within 60 minutes. Local injection site reactions may include the administration of oral 
antihistamines. Topical application of cool compresses, antihistamines, or corticosteroids 
is not recommended within 4 hours of drug administration, to avoid any changes in 
pharmacokinetics. After 4 hours, any topical treatment should be applied gently to avoid 
unnecessary friction to the site should be managed per institutional standards.
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JNJ-54767414 daratumumab
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Approved, Date: 10 October 2019
Applicable Section(s)
Description of Change(s)
Rationale: To clarify dose adjustments for cyclophosphamide.
6.3.1 Dose 
Adjustments for 
Cyclophosphamide
Table 5
Neutrophil 
count/mm3
Platelet count/µL
Dosage
>1500
>100,000
100% of the planned dose
1500 – 1000
50,000 – 100,000
50% of the planned dosea
<1000
<50,000
Dose should be heldb
a.
Cyclophosphamide dose should remain at 50% of planned dose if subject’s neutrophil 
and/or platelet counts meet these values. If count improves increases to required levels 
for 100% of planned dose, then dose may be re-escalated to 100% of planned dose.
b.
Cyclophosphamide dose should be held if subject’s neutrophil and/or platelet counts 
meet this value. However, if counts improve increase to required levels for 50% of the 
planned dose or 100% of the planned dose, then dose may be re-escalated as 
appropriate.
Rationale: To clarify dexamethasone administration in select populations.
6.5 Dexamethasone
For subjects who are older than 70 years, underweight (BMI <18.5), have hypervolemia, 
poorly controlled diabetes mellitus, or prior intolerance/adverse event AE to steroid 
therapy, the dexamethasone dose may be administered at a dose of 20 mg weekly. For 
subjects receiving dexamethasone 20 mg weekly, on days of daratumumab 
treatment, it is recommended that dexamethasone 20 mg be administered as 
premedication.
Rationale: To add criteria for the use of CYP3A4 inducers and inhibitors with the use of bortezomib.
8.3 Prohibited 
Therapies During the 
First 6 Cycles of 
Therapy
Concomitant administration of strong CYP3A4 inducers is prohibited with the use of 
bortezomib. Administration of strong CYP3A4 inhibitors (eg, ketoconazole, 
ritonavir) should be avoided and is not recommended in patients receiving 
bortezomib. If a strong CYP3A4 inhibitor must be given in combination with 
bortezomib, monitor patients for signs of bortezomib toxicity and consider a 
bortezomib dose reduction. For a list of CYP3A inhibitors and inducers, see 
Attachment 16.
Attachment 16
Added Attachment 16 to provide a list of CYP3A inducers and inhibitors.
Rationale: To make minor clarifications throughout the protocol.
Synopsis (Secondary 
Objectives, Endpoints, 
and Hypothesis)
To evaluate the clinically observable composite endpoint for major organ deterioration 
progression-free survival (MOD-PFS) following treatment with daratumumab in 
combination with CyBorD compared with CyBorD alone
Synopsis (Hypothesis)
The primary hypothesis of this study is that daratumumab in combination with CyBorD 
will improve the overall complete hematological response rate compared to CyBorD 
alone, in subjects with newly diagnosed AL amyloidosis. The primary hypothesis of this 
study is that daratumumab in combination with CyBorD will improve the overall 
complete hematological response (CHR) rate compared to CyBorD alone, in subjects with 
newly diagnosed AL amyloidosis.
3.2.4 Rationale for 
Biomarker Collection
As this is the first study of daratumumab in treatment-naïve amyloidosis and 
additional information little is known about CD38 expression on malignant 
plasma cells in amyloidosis is warranted compared to better understand the 
disease multiple myeloma.
Immune populations such as immunosuppressive Treg, Breg, and MDSC have not been 
well studied in amyloidosis.
NCT03201965


JNJ-54767414 daratumumab
Clinical Protocol 54767414AMY3001 Amendment 3
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Approved, Date: 10 October 2019
Applicable Section(s)
Description of Change(s)
6.2.1 Treatment 
Schedule and 
Administration
To clarify the location at which doses are to be administered (opposite (right and left 
sides).
7 Treatment 
Compliance
Study drug (daratumumab)Daratumumab and bortezomib will be administered by 
qualified 
site 
staff. 
Cyclophosphamide 
Dexamethasone 
and 
dexamethasone 
cyclophosphamide will be administered by qualified site staff if these drugs will be given 
as an IV dose.
11.5 Immunogenicity 
Analyses
A listing Separate listings of subjects who are positive for antibodies to daratumumab or 
positive for antibodies to rHuPH20 will be provided. The maximum titers of 
antibodies to daratumumab and rHuPH20 will also be presented.be summarized for 
subjects who are positive for antibodies to daratumumab and rHuPH20.
12.3.1 All Adverse 
Events
Serious adverse events, including those spontaneously reported to the investigator within 
30 days after the last dose of study drug treatment, and those that are considered related to 
daratumumab the study treatment within the Follow-up Phase, must be reported using 
the Serious Adverse Event Form.
Anticipated events will be recorded and reported as described in Attachment 12 in 
countries where required.
16.2.5 Long-Term 
Retention of Samples 
for Additional Future 
Research
Samples collected in this study may be stored for up to 15 years from last patient out (or 
according to local regulations) for additional research.
Attachment 7
The DuBois Formula can be used as an alternative formula for the calculation of body 
surface area. Approval from the Sponsor is required if a site wishes to use a body surface 
area formula other than the standard calculation or the DuBois formula.
Global
Differentiated study drug from study treatment.
Global
Updated drug administration to indicate subcutaneous injection or other administration.
Global and Attachment 
11
Updated all instances of SF-36 to SF-36v2. Replaced prior SF-36 with SF-36 v2.
Rationale: Alignment of text with recent protocol template changes. 
Title page
Added ‘Janssen Pharmaceutica NV’ and ‘Janssen, Inc.’ to the list of legal entities, and 
removed ‘Janssen Infectious Diseases BVBA, Inc.’.
9.8 Safety Evaluations 
– Adverse Events
12.3.1 All Adverse 
Events
Revised text to clarify that disease progression should not be considered an adverse event.
12.3.1. All Adverse 
Events
Revised text related to sponsor's responsibility for reporting anticipated events.
12.3.3. Pregnancy
Deleted text related to the unknown effect of study drug on sperm.
17.3. Subject 
Identification 
Enrollment and 
Screening Logs
Added ‘(as allowed by local regulations)’ following 2 instances of ‘date of birth’.
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Applicable Section(s)
Description of Change(s)
17.11 Use of 
Information and 
Publication
Revised text related to ICMJE: Recommendations for the Conduct, Reporting, Editing, 
and Publication of Scholarly Work in Medical Journals.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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SYNOPSIS
A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in Combination with 
Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared With CyBorD Alone in Newly 
Diagnosed Systemic AL Amyloidosis
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a unique 
epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed towards tumor 
cells that express high levels of CD38, such as plasma cells from patients with AL amyloidosis.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective is to evaluate the efficacy of daratumumab plus CyBorD compared with CyBorD 
alone in the treatment of newly diagnosed AL amyloidosis patients.
Secondary Objectives

To evaluate the clinically observable composite endpoint for major organ deterioration 
progression-free survival (MOD-PFS) following treatment with daratumumab in combination with 
CyBorD compared with CyBorD alone

To evaluate the following efficacy measures following treatment with daratumumab in combination 
with CyBorD compared with CyBorD alone:

Organ response rate (OrRR)

Overall survival (OS)

Time to and duration of response

To evaluate fatigue, mental functioning, and health-related quality of life following treatment with
daratumumab in combination with CyBorD compared with CyBorD alone

To assess the safety and tolerability of daratumumab when administered in combination with 
CyBorD

To assess the pharmacokinetics of daratumumab and the immunogenicity of daratumumab and 
rHuPH20

To explore minimal residual disease (MRD) status in amyloidosis patients as a surrogate for PFS and 
OS and as a biomarker for relapse
Exploratory Objectives

To evaluate hematologic progression-free survival (HemPFS)

To evaluate biomarkers of response following treatment with daratumumab in combination with 
CyBorD compared with CyBorD alone

To evaluate physical functioning, symptom improvement, functional improvement and health utility 
following treatment with daratumumab in combination with CyBorD compared with CyBorD alone

To evaluate diastolic function following treatment with daratumumab in combination with CyBorD 
compared with CyBorD alone

To explore the pharmacokinetic/pharmacodynamic relationship of daratumumab, such as exposure 
response relationship for efficacy/safety endpoints or disease-related or mechanism-based 
biomarkers
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Hypothesis
The primary hypothesis of this study is that daratumumab in combination with CyBorD will improve the 
overall complete hematological response (CHR) rate compared to CyBorD alone, in subjects with newly 
diagnosed AL amyloidosis.
OVERVIEW OF STUDY DESIGN
This is a randomized, open-label, active-controlled, multicenter Phase 3 study in subjects with newly 
diagnosed amyloid light chain amyloidosis. Approximately 360 subjects will be stratified by cardiac stage 
based on the Mayo Clinical Cardiac Staging System (Dispenzieri 201411; Palladini 201636) (Stages I, II, 
and IIIa) (Attachment 14), countries that typically offer transplant for patients with AL amyloidosis (List 
A or List B), and renal function (creatinine clearance [CrCl] ≥60 mL/min or CrCl <60 mL/min) and then 
assigned to receive either CyBorD or CyBorD in combination with daratumumab. Subject participation 
will include a Screening Phase, a Treatment Phase, a Post-Treatment Observation Phase, and a Long-term 
Follow-up Phase.
Given the potential safety concern with regards to the use of IV daratumumab in the amyloidosis 
population (ie, volume overload), this study will utilize the daratumumab SC co-formulation. Although 
the risk of volume overload is predicted to be lower with SC daratumumab than with IV infusion, patients 
with newly diagnosed AL amyloidosis may still develop adverse events (AEs) attributable to 
hypervolemia (for example, dyspnea, peripheral edema, etc) secondary to amyloid-induced cardiac or 
renal insufficiency. Additionally, daratumumab has not been co-administered with CyBorD. Therefore, 
prior to the start of the randomized portion of the study, a safety run-in will be conducted. Dosing of these 
subjects will be staggered so that no subject will receive their first dose sooner than 48 hours after the 
previously enrolled subject. Safety evaluation will be performed by the sponsor (and external academic 
hematologists) after at least 10 subjects have received at least 1 cycle of treatment If no safety signal is 
observed, particularly in regard to volume overload, the randomized portion of the study will begin. Once 
the randomized portion of the study begins, subjects in Treatment Arm B (CyBorD plus daratumumab) 
will be observed for at least 6 hours after the end of study drug administration during Cycle 1 Day 1 and, 
if deemed necessary by the investigator, after consecutive administrations. 
The safety run-in data have been assessed by the Study 54767414AMY3001 Steering Committee 
members consisting of 4 academic hematologists with expertise in AL amyloidosis. The Steering 
Committee members concur that the combination of daratumumab with CyBorD appears to be safe and 
tolerable for the first 15 subjects with newly diagnosed AL amyloidosis treated in the safety run-in of 
Study 54767414AMY3001 and support the start of the randomized portion of the study. 
In the randomized portion of the study, subjects randomized to Treatment Arm A will receive study 
treatment with CyBorD. All treatment cycles are 4 weeks (28 days) in length. CyBorD will be 
administered for a maximum of 6 cycles (24 weeks).
Subjects randomized to Treatment Arm B will receive CyBorD plus daratumumab at a fixed dose of 
1800 mg. A maximum of 6 cycles (24 weeks) of CyBorD plus daratumumab will be administered. After 
Cycle 6, subjects will continue to receive daratumumab as monotherapy on Day 1 of subsequent 28-day 
cycles until disease progression, start of subsequent therapy, or a maximum of 24 cycles (~2 years) from 
the first dose of study treatment.
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SUBJECT POPULATION
Adult subjects age 18 and older with newly diagnosed AL amyloidosis are eligible for the study. 
Diagnosis will be based on histopathological or electron microscopy criteria, one or more organs need to 
be affected, and disease must be measurable (by free light chain criteria or serum monoclonal protein 
[M-protein]). Eligible subjects will have an ECOG performance score of 0, 1, or 2 and adequate organ 
function. Key exclusion criteria include previous or current diagnosis of symptomatic multiple myeloma, 
evidence of significant cardiovascular conditions, any form of non-AL amyloidosis, or planned stem cell 
transplant during first 6 cycles of protocol therapy.
DOSAGE AND SC-ADMINISTRATION
Daratumumab 1800 mg co-formulated with recombinant hyaluronidase PH20 (rHuPH20) 2000 U/mL will 
be administered subcutaneously through a syringe by a manual push over approximately 5 minutes. 
Daratumumab will be administered weekly for the first 8 weeks (2 cycles), then every 2 weeks for 
4 cycles (Cycles 3-6), and then every 4 weeks until progression of disease or subsequent therapy for a
maximum of 24 cycles (~2 years) from the first dose of study treatment.
Subjects will receive 300 mg/m2 cyclophosphamide as an oral or IV weekly dose (NOTE: maximum 
absolute weekly dose of cyclophosphamide is 500 mg, irrespective of body surface area [BSA]) and 
1.3 mg/m2 VELCADE® (bortezomib) as an SC injection weekly (Days 1, 8, 15, 22) in every 28-day cycle 
for a maximum of 6 cycles.
Dexamethasone will be administered at a total dose of 40 mg weekly (ie, Days 1, 8, 15, 22). On days of 
daratumumab dosing, subjects in Treatment Arm B will receive 20 mg on the day of daratumumab dosing 
as premedication and 20 mg on the day after daratumumab dosing. On weeks that daratumumab is not 
administered, or for subjects randomized to Treatment Arm A, dexamethasone is to be given 40 mg 
weekly on a single day or divided into 2 days.
EVALUATIONS
Disease evaluations must be performed every 4 weeks during Cycles 1 through 6 and every 8 weeks from 
Cycle 7 and beyond, on the scheduled assessment day (±5 days). Samples to assess both the serum 
concentration (pharmacokinetics) of daratumumab and the generation of anti-daratumumab antibodies 
(immunogenicity) will be obtained from all subjects in the safety run-in and in Treatment Arm B 
according to the Time and Events Schedule. Samples will also be collected from all subjects in the safety 
run-in and in Treatment Arm B to evaluate the immunogenicity of rHuPH20 according to the Time and 
Events Schedule. Biomarker evaluations will focus on the evaluation of CD38 expression by IHC on the 
malignant plasma cells from core diagnostic biopsies to determine if CD38 expression correlates with 
response to daratumumab. Safety will be assessed measured by AEs, laboratory test results, ECGs, 
echocardiograms, vital sign measurements, physical examination findings, and ECOG performance status.
STATISTICAL METHODS
The sample size for this study is based on the alternative hypothesis of a 15% improvement in overall 
CHR. Taking an overall CHR rate estimated to be 25% for the CyBorD arm, adding a 15% improvement 
translates to an overall CHR rate of 40% for the CyBorD plus daratumumab arm. Approximately 
360 subjects (180 subjects per arm) would provide more than 85% power to detect a 15% improvement in 
overall CHR using a likelihood ratio test with a 2-sided alpha of 0.05. Analysis of CHR rate at 6 months 
will be performed similarly to the primary endpoint CHR rate.
The primary comparison of the 2 randomized treatments will be made with respect to overall CHR based 
on Independent Review Committee (IRC) assessment using the Cochran-Mantel-Haenszel (CMH) chi 
square test in the intent-to-treat (ITT) population stratified by cardiac risk (Stages I, II, and IIIa), countries 
that typically offer transplant for patients with AL amyloidosis (List A or List B), and renal function 
(CrCl ≥60 mL/min or CrCl <60 mL/min). A Mantel-Haenszel odds ratio, along with its 2-sided 95% 
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confidence interval, will be calculated. All binary secondary endpoints will be analyzed using the CMH 
chi-square test.
For time-to-event endpoints (eg, MOD-PFS, HemPFS, OS, etc.), Kaplan-Meier estimates will be 
presented, along with a log-rank test stratified by cardiac risk (Stages I, II, and IIIa), countries that 
typically offer transplant for patients with AL amyloidosis (List A or List B), and renal function 
(CrCl ≥60 mL/min or CrCl <60 mL/min) comparing the 2 treatment arms. Median along with 
corresponding 95% CIs will be obtained from the Kaplan-Meier estimates. Cox’s regression will be 
applied to obtain the hazard ratio estimate and the corresponding 95% CI.
Organ response/progression analysis will be performed separately for each organ involved at baseline, 
specifically for heart, kidney, and liver. Descriptive statistics will be provided to summarize organ 
response/progression at 6 months, time to organ response, and time to organ progression.
Two interim analyses are planned for this study. An Independent Data Monitoring Committee (IDMC) 
will assess the results of the interim analyses. The primary endpoint of overall CHR and secondary 
efficacy endpoints will be adjudicated by an IRC.
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TIME AND EVENTS SCHEDULES
Table 1:
Time and Events Schedule
Treatment Phase
Post-Treatment Phase
Long-
Term 
Follow-
Up +/-7 
days
Notes
Screening 
Phase
Arm A
Arm B 
Cycles 1-6
Arm B
C7+
EOT
Observation
Arm A, Cycle 7+
Arm B, post -dara
-28 days 
before C1D1
D1 of each 
cycle
D1
Post-
treatment
30 days
(+/-3 days)
Post-treatment
Week 8 and after
q16wks
Study treatment should be initiated within 72 hours after randomization. Cycles are approximately 28 days in duration. The start of each cycle may occur ±5 days of the scheduled day. Run-
in patients should follow schedule for Treatment Arm B.
Procedures
Informed consent
ICF must be signed before any study-related 
procedures are performed.
Eligibility criteria
If mass spectrometry is necessary, Screening period is 
extended to 42 days before C1D1.
X
Demographics/ 
medical history
X
Issue Subject Study 
ID Card
X
Height
X
Chest X-Ray
Pretreatment chest X-ray performed locally to 
establish baseline pulmonary status. 
X
Assessment of lytic 
disease
To exclude multiple myeloma; skeletal survey or 
other imaging modality
X
-42 days
FEV1 test
Subjects with known or suspected COPD or asthma, 
FEV1 should be measured
X
ECOG
See Attachment 1
X
X
X
LVEF assessment 
Echocardiogram preferred, other cardiac evaluation of 
LVEF also acceptable
X
C7D1 and 
when 
clinically 
indicated
X 
(if before 
C7D1)
C7D1 at start of 
Observation
12-lead ECG
X
X
Physical examination
Including neurological examination. Clinically 
significant abnormalities during the study should be 
reported as AEs.
X
Symptom and disease directed examination as clinically indicated
Vital signs, Weight
X
Please see Table 2
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Treatment Phase
Post-Treatment Phase
Long-
Term 
Follow-
Up +/-7 
days
Notes
Screening 
Phase
Arm A
Arm B 
Cycles 1-6
Arm B
C7+
EOT
Observation
Arm A, Cycle 7+
Arm B, post -dara
-28 days 
before C1D1
D1 of each 
cycle
D1
Post-
treatment
30 days
(+/-3 days)
Post-treatment
Week 8 and after
q16wks
Patient-Reported 
Outcome 
Electronic PRO (EORTC QLQ, EQ-5D-5L and SF-
36v2) before any other study procedures. Window for 
all PRO assessments is 4 days prior to dosing. Note: 
first 6-month post-treatment ePRO assessment should 
occur 6 months after the EOT visit.
Not required in the safety run-in phase.
X
Q8wks
X
Start of subsequent 
therapy; Q6 months 
until MOD-PFS 
16 weeks 
post 
MOD-
PFS±14 d
32 weeks 
post 
MOD-
PFS±14 d
Blood type, Rh and 
IAT
Arm B only. Obtain sample before first dose of 
daratumumab. 
C1D1
Arm B only
Study Treatment Administration: Please see Table 2 for detailed procedures.
CyBorD
See Table 2
Daratumumab 
Arm B ONLY
See Table 2
See Table 2
Laboratory Assessments
Pregnancy test
For women of childbearing potential only. Serum 
sample preferred. 
within 14 
days prior to 
randomization
X
X
X
Hematology
To be done by local laboratory.
X
See Table 2
X
Serum chemistry
Including TSH and T4 at Screening and subsequently 
if clinically indicated. To be done by local laboratory.
X
See Table 2
X
Hepatitis B (HBV) 
serology
Local testing for hepatitis B surface antigen (HBsAg), 
hepatitis B surface antibody (Anti-HBs), and hepatitis 
B core antibody (Anti-HBc). Refer to Section 9.9.
X
HBV DNA test
For subjects with serologic evidence of resolved HBV 
infection (ie, positive Anti-HBs or positive Anti-HBc)
or both, HBV DNA testing by PCR must be 
performed locally. Refer to Section 9.9. 
Performed locally at screening, every 12 weeks 
(Q12W) during treatment, at the End of Treatment 
visit, and Q12W for up to 6 months after last dose of 
study treatment in Arms A and B.  
X
Q12W
Q12W
X
Q12W for up to 6 
months after last dose 
of study treatment
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Treatment Phase
Post-Treatment Phase
Long-
Term 
Follow-
Up +/-7 
days
Notes
Screening 
Phase
Arm A
Arm B 
Cycles 1-6
Arm B
C7+
EOT
Observation
Arm A, Cycle 7+
Arm B, post -dara
-28 days 
before C1D1
D1 of each 
cycle
D1
Post-
treatment
30 days
(+/-3 days)
Post-treatment
Week 8 and after
q16wks
Disease Assessments: To be performed throughout all phases of the randomized study (during treatment, post-treatment, and subsequent therapy) until MOD-PFS is observed. 
Clinical Evaluation of 
MOD-PFS endpoint
The MOD-PFS endpoint is defined in Section 2.1 and 
includes clinical manifestation of cardiac or renal 
failure, or hematologic PD, or death.
X
Every 8 weeks until disease progression
NYHA Functional 
Classification
See Attachment 3
X
X
Every 8 weeks until disease progression 
Serum disease 
evaluations (SPEP)
Sample to be sent to central laboratory. Not required 
C1D1 if Screening laboratory assessments were 
within 14 days C1D1.
X
X
Every 8 weeks until disease progression 
Urine disease 
evaluations (UPEP)
Sample to be sent to central laboratory. Not required 
C1D1 if Screening laboratory assessments were 
within 14 days of C1D1.
X
X
Every 8 weeks until disease progression 
Serum FLC
Sample to be sent to central laboratory.
X
Cycle 1: D1, 
D8, D15, D22.
Cycle 2 to 6: 
D1 only.
Every 8 weeks until disease progression 
NT-proBNP assay
Sample to be sent to central laboratory.
X
X
Every 8 weeks until disease progression 
Troponin T, HS 
Troponin T
Sample to be sent to central laboratory. Note: only HS 
Troponin T sent to central laboratory in China.
X
X
Every 8 weeks until disease progression
Medical Resource 
Utilization (MRU)
Site to answer question in the eCRF at every disease 
assessment. If subject has required any additional 
encounters other than those mandated per protocol 
since the last disease evaluation visit, a Medical 
Encounters eCRF page must be completed. 
X
Cycles 1-6: Every 28 days
Cycle 7+ and during the post-treatment observation phase: Every 8 weeks; Q16W during 
the long-term follow-up phase
Subsequent Therapy
Record anticancer therapy and response to therapy.
Throughout study, and at least every 16 weeks during long-term follow-up
Stem Cell Collection
Autologous stem cell transplant is prohibited prior to 
the completion of Cycle 6.
Stem cell collection permitted. Record mobilization agents and stem cell yield (number 
of CD34+ cells per kg) and time to engraftment. See protocol Section 9.1.3.3.
Other malignancies
Throughout study, and at least every 16 weeks during long-term follow-up
Survival
Throughout study, and at least every 16 weeks during long-term follow-up
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Treatment Phase
Post-Treatment Phase
Long-
Term 
Follow-
Up +/-7 
days
Notes
Screening 
Phase
Arm A
Arm B 
Cycles 1-6
Arm B
C7+
EOT
Observation
Arm A, Cycle 7+
Arm B, post -dara
-28 days 
before C1D1
D1 of each 
cycle
D1
Post-
treatment
30 days
(+/-3 days)
Post-treatment
Week 8 and after
q16wks
Biomarkers
Bone Marrow 
Biopsy/Aspirate
Morphology, immunohistochemistry, karyotype or 
FISH required by local laboratory (del17p, t(4;14), 
etc). A portion of all aspirates collected may be used 
to evaluate MRD (central laboratory). For screening, 
fresh aspirate (3 mL) preferred. If not available, 
obtain 3 non-decalcified aspirate slides (smears or 
clots). Note: FISH may be sent to central laboratory in 
China and MRD will not be collected in China.
X 
(-56 days 
from C1D1)
When clinically feasible, bone marrow aspirate will be collected at CHR 
for MRD assessment
Archived Bone 
Marrow Biopsy
3 unstained FFPE or biopsy slides, or 2 unstained and 
1 H&E slides, sent to central laboratory. Note: not 
collected in China.
Any time 
predose
Whole blood 
biomarkers
Must be obtained before administration of study 
treatment, Samples to be sent to the central laboratory. 
Note: EOT sample not collected in China.
C1D1
C6D1
X
Plasma biomarkers
Must be obtained before administration of study 
treatment. Samples to be sent to the central laboratory. 
Note: plasma biomarker samples not collected in 
China.
C1D1
C6D1
X
Pharmacokinetics and Immunogenicity, Safety Run-in and ARM B ONLY: The 8-week post-dose sample should be obtained even if a subject has started subsequent therapy.
Daratumumab PK
Sample to be sent to central laboratory. Predose 
sample collection may occur up to 2 hours before but 
not after the start of the SC-infusion. Samples 
collected on dosing days with visit windows should be 
collected on the actual day of study drug 
administration.
C1D1 Pre
C1D4 (+/- 1 
day)
C1D8 Pre
C2D1 Pre
C3D1 Pre
C3D4 (+/- 1 
day)
C7D1 Pre
C12D1 Pre
X
8 weeks after last dose 
of dara (+/-1 week)
Daratumumab 
immunogenicity
No additional sample needed; will be taken from PK 
sample. In addition, for IRRs associated with 2nd SC-
infusion or beyond, obtain unscheduled blood sample 
as soon as possible; send to central laboratory.
C1D1 Pre
C2D1 Pre
C3D1 Pre
C7D1 Pre
C12D1 Pre
X
8 weeks after last dose 
of dara (+/-1 week)
rHuPH20 
immunogenicity 
(plasma)
In addition, for IRRs associated with 2nd SC-infusion 
or beyond, obtain unscheduled blood sample as soon 
as possible. Samples to be sent to central laboratory.
C1D1 Pre
C2D1 Pre
C3D1 Pre
C7D1 Pre
C12D1 Pre
X
8 weeks after last dose 
of dara (+/-1 week)
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Treatment Phase
Post-Treatment Phase
Long-
Term 
Follow-
Up +/-7 
days
Notes
Screening 
Phase
Arm A
Arm B 
Cycles 1-6
Arm B
C7+
EOT
Observation
Arm A, Cycle 7+
Arm B, post -dara
-28 days 
before C1D1
D1 of each 
cycle
D1
Post-
treatment
30 days
(+/-3 days)
Post-treatment
Week 8 and after
q16wks
Ongoing Subject Review
Adverse Events
See Section 12 for detailed instructions.
Continuous from the time of signing of ICF until 30 days after last 
dose of study treatment. Subsequently, only AEs considered 
possibly, probably, or very likely related to the study treatment 
need to be reported. Ongoing SAEs should be followed to 
resolution.
Concomitant 
Medications
See Section 8 for detailed instructions.
Continuous from the time of signing of ICF until 30 days after last 
dose of last study treatment.
Abbreviations to the Time and Events Schedule: AE=adverse event; Anti-HBc=hepatitis B core antibody; Anti-HBs=hepatitis B surface antibody; C=cycle; 
CCO=clinical cutoff for PFS analysis; CHR=complete hematologic response; COPD=chronic obstructive pulmonary disease; CyBorD=cyclophosphamide-bortezomib-
dexamethasone; D=day; dara=daratumumab; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; eCRF=electronic case report form; EORTC 
QLQ= European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EOT= End-of-Treatment; EQ-5D-5L= European Quality of Life 
Five Dimensions Questionnaire; FEV= Forced Expiratory Volume (in 1 second); FFPE=formalin fixed paraffin embedded; FISH=Fluorescence immunohistochemistry; 
FLC=free light chain; HBV=hepatitis B virus; HBsAg=hepatitis B surface antigen; HS=high sensitivity; IAT=indirect antiglobulin testing; ICF=informed consent form; 
ID=identification card; IRR=daratumumab infusion-related reaction; LVEF=left ventricular ejection fraction; MOD-PFS=major organ deterioration progression-free 
survival; MRD=minimal residual disease; NHYA=New York Heart Association; H&E=hematoxylin and eosin; NT-ProBNP=N-terminal pro-brain natriuretic peptide; 
rHuPH20=recombinant hyaluronidase PH20; PD=progressive disease; PK=pharmacokinetics; PRO=patient-reported outcome; Q12W=every 12 weeks; SAE=serious 
adverse event; SF-36=36-item short-form survey; SPEP=serum M-protein quantitation by electrophoresis; T4=thyroxine; TSH=thyroid-stimulating hormone; 
UPEP=urine M-protein quantitation by electrophoresis. 
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Table 2:
Time and Events Schedule: Study Treatment Dosing
Notes
Cycle 1-2
Cycle 3-6
Cycle 7+ 
(Arm B 
only)
EOT 
(within 30 
days of 
last dose)
D1
D8
D15
D22
D1
D8
D15
D22
D1
Hematology
For Cycle 1 Day 1, no need to repeat tests if they have been 
performed within the past 7 days. Testing may be performed up to 2 
days prior to study treatment administration. Results of hematology 
tests must be evaluated before each study treatment administration. 
Perform at additional time points, as clinically indicated. To be done 
by local laboratory. 
X
X
X
X
X
X
X
X
X
X
Serum Chemistry
X
X
X
X
X
X
Vital Signs
Vital signs (blood pressure, pulse, and temperature) measured in 
sitting position. Arm A: Vital signs will be measured before study 
drug administration. Arm B: Vital signs will be measured immediately 
before and after daratumumab SC-administration start and end.
X
X
X
X
X
X
X
Weight
Weight should be assessed at every visit to monitor for possible 
volume overload. Diuretic therapy is recommended should a subject 
develop weight gain as related to volume overload. If weight changes 
by more than 10% from baseline, recalculate study treatment doses.
X
X
X
X
X
X
X
X
Preinfusion Medications for Daratumumab, Treatment Arm B
Antihistamine
Diphenhydramine 25-50 mg or equivalent. paracetamol or 
acetaminophen 650mg-1000mg. May be given up to 3 hours before 
the dose of daratumumab. 
X
X
X
X
X
X
X
Paracetamol
X
X
X
X
X
X
X
Montelukast
Montelukast 10 mg PO recommended Cycle 1 Day 1, optional for all 
other doses.
X
Dexamethasone 
(premedication)
Dexamethasone 20 mg. May be given 1 to 3 hours before the dose of 
daratumumab.
For dexamethasone dosing during Cycles 1-6, see
CyborD regimen below
X
Study Treatment Administration, Treatment Arm A and Arm B
Study Drug 
Accountability
Accountability/exposure check 
D1, D8, D15, D22 of Cycles 1-6
X
X
Cyclophosphamide 
Administer PO or IV. Dispense on Day 1 after daratumumab SC 
administration if applicable.
300 mg/m2 PO or IV weekly (maximum weekly dose 500 mg) 
for each cycle until a maximum of 6 cycles (D1, D8, D15, 
D22)
Bortezomib
Administer by SC injection. Dose may be delayed up to 48 hrs, adjust 
subsequent doses as all bortezomib doses should be at least 72 hrs 
apart. Doses that need to be withheld are skipped and will not be made 
up later in the cycle.
1.3 mg/m2 SC, weekly of each cycle (28 days) until a 
maximum of 6 cycles. (D1, D8, D15, D22) 
Dexamethasone 
(treatment)
Dispense on Day 1 for self-administration. Subjects in Arm B should 
receive 20 mg dexamethasone IV or PO prior to daratumumab dosing 
as a premedication to prevent SC- infusion-related reactions, and 20 
mg the day after dosing.
40 mg weekly (or 20 mg weekly for some subjects) see 
Section 6.5 for further details until a maximum of 6 cycles
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Notes
Cycle 1-2
Cycle 3-6
Cycle 7+ 
(Arm B 
only)
EOT 
(within 30 
days of 
last dose)
D1
D8
D15
D22
D1
D8
D15
D22
D1
Study Drug Administration, Treatment Arm B
Daratumumab
Maximum 2 yr. Refer to IPPI for preparation and SC-administration 
of daratumumab.
X
X
X
X
X
X
X
Abbreviations: D=day; EOT= End-of-Treatment; hr=hour; IPPI= Investigational Product Preparation Instructions; IV-intravenous; PO=oral; SC=subcutaneous; yr=year; 
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ABBREVIATIONS
ADL
Activities of daily living
AE
Adverse event
AL amyloidosis
Light chain amyloidosis
ALT
Alanine aminotransferase
Anti-HBc
Antibodies to hepatitis B core antigen
Anti-HBs
Antibodies to hepatitis B surface antigen
AST
Aspartate aminotransferase
ATTR
Amyloidosis due to transthyretin (TTR) gene mutation
BMDex
Melphalan and dexamethasone plus bortezomib
BSA
Body surface area
CCO
Clinical cutoff
CHR
Complete hematologic response
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMH
Cochran-Mantel-Haenszel
COPD
Chronic obstructive pulmonary disease
CR
Complete response
CrCl
Creatinine clearance
CTCAE
Common Terminology Criteria for Adverse Events
CTD
Cyclophosphamide, thalidomide, dexamethasone
CyBorD
Cyclophosphamide, bortezomib and dexamethasone
CyP
Cytochrome P450
DARA-MD
Dara-mix and deliver
dFLC
Difference between involved and uninvolved free light chains
DNA
Deoxyribonucleic acid
DVd
Daratumumab, bortezomib, and dexamethasone
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
eDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
EORTC QLQ
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire
EQ-5D-5L
European Quality of Life Five Dimensions Questionnaire
EU
European Union
FEV1
Forced Expiratory Volume in 1 second
FFPE
Formalin fixed paraffin embedded
FLC
Free light chain
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HemPFS
Hematologic progression-free survival
HIV
Human immunodeficiency virus
HRQOL
Health-related quality of life
IABP
intra-aortic balloon pump
IAT
Indirect antiglobulin testing
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFE
Immunofixation electrophoresis
IHC
Immunohistochemistry
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IPPI
Investigational product preparation instructions
IRB
Institutional Review Board
IRC
Independent Review Committee
IRR
Infusion-related reaction(s)
ITT
Intent-to-treat
IV
Intravenous
IWRS
Interactive web-based randomization system
LVAD
Left ventricular assist device
LVEF
Left ventricular ejection fraction
MDex
Melphalan and dexamethasone
MDSC
Myeloid derived suppressor cells
MOD
Major organ deterioration
MOD-PFS
Major organ deterioration-progression-free survival
MRD
Minimal residual disease
MTD
Maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse Events
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
ORR
Overall response rate
OrRR
Organ response rate
OS
Overall survival
PCR
Polymerase chain reaction
PD
Progression of disease
PFS
Progression-free survival
PK
Pharmacokinetic(s)
PO
Oral administration
PQC
Product quality complaint
PR
Partial response
PRO
Patient-reported outcome
PS20
Polysorbate 20
PT
Prothrombin time
PTT
Partial thromboplastin time
RBC
Red blood cell
rHuPH20
Recombinant hyaluronidase PH20
S-IFE
Serum immunofixation
SAC
Safety Assessment Committee
SAE
Serious adverse event
SC
Subcutaneous
SF-36v2
36-Item Short Form Survey version 2
SIPPM
Site Investigational Product and Procedures Manual
SmPC
Summary of Product Characteristics
SPEP
Serum protein electrophoresis
TEAE
Treatment-emergent adverse event
TNT
Time to next treatment
TTE
Transthoracic echocardiogram
U-IFE
Urine immunofixation
ULN
Upper limit of normal
UPEP
Urine protein electrophoresis
Vd
Bortezomib and dexamethasone
VGPR
Very good partial response
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1.
INTRODUCTION
The term “sponsor” used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Amyloidosis
Amyloidosis refers to a disease in which there is extracellular deposition of insoluble fibrillar 
proteins in tissues and organs. These are part of a growing group of diseases now thought to be 
caused by misfolded proteins (Chaulagain 2013).4 Systemic light chain (AL) amyloidosis is an 
acquired plasma cell disorder caused by insoluble protein produced by clonal expansion of 
CD38+ plasma cells.
The goal of therapy for amyloidosis is to achieve “complete hematologic response (CHR) or at a 
minimum very good partial response (VGPR) in order to prevent further end-organ damage, 
reverse existing organ dysfunction, and prolong overall survival (Chaulagain 2013).4 In AL 
amyloidosis, achieving a partial hematologic response or stable disease may not offer a clinical 
benefit, because ongoing light chain production may result in further organ damage. Therefore, 
partial response (PR) should always be viewed in conjunction with organ response in the 
evaluation of treatment outcomes (Comenzo 2012).7
All current treatments for AL amyloidosis involve the destruction of plasma cells responsible for 
the production of the light chains. There are several regimens utilized for AL amyloidosis; all 
derived from the treatment experience of patients with multiple myeloma (Anderson 2014).1
However, the National Comprehensive Cancer Network (NCCN) recommends that treatment 
should be in the context of a clinical study when possible because there are insufficient data to 
recommend optimal treatment of amyloidosis. (Anderson 2014).1
Medications that target the malignant plasma cell are part of the treatment armamentarium for 
myeloma and have clinical efficacy in amyloidosis. High dose melphalan followed by stem cell 
transplant is one of the treatments; however, it is associated with significant treatment-related 
mortality. Phase 2 studies have shown that lenalidomide in combination with dexamethasone is 
active in frontline and relapsed/refractory settings (Sanchorawala 2007, Dispenzieri 2007).43,12
Severe cardiac and renal toxicities were observed in these patients, which underscores the need 
for careful monitoring of patients on this regimen. In another Phase 2 study in newly diagnosed 
patients, a combination of cyclophosphamide, lenalidomide and dexamethasone, resulted in an 
overall hematologic response rate of 60% (VGPR or better) (Kumar 2012).19 In this study, 
hematologic toxicities were the predominant adverse events (AEs). Proof of concept and Phase 2 
studies have shown that regimens like cyclophosphamide, thalidomide, dexamethasone (CTD), 
RevDex, and VELCADE® (bortezomib) have clinical utility in AL amyloidosis (Kumar 2012, 
Kastritis 2012, Sanchorawala 2013, Palladini 2013).19,15,42 ,37
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1.1.1.
Bortezomib-based Treatment Options for Amyloidosis
Results of the first prospective, randomized, Phase 3 trial comparing melphalan and 
dexamethasone (MDex) with MDex plus bortezomib (BMDex) in newly diagnosed AL 
amyloidosis were recently presented (Kastritis 2016).16 The primary endpoint, hematologic 
response at 3 months, was reached in 51% (28% CR/VGPR) of subjects with MDex versus 78% 
(53% CR/VGPR) with BMDex (P=0.001). Overall hematologic response at the end-of-treatment 
(median of 5 cycles) was 56% for MDex and 81% for BMDex (P=0.001), with 38% CR/VGPR 
and 64% CR/VGPR, respectively. Cardiac response was achieved in 24% (8/33) of MDex 
evaluable subjects and 38% (10/26) BMDex evaluable subjects. There was a numerically higher 
proportion of cardiac progression (32% vs 15%, p=0.054) in the MDex arm. Renal response was 
48% in both arms. After a median follow-up of 25 months, there was no significant difference in 
survival. Achievement of hematologic response at 3 months was associated with improved 
survival which further validates this biomarker endpoint as a surrogate for benefit. The 
conclusion of the study is that the introduction of novel therapy (bortezomib) results in superior 
efficacy compared to alkylating therapy plus steroid alone.
1.1.2.
Background on Bortezomib in Combination with Cyclophosphamide 
and Dexamethasone (CyBorD regimen)
The use of CyBorD is recommended by the NCCN, British Society of Haematology, and 
consensus 
guidelines 
(Comenzo 
2012, 
Anderson 
2014; 
Mahmood 
2014, 
Wechalekar 2008).7,1,26,49 The majority of data published on safety and efficacy of bortezomib for 
the treatment of AL amyloidosis is derived from uncontrolled, retrospective analyses. The 
regimen of cyclophosphamide, bortezomib, and dexamethasone, known as CyBorD, is 
commonly used for the treatment of newly diagnosed patients with AL Amyloidosis 
(Anderson 2014).1 For example, Mikhael et al presented a retrospective study utilizing 
bortezomib (1.5 mg/m2
weekly), cyclophosphamide (300 mg/m2
orally weekly), and 
dexamethasone (40 mg weekly) (Mikhael 2012).30 Response was observed in 16 (94%) patients, 
with 71% achieving CHR and 24% achieving PR. Time to response was 2 months. In a separate 
study with 48 patients with untreated or relapsed AL, Venner et al reported an overall 
hematologic response rate of 81.4%, including CR in 41.9%, and very good partial response with 
>90% decrease in difference between involved and uninvolved light chains (VGPR-dFLC) in 
51.4% (Venner 2012).47 Patients treated upfront had higher rates of CR (65.0%) and VGPR-
dFLC (66.7%). The estimated 2-year progression-free survival was 66.5% for patients treated 
upfront and 41.4% for relapsed patients.
The largest experience published to date was a retrospective study of 230 front line AL 
amyloidosis patients who received CyBorD at 2 academic centers (Palladini 2015).38 By intent-
to-treat, hematologic response was achieved in 138 of 230 patients (60%), with CR in 54 cases 
(23%). Among 201 patients with measurable disease, 125 (62%) responded (CR in 42, 21%; 
VGPR, in 45, 22%). Overall, 55% of patients are projected to survive 5 years, and median time 
to second line therapy or death was 13 months. Hematologic response significantly improved 
survival with deeper responses (CR and VGPR) correlating with improvements in overall 
survival.
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The dose of VELCADE chosen in the 54767414AMY3001 study is based on consensus 
guidelines and best available evidence. Specifically, the VELCADE dosing in AMY3001 
protocol is based on the above published efficacy and safety data of VELCADE 1.3 mg/ m2 once 
weekly in the treatment regimen CyBorD for newly diagnosed AL amyloidosis 
(Palladini 2015)38. While the dose of 1.3mg/m2 twice weekly has been attempted in AL 
Amyloidosis (Reece 2014)41, there is a significant concern for treatment emergent peripheral 
neuropathy. Patients with AL amyloidosis have increased risk and suffer from significant 
peripheral neuropathy secondary to amyloid deposition in the peripheral nervous system and this 
symptom may be exacerbated by VELCADE. Therefore, the company has selected 1.3 mg/m2
once weekly dose of VELCADE in the AMY3001 study, which is consistent with the 
recommendations from members of the Steering Committee who are international amyloidosis 
experts and have written the consensus guidelines for AL amyloidosis. 
1.2.
Daratumumab
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a 
unique epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed 
towards tumor cells that express high levels of CD38, such as plasma cells from patients with AL 
amyloidosis.
The mechanisms of action of daratumumab comprise immune-mediated effects, including 
complement-dependent 
cytotoxicity, 
antibody-dependent 
cell-mediated 
cytotoxicity, 
antibody-dependent cellular phagocytosis, and apoptosis by means of cross-linking 
(de Weers 2011, Overdijk 2016, Overdijk 2015, Lammerts 2014, Laubach 2015).9,33,34,20,21
Moreover, daratumumab also induces immunomodulatory effects via several different pathways 
that contribute to killing CD38+ immune cells that modulate T cell activity, namely MDSC, 
TReg, and BReg (Krejcik 2016).18 Daratumumab’s converging mechanisms of actions are 
hypothesized to lead synergistically to the deep responses observed in patients with multiple 
myeloma.
As of 30 Jun 2016, approximately 3,147 subjects have been enrolled in 14 ongoing clinical 
studies of daratumumab. Among the 156 subjects treated with 16 mg/kg daratumumab IV 
monotherapy, the most frequently reported TEAEs (incidence more than 20%) were fatigue; 
nausea and anemia, back pain, cough, neutropenia, pyrexia, upper respiratory tract infection, and 
thrombocytopenia. Six subjects (4%) were withdrawn from treatment prematurely due to 
TEAEs, none of which were considered by the investigator to be related to daratumumab. 
Daratumumab as IV combination therapy has been administered to approximately 
1,310 subjects. The safety profile of daratumumab in combination with standard background 
regimens (bortezomib, lenalidomide, pomalidomide, dexamethasone, melphalan, prednisone, 
thalidomide) is consistent with those of the background regimens and single agent daratumumab. 
With the exception of SC-infusion related reactions and neutropenia/thrombocytopenia, the 
safety profiles of daratumumab in combination with lenalidomide and dexamethasone (Rd), 
bortezomib and dexamethasone (Vd), or pomalidomide and dexamethasone (Pom-dex) were 
similar to those of the background regimens.
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Subcutaneous (SC) administration of daratumumab has been investigated in Study MMY1004. 
Preliminary data from this study show that daratumumab SC-administration is feasible and has a 
substantially shortened infusion time compared with standard IV administration. In addition, the 
data show that the incidence of IRRs is reduced with SC-administration compared with IV 
administration. Further details of the safety and efficacy of daratumumab administered SC are 
provided in Section 3.2.1. In the current study, daratumumab will be administered as an SC dose 
with recombinant hyaluronidase PH20 (rHuPH20).
For the most comprehensive nonclinical and clinical information as well as Reference Safety 
Information regarding daratumumab, refer to the latest version of the Investigator’s Brochure 
(IB). 
1.2.1.
Daratumumab in AL Amyloidosis
The phenotype of plasma cells in the bone marrow of patients with AL amyloidosis was 
investigated using flow cytometry (Matsuda 2003).28 Samples from 10 patients with AL 
amyloidosis and control samples from 4 patients with M-protein (positive controls) and 
8 patients without M-protein (negative controls) were evaluated. On flow cytometry 
CD38++CD19+CD56- cells (polyclonal plasma cells) showed no significant difference between 
patients and either control group, while CD38++CD19-CD56+ cells (monoclonal plasma cells) 
showed a significantly higher level in patients compared with either negative (p <0.005) or 
positive controls (p <0.05). Thus, monoclonal plasma cells in AL amyloidosis express CD38, the 
target of daratumumab.
There are very limited data published on daratumumab in the treatment of AL Amyloidosis. 
Twelve previously treated patients with AL amyloidosis who received daratumumab 
monotherapy at the Stanford University Amyloid Center, were retrospectively studied for 
evidence of hematologic and organ response (Kaufman 2016).17 Based on consensus criteria 
(Comenzo 2012),7 10 of 12 patients (83%) achieved objective responses (3 CHR, 3 VGPR, 4 PR) 
after a median duration of therapy of 4 months. Seven subjects were evaluable for cardiac 
response based on N-terminal pro-brain natriuretic peptide (NT-proBNP) criteria; of these, 
3 patients achieved cardiac organ response (>30% reduction and >300 ng/L decrease in 
NT-proBNP).
Weiss 201650 reported efficacy data from 4 patients with AL amyloidosis (AL) or multiple 
myeloma with AL (MM/AL) who were treated with daratumumab. Patients 
 and 
 received 
the following modification from the standard daratumumab treatment: daratumumab 8 mg/kg in 
500 mL on Cycle 1 Day 1, then 16 mg/kg in 500 mL on Day 8 and thereafter. Patients 
 and 
 
received the standard daratumumab treatment of 16 mg/kg. Patients 
 received montelukast 
on the day prior, the day of and 2 days after daratumumab. Hematologic response was assessed 
by consensus criteria (Comenzo 2012).7
PPD
P
P
P
P
P
P
P
P
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Table 3:
Efficacy of Daratumumab in AL Amyloidosis and Multiple Myeloma with AL Amyloidosis
Subject ID
Diagnosis
No. Prior Regimens
Best Hematologic Response
MM/AL
6
CHR
AL
4
PR
AL
4
unmeasurable
MM/AL
3
VGPR
CR=complete remission, PR=partial remission, VGPR=very good partial remission.
The Mayo Clinic reported safety and efficacy of daratumumab in 2 patients with multiple 
myeloma whose disease was complicated by development of co-morbid AL amyloidosis 
(Sher 2016).44 Both patients achieved an objective hematologic response, which helps confirm 
the efficacy of daratumumab in AL amyloidosis observed at other institutions.
1.3.
Overall Rationale for the Study
AL amyloidosis is a rare disease with a poor prognosis. The median survival of untreated 
patients is 13 months from diagnosis (Sanchorawala 2007, Chaulagain 2013).43,4 Therapy for AL 
amyloidosis should include eradication of plasma cells that produce toxic protein deposits 
leading to organ failure. These plasma cells express CD38 (Matsuda 2003, Shimojima 2005)28,45
and could be targeted by antibodies such as daratumumab that binds and eliminates CD38 
expressing cells.
Safety data is available from the ongoing single agent daratumumab study (GEN501), from the 
combination study of daratumumab and bortezomib-containing regimens (MMY1001 and 
MMY3004), and from the label for bortezomib. The safety profile of daratumumab, which 
predominantly involves IRRs, is not considered to contribute to the known adverse effects of the 
CyBorD regimen. The combination of daratumumab and CyBorD is therefore expected to have 
an acceptable safety profile. In addition, the safety run-in portion of this study will further 
validate the safety assumptions and provide information on the safety of daratumumab in 
combination with CyBorD in the AL amyloidosis patient population.
In summary, there is a strong rationale for evaluating daratumumab in AL amyloidosis:

There is a medical need for new treatments for AL amyloidosis, given the high morbidity 
and mortality in this patient population, because no specific standard of care exists in the 
frontline or relapsed setting. 

Flow cytometric data suggest that malignant plasma cells in AL amyloidosis express CD38 
and therefore can be targeted by daratumumab.
PPD
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2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives 
Primary Objective
The primary objective is to evaluate the efficacy of daratumumab plus CyBorD compared with 
CyBorD alone in the treatment of newly diagnosed AL amyloidosis patients.
Secondary Objectives
The secondary objectives are:

To evaluate the clinically observable composite endpoints for major organ deterioration-
progression-free survival (MOD-PFS) following treatment with daratumumab in 
combination with CyBorD compared with CyBorD alone

To evaluate the following efficacy measures following treatment with daratumumab in 
combination with CyBorD compared with CyBorD alone:

Organ response rate (OrRR)

Overall survival (OS)

Time to and duration of response

To evaluate fatigue, mental functioning, and health-related quality of life following 
treatment with daratumumab in combination with CyBorD compared with CyBorD alone

To assess the safety and tolerability of daratumumab when administered in combination 
with CyBorD

To assess the pharmacokinetics of daratumumab and the immunogenicity of daratumumab 
and rHuPH20

To explore minimal residual disease (MRD) status in amyloidosis patients as a surrogate for 
hematologic progression-free survival (HemPFS) and OS or as a biomarker for relapse
Exploratory Objectives
The exploratory objectives are:

To evaluate HemPFS

To evaluate biomarkers of response following treatment with daratumumab in combination 
with CyBorD compared with CyBorD alone

To evaluate physical functioning, symptom improvement, functional improvement and 
health utility following treatment with daratumumab in combination with CyBorD compared 
with CyBorD alone

To evaluate diastolic function following treatment with daratumumab in combination with 
CyBorD compared with CyBorD alone
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
To explore the pharmacokinetic/pharmacodynamic relationship of daratumumab, such as 
exposure response relationship for efficacy/safety endpoints or disease-related or 
mechanism-based biomarkers
2.2.
Endpoints
Primary Endpoint
The primary endpoint is overall CHR rate.
Secondary Endpoints
The secondary efficacy endpoints include:

Major organ deterioration progression-free survival (MOD-PFS). This is a composite 
endpoint of clinically observable endpoints and will be defined from randomization to any 
one of the following events, whichever comes first:
1.
Death
2.
Clinical Manifestation of Cardiac Failure:
Defined as development of dyspnea at rest (for at least 3 consecutive days) and due 
solely to amyloidosis cardiac deterioration, or need for cardiac transplant, left 
ventricular assist device (LVAD), or intra-aortic balloon pump (IABP)
3.
Clinical Manifestation of Renal Failure:
Defined as the development of end-stage renal disease (need for hemodialysis or renal 
transplant)
4.
Development of hematologic PD as per consensus guidelines
From CHR, abnormal free light chain ratio (light chain ratio must double) or from 
CHR/VGPR/PR, 50% increase in serum M-protein to >0.5 g/dL or 50% increase in 
urine M-protein to >200 mg/day (a visible peak must be present)
Free light chain increase of 50% to >100 mg/L

Organ response rate (OrRR) for kidney, heart, liver is defined as the proportion of baseline 
organ involved subjects who achieve confirmed organ response in each corresponding 
organ.

Overall survival (OS) is measured from the date of randomization to the date of the subject’s 
death. If the subject is alive or the vital status is unknown, then the subject’s data will be 
censored at the date the subject was last known to be alive.

CHR rate at 6 months is defined as the proportion of subjects who achieve a complete 
hematologic response at 6 months, according to the consensus guidelines for AL 
amyloidosis,7 during or after the study treatment.
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
Improvement in fatigue is defined as the change from baseline in the European Organization 
for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 
Fatigue scale score, improvement in mental functioning is defined as the change from 
baseline in the 36-Item Short Form Survey version 2 (SF-36v2) Mental Component 
Summary (MCS), and improvement in health-related quality of life is defined as change 
from baseline in the EORTC QLQ-C30 Global Health Status scale score.

Time to next treatment (TNT) defined as the time from the date of randomization to the start 
date of subsequent AL amyloidosis (non-protocol) treatment. Death due to PD prior to 
subsequent therapy is considered as an event. Otherwise, TNT is censored at the date of 
death or the last date known to be alive.

Hematologic VGPR or better rate is defined as the proportion of subjects who achieve 
hematologic CR or VGPR.

Time to CHR (or VGPR or better) is defined as the time between the date of randomization 
and the first efficacy evaluation at which the subject has met all criteria for hematologic CR 
(or VGPR or better). 

Duration of CHR (or VGPR or better) is defined as the time between the date of initial 
documentation of CHR (or VGPR or better) to the date of first documented evidence of 
hematologic progressive disease. For subjects who have not progressed, data will be 
censored at the last disease assessment.

Time to cardiac response, time to renal response, and time to liver response. Defined as the 
time between the date of randomization and the first efficacy evaluation at which the subject 
has each corresponding organ response. 

Duration of organ response is defined as the time between the date of initial documentation 
of each corresponding organ response to the date of first documented evidence of the 
corresponding organ progressive disease. For subjects who have not had organ progression, 
data will be censored at the last disease assessment.

Time to cardiac progression, time to renal progression, and time to liver progression. 
Defined as the time from the date of randomization to the date of each corresponding organ 
progression per consensus guidelines.
Exploratory Endpoint
Exploratory endpoints are:

Hematologic progression-free survival (HemPFS) is defined as the time from the date of 
randomization to the date of first documentation of hematologic disease progression, 
according to central laboratory results and judged by international consensus guidelines, or 
death due to any cause, whichever occurs first. For those subjects who are still alive and 
have not yet progressed, the subject’s data will be censored at the last disease assessment.

Evaluation of MRD status in subjects who achieve CHR based on next generation 
sequencing or similar technologies.

Assessment of physical functioning, symptom improvement, functional improvement, and 
health utility as measured by the SF-36v2, EORTC QLQ-C30 with supplemental symptom 
items, and the European Quality of Life Five Dimensions Questionnaire (EQ-5D-5L).
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
Assessment of diastolic heart dysfunction based on analysis of transthoracic 
echocardiograms.
2.3.
Hypothesis
The primary hypothesis of this study is that daratumumab in combination with CyBorD will 
improve the overall CHR rate compared to CyBorD alone, in subjects with newly diagnosed AL 
amyloidosis.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, open-label, active-controlled, multicenter Phase 3 study in subjects with 
newly diagnosed amyloid light chain amyloidosis. Approximately 360 subjects will be stratified 
by cardiac stage based on the Mayo Clinical Cardiac Staging System (Dispenzieri 201411; 
Palladini 2016)11,36 (Stages I, II, and IIIa) (Attachment 14), countries that typically offer 
transplant for patients with AL amyloidosis (List A or List B), and renal function (creatinine 
clearance [CrCl] ≥60 mL/min or CrCl <60 mL/min) and then assigned to receive either CyBorD 
or CyBorD in combination with daratumumab. Subject participation will include a Screening 
Phase, a Treatment Phase, a Post-Treatment Observation Phase, and a Long-term Follow-up 
Phase.
Given the potential safety concern with regards to the use of IV daratumumab in the amyloidosis 
population (ie, volume overload), this study will utilize the daratumumab SC co-formulation 
with rHuPH20. Although the risk of volume overload is predicted to be lower with SC 
daratumumab than with IV infusion, patients with newly diagnosed AL amyloidosis may still 
develop AEs attributable to hypervolemia (for example, dyspnea, peripheral edema, etc) 
secondary to amyloid-induced cardiac or renal insufficiency. Additionally, daratumumab has not 
been co-administered with CyBorD. Therefore, prior to the start of the randomized portion of the 
study, a safety run-in will be conducted (Figure 1). Dosing of these subjects will be staggered so 
that no subject will receive their first dose sooner than 48 hours after the previously enrolled 
subject. Safety evaluation will be performed by the sponsor (and external academic 
hematologists) after at least 10 subjects have received at least 1 cycle of treatment. If no safety 
signal is observed, particularly in regard to volume overload, the randomized portion of the study 
will begin.
Subjects in the safety run-in will not be required to complete PRO assessments, but will undergo 
other scheduled assessments as specified in the Time and Events Schedule for Treatment Arm B 
(Table 1).
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Figure 1:
Schematic Overview of the Safety Run-In
In the randomized portion of the study, subjects randomized to Treatment Arm A will receive 
study treatment with CyBorD (Figure 2). All treatment cycles are 4 weeks (28 days with a 
+/-5 day window) in length. CyBorD will be administered for a maximum of 6 cycles 
(24 weeks).
Subjects randomized to Treatment Arm B will receive CyBorD plus daratumumab at a fixed 
dose of 1800 mg. A maximum of 6 cycles (24 weeks) of CyBorD plus daratumumab will be 
administered. After Cycle 6, subjects may receive daratumumab monotherapy on Day 1 of 
subsequent 28-day cycles until disease progression, start of subsequent therapy, or a maximum 
of 24 cycles (~2 years) from the first dose of study treatment. Treatment with daratumumab after 
Cycle 6 is based on the approved daratumumab dosing regimen for multiple myeloma (weekly 
for the first 2 cycles [8 weeks] of treatment, followed by every 2 weeks for 4 cycles [16 weeks] 
and then every 4 weeks until a maximum of 24 cycles of therapy [~2 years]).
Once the randomized portion of the study begins, subjects in Treatment Arm B (CyBorD plus 
daratumumab) will be observed for at least 6 hours after the end of study drug administration 
during Cycle 1 Day 1 and, if deemed necessary by the investigator, after consecutive 
administrations.
Two interim analyses are planned for this study. The first interim analysis is a pre-specified 
safety analysis that will occur after the first 30 subjects complete at least 1 cycle of treatment. 
The second interim analysis will assess safety and efficacy, and will occur after 180 subjects 
have been treated for at least 6 cycles. Both interim analyses will be conducted by an 
Independent Data Monitoring Committee (IDMC). The primary endpoint of overall CHR and 
secondary efficacy endpoints will be adjudicated by an Independent Review Committee (IRC). 
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Figure 2:
Schematic Overview of the Randomized Study
3.2.
Study Design Rationale
3.2.1.
Rationale for Dose and Subcutaneous Administration
Daratumumab monotherapy for subjects with multiple myeloma is approved for the treatment of 
patients with relapsed/refractory multiple myeloma in the United States, European Union, and 
other countries at a dose of 16 mg/kg (weekly for 8 weeks, then every 2 weeks for 16 weeks, 
then every 4 weeks thereafter) administered via IV infusion until disease progression, start of 
subsequent therapy, or unacceptable toxicity. 
Study MMY1004 is an ongoing, open-label Phase 1b study of daratumumab-mix and deliver 
(Dara-MD), produced by mixing daratumumab 20 mg/mL with rHuPH20. The Dara-MD 
mixture, in a volume of 90 mL, is administered SC weekly for 8 weeks, every 2 weeks for 
16 weeks, and then every 4 weeks thereafter. Preliminary data from this study show that SC 
daratumumab administration is feasible and has a substantially shortened SC-infusion time 
compared with standard IV administration. Furthermore, the data show that the incidence of 
IRRs is reduced with SC-administration compared with IV administration and that SC 
daratumumab at the 1800 mg dose has antitumor activity (ORR 38%) which is consistent with 
IV daratumumab in a similar patient population (Usmani 2016).46 The median time to response 
was 4 weeks (range 4-8 weeks).
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The PK profile in MMY1004 Part 1 is generally consistent with the approved IV dose regimen of 
16 mg/kg, but the peak-and-trough fluctuation for daratumumab serum concentration is reduced 
and the maximum trough concentration (predose level prior to Cycle 3 Day 1) is comparable or 
higher compared to IV administration.
Daratumumab 1800 mg co-formulated with rHuPH20 2000 U/mL administered SC was 
well-tolerated, with clinically manageable side effects. The incidence of IRRs (24%) appeared to 
be substantially less when compared with the IV administration of daratumumab. Other TEAEs 
for SC-daratumumab appear to be similar to those reported in the 2 previous studies in which 
daratumumab was administered IV as a single agent (Lokhorst 2015, Lonial 2016).24,25 After a 
median treatment duration of 3.4 months (range 0.7-8.6) for the 1800 mg cohort, the key safety 
findings are summarized below:

The incidence of all-grade IRRs was 24% in the Dara MD 1800 mg cohort. By comparison, 
IRRs were reported in 48% of subjects in single-agent or combination therapy studies of 
Dara IV.

IRRs were mostly Grade 1 or 2. 

All IRRs developed during or within 6 hours of the start of the first SC-administration and 
did not result in treatment discontinuation. No IRRs were reported on subsequent 
SC-administrations. 

The most frequently reported treatment-emergent adverse events (TEAEs) (≥20% of all 
subjects) with Dara MD were anemia (30%), pyrexia (23%), thrombocytopenia (21%), and 
fatigue (21%). These events were reported with similar incidences in single agent studies of 
Dara IV 16 mg/kg.

Grade 3 or 4 TEAEs were reported in 40% of subjects in the 1800 mg cohort. By 
comparison, Grade 3 or 4 TEAEs were reported in 56% of subjects in single-agent studies of 
Dara IV 16 mg/kg. 

Serious adverse events (SAEs) were reported in 22% of subjects in the 1800 mg cohort. By 
comparison, SAEs were reported in 33% of subjects in single-agent studies of Dara IV 
16 mg/kg.

There were no treatment-related deaths. 
The majority of patients with amyloidosis have cardiac and renal co-morbidities. The IV infusion 
of daratumumab (1000 mL for the first infusion and 500 mL for the subsequent infusions) could 
have resulted in signs or symptoms of volume overload, particularly for the patients with cardiac 
or renal insufficiency. Given the potential advantages of SC-administration of daratumumab 
(eg, small volume; fewer IRRs), this study will use a new, co-formulated drug product 
administered SC. The co-formulated daratumumab and rHuPH20 is a single, pre-mixed vial with 
daratumumab at a higher concentration of 120 mg/mL and rHuPH20 at a concentration of 
2000 U/mL. The co-formulated drug product will reduce the time for drug preparation, reduce 
the SC-infusion volume to approximately 15 mL, and can be administered in 5 minutes by 
manual SC push. Daratumumab co-formulated product contains 1800 mg of daratumumab and 
30,000 U of rHuPH20.
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3.2.2.
Rationale for Study Treatment Regimen
Therapeutic options which form the basis of the systemic AL amyloidosis treatment paradigm 
are derived from experience in multiple myeloma, as both diseases originate from malignant 
plasma cells. Consequently, treatments include autologous stem cell transplantation, the 
combination of steroids and alkylating agents, immunomodulatory drugs, and various 
proteasome-inhibitor-based therapies. Treatment for amyloidosis is taken directly from the 
myeloma experience, with all anti-myeloma drugs used without modification of dose or schedule 
for treatment of amyloidosis. Daratumumab, with its novel, diverse mechanism of action, is 
highly efficacious in the treatment of patients with multiple myeloma and has a favorable safety 
profile. Thus, daratumumab may be a potential new treatment for the systemic AL amyloidosis 
patient population.
In addition to its use as a single agent, daratumumab has been successfully combined with 
standard anti-plasma cell directed treatment regimens. All combinations have been at the full 
dose for each regimen, and dose-finding preliminary studies have not been necessary. For 
example, with regard to the current study that will combine daratumumab with bortezomib, a 
Phase 3 study (MMY3004 known also as CASTOR) compared daratumumab, bortezomib, and 
dexamethasone (DVd) with bortezomib and dexamethasone (Vd) in patients with multiple 
myeloma who had received at least 1 prior therapy (DVd=243; Vd=237) (Palumbo 2016).39 This 
study was a randomized, controlled, open-label study. All subjects received Vd (bortezomib 
1.3 mg/m2 on Days 1, 4, 8, 11 of a 21-day cycle, and dexamethasone 80 mg every week for 2 out 
of 3 weeks) for a maximum of 8 cycles, as recommended in the bortezomib prescribing 
information. Subjects randomized to the DVd group also received daratumumab 16 mg/kg every 
week for the first 9 weeks (Cycle 1 to Cycle 3), then on Day 1 of every 3-week cycle until the 
end of Vd (Cycle 4 to Cycle 8). Patients receiving DVd continued to receive daratumumab 
monotherapy beyond Cycle 8.
The addition of daratumumab to bortezomib and dexamethasone significantly improved clinical 
outcomes in subjects with relapsed or relapsed and refractory multiple myeloma, with a 
statistically significant 61% reduction in the risk of disease progression or death for the DVd 
group compared with the Vd group (HR=0.39; 95% CI: 0.28, 0.53; p <0.0001). As of the clinical 
cutoff date of 11 January 2016, median PFS was not reached for the DVd group and was 
7.2 months for the Vd group at a median follow-up of 7.4 months. The estimated 12-month PFS 
rate was 61% (DVd group) versus 27% (Vd group). The PFS results were consistent for all 
preplanned sensitivity analyses and across all predefined subgroups. Results of secondary 
efficacy analyses support the improved benefit for the addition of daratumumab to the standard 
regimen of bortezomib and dexamethasone. This combination of daratumumab, bortezomib, and 
dexamethasone has been approved for myeloma patients with at least one prior therapy in the US 
and the EU.
In the DVd and Vd groups, the most common TEAEs (≥30% of subjects in either treatment 
group) were thrombocytopenia (DVd: 59%; Vd: 44%), peripheral sensory neuropathy (DVd: 
47%; Vd: 38%), diarrhea (DVd: 32%; Vd: 22%), and anemia (DVd: 26%; Vd: 31%). 
Daratumumab may increase thrombocytopenia, known to be associated with bortezomib 
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treatment. However, in the DVd and Vd groups, bleeding events were low and the majority of 
events were minor. Grade 3 or 4 bleeding events were experienced by less than 1% of subjects. 
Discontinuation of treatment due to TEAEs and deaths due to TEAEs was low and balanced 
between treatment groups: DVd: 7%; Vd: 9%; DVd: 5%; Vd: 5%, respectively. Subgroup 
analyses based on age, sex, race, baseline renal function, baseline hepatic function, and 
geographic region did not identify any differences that were clinically meaningful.
Based on the assessment of TEAEs, deaths, and laboratory findings, the safety profile of 
daratumumab in combination with bortezomib/dexamethasone, was consistent with the known 
safety profiles of daratumumab and bortezomib/dexamethasone. With the exception of IRRs, the 
safety profile of this combination was similar to that of the background therapy.
AMY3001 is designed to evaluate the efficacy of daratumumab in combination with CyBorD 
compared with CyBorD alone. Based on clinical study data, CyBorD represents an emerging 
standard of care for subjects with newly diagnosed systemic AL amyloidosis (Palladini 2015, 
Jaccard 2014).38,14 The use of CyBorD is recommended by the NCCN, British Society of 
Haematology, and consensus guidelines from academic institutions (Comenzo 2012, 
Anderson 2014; Mahmood 2014, Wechalekar 2008).7,26,49
Daratumumab has been administered successfully with several background
regimens 
(including bortezomib, 
lenalidomide, 
pomalidomide, 
dexamethasone, 
melphalan, 
and 
prednisone) (Chari 2015, Dimopoulos 2016, Rajkumar 2016).3,10,40 As described above, the 
combination of daratumumab with a bortezomib based regimen was synergistic and did not 
result in treatment terminating additive toxicity. Daratumumab has also already been combined 
with melphalan, an alkylating agent similar in toxicity profile to cyclophosphamide. It is 
therefore expected that daratumumab and CyBorD can be combined at the full dose of each 
regimen, and that the tolerability of the combination will be similar to the known safety profile 
of CyBorD, which would be added to the occurrence of IRRs due to daratumumab.
3.2.3.
Rationale for Run-in Phase
As this is the first study of daratumumab in treatment-naïve amyloidosis, the study will start with 
a safety run-in of at least 10 subjects who will receive daratumumab plus CyBorD at the full 
dose for each regimen. As described above in Section 3.2.2, combinations of daratumumab with 
other standard treatment regimens have all been at full dose. Based on that prior experience, it is 
unlikely that dose reductions of either daratumumab or CyBorD will be needed when they are 
administered together. The safety run-in will confirm this is the case, and will also confirm the 
safety of the new co-formulated drug product. While not statistically driven, 10 subjects were 
considered appropriate for this initial phase of the study. Dosing of the subjects will be staggered 
to allow for assessment of both early or delayed IRRs. After at least 10 subjects have completed 
at least 1 cycle of treatment, there will be an analysis of safety by the sponsor (and external 
academic hematologists) before proceeding to randomization.
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3.2.4.
Rationale for Biomarker Collection
As this is the first study of daratumumab in treatment-naïve amyloidosis and additional 
information about CD38 expression on malignant plasma cells in amyloidosis is warranted to 
better understand the disease, CD38 will be assessed by immunohistochemistry (IHC) in a subset 
of patients. Minimal residual disease assessment of bone marrow allows deeper evaluation of 
clinical response beyond standard measures. MRD assessment has been shown to have 
prognostic significance in many hematological malignancies and may have utility in 
amyloidosis. Methodologies such as the Clonoseq next generation sequencing assay that 
quantitatively evaluate neoplastic plasma cell DNA from bone marrow aspirates may be used to 
evaluate MRD negativity. MRD may be assessed in patients who achieve CHR to evaluate depth 
of response in bone marrow. Immune populations such as immunosuppressive Treg and MDSC 
have not been well studied in amyloidosis. These cells have been shown to express CD38 and 
can be depleted by daratumumab in patients with multiple myeloma (Krejcik 2016)18 and may 
play a role in daratumumab’s mechanism of action in amyloidosis. Flow cytometry will be 
performed on peripheral blood to evaluate the effect of daratumumab treatment on these 
immunosuppressive cell populations in amyloidosis. The goal of the biomarker analysis is to 
evaluate the pharmacodynamics of daratumumab in amyloidosis and aid in evaluating the 
drug-clinical response relationship. Biomarker samples may be used to help address emerging 
issues and to enable the development of safer, more effective, and ultimately individualized 
therapies.
3.2.5.
Rationale for Patient-Reported Outcome Measures
Patient-reported outcome (PRO) measures, including health-related quality of life (HRQOL) 
concepts, are included to complement clinical data and data collected by other methods. PRO 
data contributes to enhanced communication of treatment efficacy and value to patients, 
clinicians, regulators, and payers.
To collect PRO data, the study includes the EQ-5D-5L, SF-36v2, and EORTC QLQ-C30 with 
3 supplemental questions from the EORTC item bank. The EQ-5D-5L is a preference-based 
measure included to obtain utility values from the study population to support cost-effectiveness 
modeling. The SF-36v2 is a generic PRO measure included based on the recommendation from 
the Amyloidosis Research Consortium. The EORTC QLQ-C30 is a generic PRO measure 
designed for use in cancer patient populations; included with 3 additional questions to capture 
core symptoms and concepts relevant to patients with amyloidosis.
4.
SUBJECT POPULATION
Adult subjects age 18 and older with newly diagnosed AL amyloidosis are eligible for the study.
Screening for eligible subjects will be performed within 28 days before Cycle 1 Day 1. The 
inclusion and exclusion criteria for enrolling subjects in this study are described in the following 
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 subject in the study. Waivers are not allowed.
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For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
All subjects will require approval from the sponsor before randomization into the study. If the 
sponsor agrees that the eligibility criteria have been met, then the investigator will receive 
confirmation that the subject may be randomized into the study. If the sponsor considers that the 
eligibility criteria have not been met, then the sponsor will contact the investigator to discuss.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
18 years of age (or the legal age of consent in the jurisdiction in which the study is 
taking place) or older.
2.
Histopathological diagnosis of amyloidosis based on detection by IHC and polarizing 
light microscopy of green bi-refringent material in congo red-stained tissue specimens 
(in an organ other than bone marrow) or characteristic electron microscopy appearance 
(please refer to Section 9.1.2.1).
Considerations for specific populations where other types of amyloidosis may be 
encountered:

For male subjects 70 years of age or older who have cardiac involvement only, 
and subjects of African descent (black subjects), mass spectrometry typing of 
AL amyloid in a tissue biopsy is recommended to rule out other types of 
amyloidosis such as age-related amyloidosis or hereditary amyloidosis 
(ATTR mutation)
3.
Criterion modified per Amendment 2.
3.1 Measurable disease of amyloid light chain amyloidosis as defined by at least ONE 
of the following:

serum M-protein ≥0.5 g/dL by protein electrophoresis (routine serum protein 
electrophoresis and immunofixation (IFE) performed at a central laboratory),

serum free light chain ≥50 mg/L with an abnormal kappa:lambda ratio or the 
difference 
between 
involved 
and 
uninvolved 
free 
light 
chains 
(dFLC) ≥50 mg/ L.
Note: Measurable disease by urine Bence-Jones proteinuria is not sufficient for study 
enrollment.
4.
One or more organs impacted by AL amyloidosis according to consensus guidelines 
(See Attachment 2).
5.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2 
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(Attachment 1).
6.
Pretreatment clinical laboratory values meeting the following criteria during the 
Screening Phase:
a.
Absolute neutrophil count ≥1.0 × 109/L;
b.
Hemoglobin level ≥8.0 g/dL (≥5 mmol/L); red blood cell transfusion allowed 
until 7 days before randomization
c.
Platelet count ≥50 × 109/L; Platelet transfusions are acceptable without 
restriction during the Screening period
d.
Alanine aminotransferase level (ALT) ≤2.5 times the ULN
e.
Aspartate aminotransferase (AST) ≤2.5 times the ULN
f.
Total bilirubin level ≤1.5 × ULN except for subjects with Gilbert syndrome, in 
which case direct bilirubin ≤2 × ULN
g.
Estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2. Please note 
the eGFR is measured by using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation (see Attachment 5 for details)
7.
Women of childbearing potential must commit to either abstain continuously from 
heterosexual sexual intercourse (if this is the preferred and usual lifestyle of the subject) 
or to use 2 methods of reliable birth control simultaneously. This includes one highly 
effective form of contraception (tubal ligation, intrauterine device, hormonal 
[birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s 
vasectomy) and one additional effective contraceptive method (male latex or synthetic 
condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing 
and continue for 1 year after discontinuation of cyclophosphamide or 3 months after 
discontinuation of daratumumab, whichever is longer. Reliable contraception is 
indicated even where there has been a history of infertility, unless due to hysterectomy 
or bilateral oophorectomy.
8.
During the study and for 1 year after stopping cyclophosphamide or 3 months after 
receiving the last dose of daratumumab, whichever is longer, a woman must agree not to 
donate eggs (ova, oocytes) for the purposes of assisted reproduction.
9.
Criterion modified per Amendment 1.
9.1 A man who is sexually active with a woman of childbearing potential and has not 
had a vasectomy must agree to use a barrier method of birth control; eg, either condom 
with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository 
during and up to 6 months after discontinuation of cyclophosphamide or 3 months after 
discontinuation of daratumumab, whichever is longer. All men must also not donate 
sperm during the study and for 6 months after discontinuation of cyclophosphamide or 
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3 months after discontinuation of daratumumab, whichever is longer. 
10.
Criterion modified per Amendment 1.
10.1 A woman of childbearing potential must have a negative serum or urine pregnancy 
test (serum preferred) result within 14 days prior to randomization. For requirements 
during the Treatment Phase, please see the Time and Events Schedule (Table 1).
11.
Each subject, or legally acceptable representative, must sign an informed consent form 
(ICF) indicating that he or she understands the purpose of and procedures required for 
the study and are willing to participate in the study. Subjects must be willing and able to 
adhere to the prohibitions and restrictions specified in this protocol, as referenced in the 
ICF.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Prior therapy for AL amyloidosis or multiple myeloma including medications that target 
CD38, with the exception of 160 mg dexamethasone (or equivalent corticosteroid) 
maximum exposure prior to randomization
2.
Previous or current diagnosis of symptomatic multiple myeloma, including the presence of 
lytic bone disease, plasmacytomas, ≥60% plasma cells in the bone marrow, or 
hypercalcemia
3.
Evidence of significant cardiovascular conditions as specified below:
a.
NT-ProBNP >8500 ng/L
b.
New York Heart Association (NYHA) classification IIIB or IV heart failure 
(see Attachment 3)
c.
Heart failure that in the opinion of the investigator is on the basis of ischemic 
heart disease (eg prior myocardial infarction with documented history of cardiac 
enzyme elevation and ECG changes) or uncorrected valvular disease and not 
primarily due to AL amyloid cardiomyopathy
d.
Inpatient admission to a hospital for unstable angina or myocardial infarction 
within the last 6 months prior to first dose or percutaneous cardiac intervention 
with recent stent within 6 months or coronary artery bypass grafting within 
6 months
e.
For subjects with congestive heart failure, cardiovascular-related hospitalizations 
within 4 weeks prior to randomization
f.
Subjects with a history of sustained ventricular tachycardia or aborted ventricular 
fibrillation or with a history of atrioventricular nodal or sinoatrial (SA) nodal 
dysfunction for which a pacemaker/ICD is indicated but not placed (Subjects who 
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do have a pacemaker/ICD are allowed on study)
g.
Screening 12-lead ECG showing a baseline QT interval as corrected by 
Fridericia’s formula (QTcF) >500 msec. Subjects who have a pacemaker may be 
included regardless of calculated QTc interval.
h.
Supine systolic blood pressure <90 mm Hg, or symptomatic orthostatic 
hypotension, defined as a decrease in systolic blood pressure upon standing of 
>20 mmHg despite medical management (eg, midodrine, fludrocortisones) in the 
absence of volume depletion
4.
Planned stem cell transplant during the first 6 cycles of protocol therapy are excluded. 
Stem cell collection during the first 6 cycles of protocol therapy is permitted
5.
History of malignancy (other than AL amyloidosis) within 3 years before the date of 
randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma 
in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the 
investigator, with concurrence with the sponsor's medical monitor, is considered cured 
with minimal risk of recurrence within 3 years).
6.
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 
subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of 
predicted normal.
7.
Moderate or severe persistent asthma within the past 2 years (see Attachment 6), or 
currently has uncontrolled asthma of any classification. (Note that subjects who currently 
have controlled intermittent asthma or controlled mild persistent asthma are allowed in the 
study).
8.
Known to be seropositive for human immunodeficiency virus (HIV). 
9.
Criterion modified per Amendment 1.
9.1 Criterion modified per Amendment 2.
9.2 Any of the following:
a.
seropositive for hepatitis B (defined by a positive test for hepatitis B surface 
antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg 
negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or 
antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-
time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) 
DNA levels. Those who are PCR positive will be excluded. EXCEPTION: 
Subjects with serologic findings suggestive of HBV vaccination (anti-HBs 
positivity as the only serologic marker) AND a known history of prior HBV 
vaccination, do not need to be tested for HBV DNA by PCR.
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b. Known to be seropositive for hepatitis C (except in the setting of a sustained 
virologic response [SVR], defined as aviremia at least 12 weeks after completion 
of antiviral therapy).
10.
Grade 2 sensory or Grade 1 painful peripheral neuropathy.
11.
Criterion modified per Amendment 1.
11.1 Known hypersensitivity or contraindication to any of the study drugs including 
bortezomib, boron, mannitol, or cyclophosphamide or any of its metabolites.
12.
Concurrent medical condition or disease (eg, active systemic infection) that is likely to 
interfere with study procedures or results, or that in the opinion of the investigator would
constitute a hazard for participating in this study.
13.
Any form of non-AL amyloidosis, including wild type or mutated (ATTR) amyloidosis. 
14.
Criterion modified per Amendment 1.
14.1 Known allergies, hypersensitivity, or intolerance to monoclonal antibodies, 
hyaluronidase, human proteins, or their excipients (refer to IB), or known sensitivity to 
mammalian-derived products.
15.
Known or suspected of not being able to comply with the study protocol (eg, because of 
alcoholism, drug dependency, or psychological disorder) or the subject has any condition 
for which, in the opinion of the investigator, participation would not be in the best interest 
of the subject (eg, compromise their well-being) or that could prevent, limit, or confound 
the protocol-specified assessments.
16.
Woman who is pregnant or breastfeeding or planning to become pregnant while enrolled 
in this study or within 1 year after discontinuation of cyclophosphamide or 3 months 
following discontinuation of daratumumab, whichever is longer
17.
Received an investigational drug (including investigational vaccines) or used an invasive 
investigational medical device within 4 weeks before Cycle 1 Day 1.
18.
Major surgery within 2 weeks before Cycle 1 Day 1, or will not have fully recovered from 
surgery, or has surgery planned during the time the subject is expected to participate in the 
study or within 2 weeks after the last dose of study treatment administration. Note: 
subjects with planned surgical procedures to be conducted under local anesthesia may 
participate.
19.
Criterion modified per Amendment 2.
19.1 Subjects who are taking strong CYP3A4 inducers must discontinue their use at least 5 
half-lives prior to the first dose of study treatment.
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NOTE: Investigators should ensure that all study enrollment criteria have been met at Screening. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after Screening but before the first dose of study treatment is given 
such that he or she no longer meets all eligibility criteria, then the subject should be excluded 
from participation in the study. Section 17.4 describes the required documentation to support 
meeting the enrollment criteria. Subjects may be rescreened upon approval by the sponsor.
5.
TREATMENT ALLOCATION AND BLINDING
Eligible subjects will be stratified by cardiac stage based on the Mayo Clinical Cardiac Staging 
System (Dispenzieri 201411; Palladini 201636) (Stages I, II, and IIIa) (Attachment 14), countries 
that typically offer transplant for patients with AL amyloidosis (List A or List B), and renal 
function (CrCl ≥60 mL/min or CrCl <60 mL/min). Country List A contains the countries that 
typically offer stem cell transplant while country List B contains the countries that do not offer 
stem cell transplant for patients with AL amyloidosis. Randomization will be in a 1:1 ratio to 
either Treatment Arm A (CyBorD alone) or Treatment Arm B (CyBorD plus daratumumab). The 
method of randomization is randomly permuted blocks. An interactive web-based randomization 
system (IWRS) will be used. Each subject will be assigned a unique subject number.
Blinding
As this is an open-label study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
In this protocol, the term “study drug” refers to daratumumab only, and “study treatment” refers 
to daratumumab, cyclophosphamide, VELCADE (bortezomib), and dexamethasone.
Treatment should be administered in the following order: 

Treatment Arm A (CyBorD alone): dexamethasone first, then cyclophosphamide, and 
finally bortezomib.

Treatment Arm B (CyBorD plus daratumumab): premedication dexamethasone (refer to 
Section 6.5), followed by administration of daratumumab, then cyclophosphamide, 
bortezomib and the remaining dose of dexamethasone.
6.1.
Treatment Cycles
All cycles are 28-day cycles. Cycle 1 should begin within 72 hours of randomization. Each 
following cycle should begin 28 days after Day 1 of the previous cycle, with a 5-day window 
permitted to accommodate holidays, weekends, or other site scheduling concerns. If Day 1 of a 
cycle is delayed for more than 5 days, then the entire cycle is delayed and the reason should be 
recorded in the eCRF. Whenever study treatment is administered for the first time in a cycle, that 
day will be considered Day 1.
Any delay in the start of a cycle by more than 28 days in Cycles 1 to 6 may be reason for 
permanent discontinuation in the study treatment, but should prompt discussion with the sponsor 
before withdrawing the subject from the protocol.
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6.2.
Daratumumab
Detailed descriptions for preparation and SC-administration of daratumumab will be supplied in 
the Investigational Product Preparation Instructions (IPPI).
6.2.1.
Treatment Schedule and Administration
Daratumumab 1800 mg will be administered subcutaneously through a syringe by a manual push 
over approximately 5 minutes. Daratumumab will be administered weekly for the first 8 weeks 
(2 cycles), then every 2 weeks for 4 cycles (Cycles 3-6), and then every 4 weeks until 
progression of disease or subsequent therapy for a maximum of 24 cycles (~2 years) from the 
first dose of study treatment. Doses will be administered on alternating opposite (right/left) sides 
of the abdomen. Subjects will receive preinfusion and postinfusion medications as detailed in 
Section 6.2.3. A schematic of the daratumumab dosing schedule is provided in Figure 3. 
Information and details regarding preparation and SC-administration of daratumumab are 
provided in the IPPI.
Figure 3:
Daratumumab Dosing Schedule
Subjects enrolled in the safety run-in phase of the study will be kept in the hospital for 
observation for at least 24 hours after the end of the Cycle 1 Day 1 SC-administration. Subjects 
enrolled in the randomized portion of the study and randomized to Treatment Arm B (CyBorD 
plus daratumumab) will be observed for at least 6 hours after the end of study drug 
administration during Cycle 1 Day 1 and, if deemed necessary by the investigator, after 
consecutive administrations. 
Study drug administration will be performed as outpatient visits. Every effort should be made to 
keep subjects on the planned dosing schedule. However, within any given cycle, doses given 
within 3 days of the scheduled dose are permitted. The dose of daratumumab will remain 
constant throughout the study.
Additional details for SC-administration times and rates, as well as preinfusion medications, will 
be provided in the IPPI and Site Investigational Product Procedures Manual (SIPPM).
As noted in the Time and Events Schedule (Table 2), all subjects should have vital signs 
monitored before and at the end of all treatment administrations. If a subject experiences any 
significant medical event, then the investigator should assess whether the subject should stay 
overnight for observation. If the subject has not experienced a significant medical event but is 
hospitalized overnight only for observation, then the hospitalization should not be reported as an 
SAE.
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6.2.2.
Dose Delays and Dose Modification
6.2.2.1.
Dose Modification
No daratumumab dose modification (increase or decrease) will be permitted in response to 
toxicity. Dose delay is the only method for managing daratumumab-related toxicities.
6.2.2.2.
Toxicity Management
If any of the following criteria are met, then all study treatment must be held to allow for 
recovery from toxicity. The criteria for a hold in study treatment (applicable to both arms) are:

Grade 4 hematologic toxicity (anemia, neutropenia or thrombocytopenia)

Grade 3 or higher thrombocytopenia with bleeding

Febrile neutropenia of any grade

Neutropenia with infection, of any grade

For other Grade 3 or 4 toxicities which, in the investigator’s medical opinion, would cause 
excess risk to the patient, all study medications may be held until the toxicity has resolved to 
Grade 2 or less.
If daratumumab SC-administration does not commence within the prespecified window 
(Table 4) of the scheduled SC-administration date within an individual cycle, then the dose will 
be considered a missed dose. Subcutaneous administration may resume at the next planned 
dosing date. A missed dose will not be made up. Note: there should be at least 4 days between 
each daratumumab administration.
Table 4:
Daratumumab-Related Toxicity Management
Cycles
Frequency
Dose Miss
Dosing Resumption*
1 -2
Weekly (Q1wk)
>3 days
next planned weekly dosing date
3-6
Every 2 weeks 
(Q2W)
>7 days
next planned every 2 weeks dosing date
7+
Every 4 weeks 
(Q4W)
>14 days
next planned every 4 weeks dosing date
*Dosing on Day 1 of a cycle must not be skipped.
If a dose is delayed on Day 1 of a cycle, then the dates of all the subsequent doses should be 
adjusted. However, if a within-cycle dose is delayed, then the dates of the subsequent doses 
should not be adjusted. If dosing is delayed, then pharmacokinetic and pharmacodynamic 
assessments should be performed on the actual day of study drug administration, not on the 
original scheduled administration day. In addition, if D1 of a cycle has been delayed, disease 
evaluation schedule should not change but will continue to be performed according to the 
original schedule (every 28 days during Cycles 1 through 6 and every 8 weeks Cycle 7 and 
beyond). Please refer to Section 9.2.1 of the protocol.
Any AE deemed to be related to daratumumab that requires a dose hold of more than 28 days 
(Cycle 1 to Cycle 6) or more than 6 weeks (Cycle 7 and beyond) will result in permanent 
discontinuation of daratumumab.
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If a dose of daratumumab is not given due to toxicity, or if daratumumab treatment is 
discontinued because of an SC daratumumab-related infusion reaction, doses of 
cyclophosphamide, bortezomib, and dexamethasone may continue, unless criteria exist to hold 
these medications as well (see subsequent sections).
6.2.2.3.
Interruption or Missed Doses
A daratumumab dose held for more than 3 days from the per protocol administration date for any 
reason other than toxicities suspected to be related to daratumumab, or a delay of more than 
5 days before the start of a new cycle, should be brought to the attention of the sponsor at the 
earliest possible time. Subjects missing ≥3 consecutive planned doses of daratumumab for 
reasons other than toxicity should be withdrawn from treatment, unless, upon consultation with 
the sponsor and the review of safety and efficacy, continuation is agreed upon.
6.2.3.
Guidelines for Prevention and Management of Daratumumab 
Infusion-related Reactions
For the purpose of this protocol, infusion-related reactions (IRRs) are defined as systemic 
reactions related to the SC administration of the investigational agent.
6.2.3.1.
Preinfusion Medication
In an effort to prevent infusion-related reactions, all subjects will receive the following 
medications 1 to 3 hours prior to each SC-daratumumab administration (1 hour prior to 
daratumumab administration is preferred):
Preinfusion medications include the following:

Dexamethasone 20 mg IV or PO (an equivalent of long-acting corticosteroid may substitute 
[see Attachment 4 for conversion table])

Antipyretic: Paracetamol (acetaminophen) 650 to 1000 mg PO or IV

An antihistamine (diphenhydramine 25 to 50 mg, or equivalent) either given IV or PO. 
Avoid IV use of promethazine.

Montelukast (leukotriene inhibitor): Predose administration of a leukotriene inhibitor 
(montelukast 10 mg PO or equivalent) is optional on Cycle 1 Day 1 and can be administered 
up to 24 hours before SC-infusion as per investigator discretion.
If necessary, oral preinfusion medications may be administered outside the clinic on the day of 
the daratumumab treatment, provided they are taken within 3 hours prior to the 
SC-administration of daratumumab infusion.
6.2.3.2.
Postinfusion Medication
Consider administering low-dose oral methylprednisolone (≤20 mg) or equivalent, the day after 
the SC- infusion.
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However, if a background regimen-specific corticosteroid (eg, dexamethasone) is administered 
the day after the SC-infusion, additional postinfusion steroids are not required, but may be 
considered by the investigator. Refer to Section 6.5.
Subjects who continue daratumumab monotherapy after completing 6 cycles in Treatment 
Arm B: in the absence of SC infusion-related AEs, postinfusion corticosteroids may be 
administered per investigator discretion. Note: Subjects will continue to receive 20 mg of 
dexamethasone, or equivalent, as pretreatment medication prior to each dose of daratumumab.
For subjects with a higher risk of respiratory complications (eg, subjects with mild asthma or 
subjects with COPD who have an FEV1 <80% at Screening or developed FEV1 <80% during 
the study without any medical history), the following postinfusion medications should be 
considered:

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 plus long-acting 
β2 adrenergic receptor agonists for subjects with asthma; long-acting bronchodilators such 
as tiotropium or salmeterol + inhaled corticosteroids for subjects with COPD).
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after 
daratumumab SC administration. If subjects are hospitalized, then their FEV1 should be 
measured before discharge. If at-risk subjects are not hospitalized, then a follow-up telephone 
call should be made to monitor their condition within 48 hours. If the subject has not experienced 
a significant medical event but is hospitalized overnight only for observation, then the 
hospitalization should not be reported as an SAE. Investigators may prescribe bronchodilators, 
H1-antihistamines, and corticosteroids that are deemed necessary to provide adequate supportive 
care in the event a bronchospasm occurs after subjects are released from the hospital/clinic. If an 
at-risk subject experiences no major IRRs, then these postinfusion medications may be omitted 
after 4 doses at the investigator’s discretion.
Any postinfusion medication will be administered after the SC-infusion has completed.
6.2.3.3.
Management of Infusion-Related Reactions
Subjects should be observed during daratumumab SC-administration. Trained study staff at the 
clinic should be prepared to intervene in case of any IRRs and resources necessary for 
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, also medical 
equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available 
at the bedside. Attention to staffing should be considered when multiple subjects will be dosed at 
the same time.
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If an IRR develops, then the administration of daratumumab should be temporarily interrupted 
(see IPPI for further details). Subjects who experience AEs during daratumumab SC 
administration must be treated for their symptoms. The following recommendations apply:

Subjects should be treated with acetaminophen, antihistamine, or corticosteroids as needed. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects may 
require antihistamines, oxygen, corticosteroids, or bronchodilators. For hypotension, 
subjects may require vasopressors.

In the event of a life-threatening IRR (which may include pulmonary or cardiac events) or 
anaphylactic reaction, daratumumab should be discontinued and no additional daratumumab 
should be administered to the subject. 
6.2.3.3.1.
Infusion-Related Reactions of Grade 1 or Grade 2
If the investigator assesses a Grade 1-2 IRR to be related to the daratumumab SC administration, 
then the administration of daratumumab should be paused. When the subject’s condition is 
stable, daratumumab administration may be restarted at the investigator’s discretion.
If the subject experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 
6 hours from onset, then the subject must be withdrawn from daratumumab treatment.
6.2.3.3.2.
Infusion-Related Reactions of Grade 3 or Higher
For SC-infusion-related AEs (other than laryngeal edema or bronchospasm) that are Grade 3, the 
daratumumab SC administration must be stopped and the subject must be observed carefully 
until resolution of the AE or until the intensity of the event decreases to Grade 1, at which point 
daratumumab SC-administration may be restarted at the investigator’s discretion. If the intensity 
of the AE returns to Grade 3 after restart of daratumumab SC-administration, then the subject 
must be withdrawn from daratumumab treatment.
For IRR AEs that are Grade 4, the daratumumab SC-administration must be stopped and the 
subject withdrawn from daratumumab treatment.
6.2.3.3.3.
Recurrent Infusion-Related Reactions 
If a Grade 3 IRR (or Grade 2 or higher) event of laryngeal edema or bronchospasm recurs during 
or within 24 hours after a subsequent daratumumab SC-administration, daratumumab treatment 
must be discontinued.
6.2.4.
Guidelines for Management of Daratumumab Administration-related 
Reactions
For the purpose of this protocol, “administration-related reactions” are defined as localized 
reactions at the injection site (eg, erythema, local tenderness, swelling, etc).
In Study MMY1004 Part 1, SC administration of daratumumab in abdominal SC tissue was 
associated with local injection-site reactions such as induration and erythema in some subjects. 
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The reactions usually resolved within 60 minutes. Local injection site reactions should be 
managed per institutional standards.
6.3.
Cyclophosphamide
Subjects will receive 300 mg/m2 cyclophosphamide as an oral or IV weekly dose (NOTE: 
maximum absolute weekly dose of cyclophosphamide is 500 mg, irrespective of body surface 
area [BSA]) (Days 1, 8, 15, 22) in every 28-day cycle for a maximum of 6 cycles. The amount 
(in mg) of cyclophosphamide to be administered will be determined by body surface area, 
calculated according to a standard nomogram (Attachment 7). The dose can be rounded to the 
nearest pill size. For example, a dose of 310 mg can be rounded to 300 mg if 10 mg pills are not 
available. The exact dose of cyclophosphamide administered will be recorded in the eCRF.
Subjects may instead receive cyclophosphamide 300 mg/m2 (maximum absolute weekly dose
500 mg, irrespective of BSA) via intravenous infusion at the discretion of the investigator. 
Mannitol can be used as a concomitant medication for subjects who receive IV 
cyclophosphamide to prevent cystitis per investigator’s discretion. In the case of IV 
cyclophosphamide administration, the dose should be rounded to the nearest 1 mg.
For both IV and PO cyclophosphamide, subjects in Treatment Arm B should complete 
SC-administration of daratumumab prior to administration of cyclophosphamide. The dose of 
cyclophosphamide should be recalculated should the subject experience a weight change of more 
than 10% from baseline weight.
6.3.1.
Dose Adjustments for Cyclophosphamide
Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia, or 
anemia), or bone marrow failure, or both. Monitoring of complete blood counts is essential 
during cyclophosphamide treatment so that the dose can be adjusted, if needed, according to 
Table 5.
Table 5:
Cyclophosphamide Dose Adjustment
Neutrophil count/mm3
Platelet count /μL
Dosage
>1500
>100,000
100% of the planned dose
1500 – 1000
50,000 – 100,000
50% of the planned dosea
<1000
<50,000
Dose should be heldb
a.
Cyclophosphamide dose should remain at 50% of planned dose if subject’s neutrophil or platelet counts or both meet these 
values. If count increases to required levels for 100% of planned dose, then dose may be re-escalated to 100% of planned 
dose.
b.
Cyclophosphamide dose should be held if subject’s neutrophil or platelet counts or both meet this value. However, if counts 
increase to required levels for 50% of the planned dose or 100% of the planned dose, then dose may be re-escalated as 
appropriate.
G-CSF may be administered to reduce the risks of neutropenia complications associated with 
cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in 
all subjects considered to be at increased risk for neutropenia complications.
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6.3.2.
Urinary Tract and Renal Toxicity
Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with 
cyclophosphamide therapy. Bladder ulceration/necrosis, fibrosis/contracture, and secondary 
cancer may develop. Before starting treatment, it is necessary to exclude or correct any urinary 
tract obstructions. Urinary sediment should be checked regularly for the presence of erythrocytes 
and other signs of uro/nephrotoxicity. Adequate treatment with Mesna or strong hydration to 
force diuresis can markedly reduce the frequency and severity of bladder toxicity. It is important 
to ensure that patients empty the bladder at regular intervals.
It is recommended to withhold cyclophosphamide if the subject has Grade 2 or higher urinary or 
bladder toxicity and resume when the toxicity resolves to Grade 1 or lower. The use of 
concomitant medications to treat urinary or bladder toxicity is at the discretion of the treating 
physician and allowed per protocol. Reference should also be made to the USPI, SmPC, or 
locally approved prescribing information for further discussion of cyclophosphamide 
reconstitution and dispensing guidelines and management of AEs.
6.4.
Bortezomib
Subjects will receive 1.3 mg/m2 bortezomib as an SC injection weekly (Days 1, 8, 15, 22) in 
every 28-day cycle for a maximum of 6 cycles. The amount (in mg) of bortezomib to be 
administered will be determined by BSA, calculated according to a standard nomogram 
(Attachment 7). The total calculated dose of bortezomib may be rounded to the nearest decimal 
point (eg, a calculated dose of 2.47 mg can be rounded to 2.5 mg). For subjects who experience 
injection site reactions, bortezomib may be administered by IV injection (see bortezomib locally 
approved prescribing information or SmPC). On daratumumab treatment days, subjects in 
Treatment Arm B should receive bortezomib after daratumumab and cyclophosphamide have 
been administered. The dose of bortezomib should be recalculated should the subject experience 
a weight change of more than 10% from baseline weight.
6.4.1.
Dose Adjustments of Bortezomib
Dose adjustments should be based on the highest grade of toxicity that is ascribed to bortezomib. 
Bortezomib therapy should be withheld at the onset of any Grade 3 non-hematological or 
Grade 4 hematological toxicities excluding neuropathy as discussed in Table 6. Once the 
symptoms of the toxicity have resolved, bortezomib therapy may be reinitiated at a 25% reduced 
dose per approved labelling, as follows:

Starting dose – 1.3 mg/m2

Dose level 1 – 1.0 mg/m2

Dose level 2 – 0.7 mg/m2

Dose level 3 – discontinue bortezomib.
For subjects whose bortezomib is discontinued because of a bortezomib-related toxicity 
(eg, peripheral neuropathy), doses of daratumumab, cyclophosphamide, and dexamethasone may 
continue unless criteria exist to hold these medications as well.
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6.4.2.
Neurologic Toxicity
If the subject experiences peripheral neuropathy, then dose adjustments should be made 
according to the recommendations in Table 6.
Table 6:
Recommended Dose Modification for Bortezomib-related Neuropathic Pain or Peripheral 
Sensory or Motor Neuropathy
Severity of Peripheral Neuropathy Signs and 
Symptoms 
Modification of Dose and Regimen
Grade 1 (asymptomatic; loss of deep tendon reflexes or 
paresthesia) without pain or loss of function
No action
Grade 1 with pain or Grade 2 (moderate symptoms; 
limiting instrumental ADL)
Reduce bortezomib by one dose level 
Grade 2 with pain or Grade 3 (severe symptoms; 
limiting self-care ADL)
Withhold bortezomib treatment until symptoms of 
toxicity have resolved. When toxicity resolves, 
reinitiate with a reduced dose of bortezomib at 
0.7 mg/m2 once per week
Grade 4 (life-threatening consequences; urgent 
intervention indicated)
Discontinue bortezomib
Abbreviations: ADL, activities of daily living; Common Terminology Criteria for Adverse Events; NCI, National Cancer 
Institute.
Grading based on NCI CTCAE v4.03
Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money etc.
Self-care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
6.4.3.
Other Grade 3 or 4 Adverse Events
For other Grade 3 or 4 toxicities judged by the investigator to be related to bortezomib alone, 
treatment with bortezomib should be interrupted and restarted at the next lower dose level once 
the toxicity has resolved to Grade 2 or less. For complete details on bortezomib, refer to the most 
current locally approved product prescribing information or SmPC.
6.5.
Dexamethasone
Dexamethasone will be administered at a total dose of 40 mg weekly (ie, Days 1, 8, 15, 22). On 
days of daratumumab dosing, subjects in Treatment Arm B will receive 20 mg on the day of 
daratumumab dosing as premedication and 20 mg on the day after daratumumab dosing. On 
weeks that daratumumab is not administered, or for subjects randomized to Treatment Arm A, 
dexamethasone is to be given 40 mg weekly on a single day or divided into 2 days. An 
appropriate substitute for dexamethasone is allowed (as per local standards; see Attachment 4 for 
conversion table).
For subjects who are older than 70 years, underweight (BMI <18.5), have hypervolemia, poorly 
controlled diabetes mellitus, or prior intolerance/AE to steroid therapy, the dexamethasone dose 
may be administered at a dose of 20 mg weekly. For subjects receiving dexamethasone 20 mg 
weekly, on days of daratumumab treatment, it is recommended that dexamethasone 20 mg be 
administered as premedication.
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For management of dexamethasone toxicity, see Table 7. This table represents suggested dose 
modifications of dexamethasone, but physician discretion and clinical judgment should prevail. 
For complete details on dexamethasone, refer to the most current locally approved product 
prescribing information.
Table 7:
Dexamethasone Dose Modification Based on Toxicity
CTCAE Category
Toxicity
Dose Change
Gastrointestinal
Grade 1-2 dyspepsia, gastric, or 
duodenal ulcer, gastritis 
requiring medical management
Treat with histamine antagonists, sucralfate, or proton 
pump inhibitors such as omeprazole. If symptoms 
persist despite these measures, decrease dexamethasone 
dose by 50%.
≥Grade 3 requiring 
hospitalization or surgery
Hold dexamethasone until symptoms are adequately 
controlled. Restart at 50% of current dose along with 
concurrent therapy with H2 blockers, sucralfate, or 
proton pump inhibitors. If symptoms persist despite 
these measures, discontinue dexamethasone and do not 
resume.
Acute pancreatitis
Discontinue dexamethasone and do not resume.
Cardiovascular
≥Grade 3 edema limiting 
function and unresponsive to 
therapy or anasarca
Diuretics as needed and decrease dexamethasone dose 
by 25%. If edema persists despite these measures, 
decrease dose to 50% of initial dose. Discontinue 
dexamethasone and do not resume if symptoms persist 
despite 50% reduction.
Neurology/
Psychiatric
≥Grade 2 interfering with 
function but not interfering with 
activities of daily living
Hold dexamethasone until symptoms adequately 
controlled. Restart at 50% of current dose. If symptoms 
persist despite these measures, discontinue 
dexamethasone and do not resume.
Musculoskeletal
≥Grade 2 muscle weakness 
symptomatic and interfering with 
function but not interfering with 
activities of daily living
Decrease dexamethasone dose by 25%. If weakness 
persists despite these measures, decrease dose to 50% 
of initial dose. Discontinue dexamethasone and do not 
resume if symptoms persist despite 50% decrease.
Metabolic
≥Grade 3 hyperglycemia
Treat with insulin or oral hypoglycemic agents as 
needed. If uncontrolled despite these measures, 
decrease dose by 25% decrements until levels are 
satisfactory.
7.
TREATMENT COMPLIANCE
Daratumumab and bortezomib will be administered by qualified site staff. Dexamethasone and 
cyclophosphamide will be administered by qualified site staff if given as an IV dose. The details 
of each administration will be recorded in the electronic case report form (eCRF). Subjects will 
be provided with a treatment diary which will be used to assess compliance with 
cyclophosphamide and dexamethasone treatment, when self-administered. Additional details are 
provided in the SIPPM or equivalent document.
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8.
PRESTUDY AND CONCOMITANT THERAPY
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in Section 8.3. 
Systemic use of the following concomitant medications will be collected in the eCRF and 
recorded in the source documents beginning with signing of the ICF and ending 30 days after the 
last dose of the last study treatment or until the start of subsequent anticancer treatment, if 
earlier: growth factors, transfusions, anti-infectives (antibacterials, antivirals, and antimycotics), 
steroids, anti-arrhythmics and other cardiac supportive therapy (including diuretics), anti-
epileptics, centrally acting psychiatric medication, antihistamines and other medications 
targeting postinfusion systemic reactions, and any anti-amyloid therapy. The sponsor must be 
notified in advance (or as soon as possible thereafter) of any instances in which prohibited 
therapies are administered.
For subjects who may need stem cell transplant at a later time, stem cell harvest following 
mobilization with G-CSF or plerixafor or cyclophosphamide or any combination of the three is 
permitted while on study.
8.1.
Recommended Therapies
8.1.1.
Prophylaxis for Pneumocystis carinii (jirovicii)
Pneumocystis carinii (jirovicii) pneumonia prophylaxis is recommended, as per institutional 
guidelines.
8.1.2.
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation as per local standard of care is recommended during 
the Treatment Phase. Acceptable antiviral therapy includes acyclovir (eg, 200 mg given orally 
3 times a day, or 400 mg given orally 2 times a day or per institutional standards), famciclovir 
(eg, 125 mg given orally, twice a day or per institutional standards), or valacyclovir (eg, 500 mg 
given orally, once a day or per institutional standards), initiated within 1 week after the start of 
study drug.
8.1.3.
Prophylaxis or Management of Hemorrhagic Cystitis
Medications used to treat hemorrhagic cystitis, including but not limited to mannitol, Mesna, 
normal saline hydration, are permitted during the study.
8.1.4.
Management of Hepatitis B Virus Reactivation
Primary antiviral prophylaxis is permitted as per local standard of care. Per protocol, HBV DNA 
testing by PCR is mandatory for subjects at risk for HBV reactivation see Section 9.9.
For subjects who are diagnosed with HBV reactivation while on treatment, study treatment 
should be interrupted until the infection is adequately controlled. If the benefits outweigh the 
risks, study treatment may be resumed with concomitant antiviral prophylaxis as per local 
standard of care. Consult a liver disease specialist as clinically indicated. 
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8.1.5.
Management of Peripheral Edema, Pulmonary Edema, Congestive 
Heart Failure.
Patients with AL amyloidosis are prone to volume overload secondary to their underlying illness 
and secondary to the administration of dexamethasone, which may also cause peripheral edema. 
The subject will have weight assessments as described in the Time and Events Schedule 
(Table 1). Any weight gain should prompt evaluation and management of volume overload, if 
appropriate. Management of volume overload is at the discretion of the treating physician, but 
will likely include loop diuretics (furosemide, torsemide or equivalent), nitrate preparations, or 
positive ionotropic agents. Use of these medications is permissible during the study and should 
be recorded in the eCRF as concomitant medications. Dose reductions of dexamethasone are also 
recommended according to Section 6.5 of the protocol.
8.2.
Permitted Therapies
In addition, subjects are to receive full supportive care. The following medications and 
supportive therapies are examples of support therapies that may be used during the study:

Antiviral, antibacterial, and antifungal medications

Colony stimulating factors, erythropoietin, and transfusion of platelets and red cells

G-CSF/plerixafor for mobilization of stem cells

Single dose of cyclophosphamide for mobilization of stem cells
8.3.
Prohibited Therapies During the First 6 Cycles of Therapy
Concomitant administration of any other therapy for the intention of treating AL Amyloidosis is 
prohibited including medications that target CD38.
Concurrent use of corticosteroids is prohibited, unless subjects are on chronic steroids 
(maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders other 
than amyloidosis; ie, adrenal insufficiency, rheumatoid arthritis, etc.
Concomitant administration of investigational agents is prohibited. Concurrent use of NEOD-1 
(currently under clinical investigation for amyloidosis) is prohibited. Use of chronic doxycycline 
(under clinical investigation for amyloidosis) is prohibited. Administration of commercially 
available agents with activity against or under investigation for AL amyloidosis, including 
systemic corticosteroids (>20 mg prednisone per day or equivalent) (other than those given for 
IRRs as described in Section 6.2.3) should be avoided. If steroids are given for other AEs (for 
example, asthma exacerbation), treatment duration greater than 14 days should be avoided.
Concomitant administration of strong CYP3A4 inducers is prohibited with the use of 
bortezomib. Administration of strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir) should be 
avoided and is not recommended in patients receiving bortezomib. If a strong CYP3A4 inhibitor 
must be given in combination with bortezomib, monitor patients for signs of bortezomib toxicity 
and consider a bortezomib dose reduction. For a list of CYP3A4 inhibitors and inducers, see 
Attachment 15. 
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9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule (Table 1) summarizes the frequency and timing of measurements 
applicable to this study. Study assessments will be performed only after written informed consent 
is obtained. It is acceptable to obtain informed consent before the first day of the Screening 
Phase. Every effort should be made to keep subjects on the planned study schedule. At each visit, 
study assessments should be completed before study treatment administration. All visit-specific 
PRO assessments should be completed before any tests, procedures, or other consultations for 
that visit to prevent influencing subject perceptions. If a patient has completed the PRO 
assessment and dosing is delayed, the PRO assessment does not need to be repeated if the 
assessment occurs ≤4 days before dosing. Medical resource utilization data will be collected (see 
Section 9.7).
Post-baseline disease evaluations may be conducted ±5 days from the scheduled visit date (based 
on Study Day 1, ie, the first day of dosing), if necessary. At the following study visit, the subject 
should return to the original planned schedule. Any missed study visits, tests not performed, or 
examinations that are not conducted must be reported as such on the eCRF. Additional serum or 
urine pregnancy tests (serum preferred) may be performed, as determined necessary by the 
investigator, to establish the absence of pregnancy at any time during the subject's participation 
in the study.
The total blood volume to be collected is approximately 25 mL during Screening, 280 mL during 
the first 6 cycles, 20 mL at each subsequent cycle (daratumumab monotherapy and observation 
phase), with an additional 10 mL at Cycle 7 Day 1 and Cycle 12 Day 1 and 15 mL at the 
End-of-Treatment visit. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples.
9.1.1.1.
Bone Marrow Biopsy/Aspirate Considerations
Three unstained formalin fixed paraffin embedded (FFPE) slides from the bone marrow biopsy 
or 2 unstained slides and 1 hematoxylin and eosin (H&E)-stained slide should be sent to the 
central laboratory to assess CD38 expression on the plasma cells. These slides may be from 
samples collected at any time, although it is preferable that the samples were collected within 
56 days before randomization. In addition to the bone marrow biopsy slides, a fresh bone 
marrow aspirate (3 mL) should be collected and sent to the central laboratory for baseline MRD 
clone analysis. If a fresh bone marrow aspirate will not be performed at Screening because a 
sample is available within 56 days prior to Cycle 1 Day 1, then non-decalcified diagnostic tissue 
(3 non-decalcified bone marrow aspirate slides, touch-prep from biopsy (rolled biopsy) slides, or 
clot specimen slides) is requested.
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Bone Marrow Aspirate to be Obtained at Complete Hematologic Response
For this study, subjects will be asked for a repeat bone marrow aspirate collection, if feasible, at 
the time CHR is assessed. All subjects, regardless of treatment assignment, are highly 
encouraged to provide this additional sample for research purposes. If a repeat sample is 
obtained at CHR, 3 mL of bone marrow aspirate should be sent to the central laboratory for 
biomarker analysis.
9.1.2.
Screening Phase
The signed ICF must be obtained before any study-specific procedures are performed. Routine 
procedures performed as standard of care can be used for the study and do not need to be 
repeated if performed within the specified screening window. The Screening Phase begins when 
the first screening procedure is conducted (that was not performed as part of the subject’s 
standard of care). During the Screening Phase, eligibility criteria will be reviewed and a 
complete clinical evaluation will be performed as specified in the Time and Events Schedule 
(Table 1). Screening procedures will normally be performed within 28 days before Cycle 1 
Day 1. For subjects requiring mass spectrometry typing, the screening period is extended to 
42 days. During Screening, a pregnancy test (serum preferred), for women of childbearing 
potential only, must be performed within 14 days prior to randomization. Blood type assessment 
and IAT testing must be done before the Cycle 1 Day 1 SC-administration of daratumumab (Arm 
B only). Results from skeletal surveys obtained within 42 days before Cycle 1 Day 1 and bone 
marrow aspirate/biopsy obtained within a maximum of 56 days before Cycle 1 Day 1 may be 
used without these tests being repeated. If laboratory tests are performed within 7 days before 
Cycle 1 Day 1, it is not mandatory to collect these samples again at the Cycle 1 Day 1 visit 
before administration of study treatment. Retesting of abnormal screening values that lead to 
exclusion are allowed only once during the screening period (to reassess eligibility). The last 
result known prior to Cycle 1 Day 1 will be used to determine eligibility. If approved by the 
sponsor, subjects who are screen failures may be rescreened once if their condition changes.
9.1.2.1.
Histopathological Diagnosis of Amyloidosis
Tissue Specimens: based on detection of homogenous amorphous, eosinophilic, hyaline-like, 
extracellular (subepithelial) material by light microscopy of a hematoxylin and eosin stained 
biopsy (4-6µ thick sections) and concomitant congo red staining (organophilic/eosinophilic 
under bright light; apple green birefringence under polarized light (4-6µ thick sections) followed 
by immunohistochemical confirmation.
Electron microscopy appearance: unbranched 10 nm thick fibrils
Immunohistochemistry: Suggested antibodies for IHC evaluation include:

Kappa light chain (monoclonal/ in situ hybridization or IHC)

Lambda light chain (monoclonal/ in situ hybridization or IHC)

Amyloid A (monoclonal)

Transthyretin (polyclonal) should be negative in AL Amyloidosis
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
Amyloid P component (polyclonal)

Antihuman β amyloid (polyclonal)

Anti-human β2 microglobulin (polyclonal)

Fibrinogen (polyclonal)

Lysozyme (polyclonal)
Mass Spectrometry Typing of AL Amyloid (Liquid Chromatography-Tandem Mass 
Spectrometry [LC-MS/MS]):
For male subjects over 70 years of age who have cardiac involvement only, and subjects of 
African descent (black subjects), a mass spectrometry typing of AL amyloid in a tissue biopsy is 
recommended to rule out age-related amyloid or hereditary amyloid (ATTR mutation). Mass 
spectrometry typing may be performed locally. However, if local mass spectrometry typing is 
not feasible, central testing is available. If using central testing, paraffin-embedded tissue biopsy 
specimens should be sent to the central laboratory to identify the amyloid protein as AL. 
Processes for collection and transmission to the central vendor can be found in the central 
laboratory manual. Of note, mass spectrometry will not be available in China.
9.1.2.2.
Factor X Deficiency
Subjects with AL amyloidosis may develop acquired factor X deficiency (Choufani 2001).5
Testing coagulation parameters and factor X levels for all subjects is recommended if a subject 
will have an invasive procedure, but not required. Any clinically significant bleeding should 
prompt testing for acquired factor X level and supportive therapy including factor replacement if 
needed.
9.1.3.
Treatment Phase
Details of the procedures performed during the Treatment Phase are outlined in the Time and 
Events Schedule (Table 1). Subjects should start study treatment within 72 hours after 
randomization. Subjects will be closely monitored for AEs, laboratory abnormalities, and clinical 
response. Clinical evaluations and laboratory assessments may be repeated more frequently, if 
clinically indicated.
9.1.3.1.
Safety Run-In
Subjects in the safety run-in will receive daratumumab plus CyBorD, with dosing staggered by at 
least 48 hours between subjects. After at least 10 subjects in the run-in have had at least 1 cycle 
of study treatment, an analysis of safety will be conducted by the sponsor and external academic 
hematologists. Subjects in the safety run-in will not be required to complete PRO assessments, 
but will follow all other scheduled assessments as specified in the Time and Events Schedule for 
Treatment Arm B including pharmacokinetic and immunogenicity blood sampling (Table 1). 
Data from these subjects will contribute to the overall safety evaluation but will not contribute to 
the efficacy evaluation.
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9.1.3.2.
Randomized Study
For subjects in Treatment Arm A, treatment will be from Cycle 1 to Cycle 6. Thirty days after 
the end of Cycle 6, subjects will have an End-of-Treatment visit and then enter the Post-
Treatment Observation Phase.
For subjects in Treatment Arm B, combination treatment will be from Cycle 1 to Cycle 6. From 
Cycle 7, subjects may receive daratumumab SC as monotherapy for up to 24 cycles (~2 years) 
from the first dose of study treatment. Subjects will then have an End-of-Treatment visit and 
enter the Post-Treatment Observation Phase.
Before subjects discontinue study treatment due to disease progression as defined by the 
MOD-PFS composite endpoint, sites will document disease progression by completing a disease 
progression form and sending the completed form by facsimile (fax) to the sponsor’s medical 
monitor within 24 hours of disease progression assessment. Patients who meet disease 
progression criteria based only on biomarker progression will continue study therapy until 
criteria for the MOD-PFS endpoint are met. If continued treatment is desired after MOD-PFS is 
met, a discussion between the investigator and medical monitor should occur about whether 
further study treatment would benefit a subject, without safety concerns. If disease progression is 
confirmed by the sponsor and no benefit is expected from further treatment, the subject will 
discontinue study treatment, complete the End-of-Treatment visit, and enter the Long-Term 
Follow-up Phase.
9.1.3.3.
Autologous Stem Cell Collection Considerations
Stem cell collection is permitted during the study. Granulocyte colony-stimulating factor or 
plerixafor may be used as mobilization agents. Additional cyclophosphamide may also be used 
for mobilization. Investigators will record details of the stem cell yield (number of days of 
collection, number of failed collections, and total CD34+ cells per kg). A cycle delay of 4 weeks 
is permissible to accomplish stem cell mobilization and harvesting. Thereafter, the subject should 
continue treatment with study medications. Subcutaneous administration of daratumumab will 
not be extended beyond 24 cycles (~2 years) if treatment was delayed for stem cell collection.
Subjects for whom stem cell transplantation is planned within the first 6 cycles of study 
treatment are excluded from the study (see exclusion criterion 4). After 6 cycles of study 
treatment and evaluation of the primary endpoint of CHR have been completed, subjects may 
electively undergo stem cell transplantation. If they were in Treatment Arm B, these subjects will 
discontinue treatment with daratumumab. The reason for discontinuation should be recorded in 
the eCRF. However, these subjects will continue in the study for follow-up assessments. Disease 
assessments should continue for the first 2 years after transplantation or until progression of 
disease. Investigators will record time from transplant to engraftment. Engraftment will be 
defined as the day on which absolute neutrophil count is ≥1000 and platelet count is ≥50,000. 
Adverse events that are attributable to study treatment should be recorded for 30 days after the 
last dose of study treatment.
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9.1.4.
End-of-Treatment
The end-of-treatment is defined as any of the following:

Completion of 6 cycles of CyBorD in Treatment Arm A

Completion of 24 cycles (~2 years) of daratumumab treatment in Treatment Arm B

Meeting any criterion in the MOD-PFS endpoint at any time (see Section 2.2 for definition 
of MOD-PFS)
Reasons for premature discontinuation of treatment are listed in Section 10.2. Subsequent 
therapy may be started after the end-of-treatment. Please refer to Section 9.1.4.1 for further 
considerations.
9.1.4.1.
Subsequent Therapy
If a subject starts subsequent therapy prior to meeting the MOD-PFS endpoint, disease 
assessments should continue as scheduled until disease progression per the MOD-PFS endpoint 
has been recorded. In addition, collection of PRO data will occur when subsequent therapy is
started and continue at a frequency of every 6 months until the MOD-PFS endpoint is met.
Prior to completion of 6 cycles in either Treatment Arm A or Treatment Arm B, subjects should 
not receive any non-protocol therapy for the treatment of AL amyloidosis unless the subject 
develops MOD-PFS. However, certain patients who have not responded after 3 cycles of 
treatment have a poor prognosis and may benefit from a switch to second line therapy 
(Wechalekar 2012).48 While the goal is for all subjects to complete 6 cycles of treatment if 
possible, any subject who has achieved a best response of PR but has worsening organ function 
on Cycle 4 Day 1 may discontinue protocol therapy to switch to a second line therapy. For 
subjects who do not meet this criterion but for whom subsequent therapy might be optimal, 
please contact the sponsor’s medical monitor to discuss continued treatment.
After completion of 6 cycles in either Treatment Arm A or Arm B and the post-treatment or 
Cycle 7 disease assessment, subsequent anti-amyloidosis therapy may be started. Subjects in 
Treatment Arm B who start subsequent therapy must discontinue daratumumab. Subsequent 
therapy may be started if the subject has had an insufficient response to initial therapy (eg, PR or 
stable disease) or if there has been cardiac or renal deterioration. Autologous stem cell transplant 
would also be considered subsequent therapy (see Section 9.1.3.3). For Treatment Arm A 
subjects who continue CyBorD post 6-cycles, the continued CyBorD treatment will be 
considered subsequent therapy.
Please refer to Table 8 for recommendations regarding subsequent therapy. Sites will document 
subsequent therapy by completing a subsequent therapy form and sending the completed form by 
fax to the sponsor’s medical monitor prior to the start of salvage therapy.
Note: Isolated changes in cardiac biomarkers (Troponin and NT-proBNP) should not prompt any 
subsequent therapy unless accompanied by objective signs/symptoms of progressive cardiac 
dysfunction.
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Table 8:
Recommendations for Subsequent Therapy After Cycle 6
Response after
6 cycles of initial therapy
Action taken
Hematologic Response (PR or better) with improved 
major organ function
Observation or daratumumab monotherapy until disease 
progression
Hematologic Response (PR or better) with stable or 
worsening major organ function
Subsequent therapy may be considered
Hematologic Non-Response or disease progression 
with stable/improved organ function 
Subsequent therapy may be considered
Hematologic Non-Response or disease progression 
with worsening organ function
Subsequent therapy recommended
9.1.4.2.
End-of-Treatment Visits
Unless a subject withdraws consent for study participation or is lost to follow-up, an 
End-of-Treatment visit is to occur 30 days (±3 days) after the last dose of study treatment, or as 
soon as possible before the start of subsequent therapy. Every effort should be made to conduct 
the End-of-Treatment visit before the subject starts subsequent treatment. If a subject is unable to 
return to the study site for the End-of-Treatment visit, then the subject should be contacted to 
collect information on AEs that occur up to 30 days after the last dose of study treatment. 
Additional information on reporting of AEs is presented in Section 12.
9.1.5.
Post-Treatment Observation Phase and Long-Term Follow-up
For subjects who discontinue study treatment before disease progression has been observed, 
disease evaluations should continue to be performed in the Post-Treatment Observation Phase as 
specified in the Time and Events Schedule (Table 1). Subjects will be instructed that study drug 
will not be made available to them after they have completed/discontinued study treatment and 
that they should return to their primary physician to determine standard of care.
Subjects with confirmed disease progression according to MOD-PFS will enter the Long-term 
Follow-up Phase.
After the clinical cutoff, currently defined as 200 MOD-PFS events, all subjects in the 
post-treatment observation phase of the study will enter Long-Term Follow-up. Subsequent 
anticancer treatment, response to subsequent treatment, and date of progression will be recorded 
and survival status will be obtained every 16 weeks. Information on secondary malignancies will 
also be collected. Information may be obtained via telephone contact, in which case written 
documentation of the communication must be available for review in the source documents. If 
the subject has died, then the date and cause of death will be collected and documented on the 
eCRF.
9.2.
Efficacy Evaluations
Disease response and progression will be based on assessments for hematologic response as 
defined in Section 9.2.1. A blinded IRC consisting of 3 experts in AL amyloidosis will evaluate 
and adjudicate responses. The investigator should also continue to evaluate responses locally and 
document in the eCRF. 
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Daratumumab detection on serum IFE (S-IFE) has been demonstrated in subjects treated with 
16 mg/kg, and may interfere with the traditional criteria of negative S-IFE for hematological 
complete response (McCudden 2015)29. To mitigate this interference, the sponsor has developed 
a reflex assay that utilizes anti-idiotype antibody to bind daratumumab and confirm its 
interference on IFE. For all subjects on Arm B (daratumumab plus CyBorD) with VGPR, and a 
negative M-protein by SPEP, reflex IFE testing may be performed by the central laboratory to 
confirm daratumumab interference on IFE. 
9.2.1.
Hematologic Response Categories
Disease evaluations must be performed on the scheduled assessment day (±5 days) every 
4 weeks during Cycles 1 through 6 and every 8 weeks at Cycle 7 and beyond (including during 
the Post-Treatment observation phase) until MOD-PFS is observed. If study treatment has been 
delayed for any reason, disease evaluations will continue to be performed according to the 
original schedule, regardless of any changes to the dosing regimen.
Disease evaluations will be performed by a central laboratory (unless otherwise specified) 
according to the Time and Events Schedules (Table 1) until disease progression as defined by the 
MOD-PFS endpoint is documented, death, withdrawal of consent for study participation, or the 
end of study, whichever occurs first. Disease evaluations scheduled for study treatment days 
should be collected before study treatment is administered. For free light chain assessment, 
M-protein, and IFE measurements in serum and 24-hour urine, the investigator will use results 
provided by the central laboratory. This study will use the consensus recommendations for AL 
amyloidosis treatment response criteria (Comenzo 2012)7 presented in Table 9. Subjects with 
positive S-IFE and confirmed daratumumab IFE interference, that meet all other clinical criteria 
for CHR, will be considered CHR.
Table 9:
International Amyloidosis Consensus Criteria
Hematologic response and progression criteria
Response Category
Criteria
Complete
Normalization of free light chain levels and ratio, negative serum and urine IFEa
Very Good Partial 
Baselineb dFLC >50 mg/L: Reduction in the dFLC <40 mg/L
Baselineb dFLC < 50 mg/L: > 90% reduction in serum M-protein plus urine M-protein <100 
mg/24 hours
Partial
Baselineb dFLC >50 mg/L: A greater than 50% reduction in the dFLC
Baselineb dFLC < 50 mg/L: >50% reduction in serum M-protein plus reduction in 24-hr 
urine M-protein by >90% or to <200 mg/24 hours.
No response
Less than a PR
Progression
From CHR, abnormal free light chain ratio (involved light chain must double), Or
From CHR/VGPR/PR, 50% increase in serum M-protein to >0.5 g/dL or 50% increase in 
urine M-protein to >200 mg/day (a visible peak must be present)
Involved Free light chain increase of 50% to >100 mg/L
Abbreviations: CHR=Complete hematologic response; dFLC=difference between iFLC and uninvolved FLC; 
FLC=free light chain; IFE=immunofixation; PR=partial response.
a.
If iFLC <ULN and serum and urine IFE are negative, then neither a normal uFLC level nor a normal FLC ratio 
are required for complete response (CR).6,27,31
b.
Baseline measurement is defined as the closest non-missing measurement taken on or prior to the first study 
treatment administration.
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Hematologic response/disease progression must be documented consistently across clinical study 
sites using the criteria shown in Table 9. It is important that instances of suspected disease 
progression be reported to the sponsor as soon as possible. Laboratory values can fluctuate for a 
variety of reasons. Therefore, it is strongly recommended that hematologic disease progression 
be confirmed in a subsequent disease evaluation visit via central laboratory values prior to 
determining MOD-PFS.
Diagnosis and documentation of disease progression will be faxed within 24 hours to the 
sponsor. The medical monitor will review the form to confirm that the criteria for disease 
progression have been met. If the medical monitor agrees that disease progression has occurred, 
then a confirmation fax or e-mail will be returned to the investigator, and the subject will be 
withdrawn from study treatment. If the medical monitor considers that the criteria for disease 
progression have not been met, then the medical monitor will contact the investigator to discuss 
the subject.
For continuation of study treatment, response will be determined on an ongoing basis by the 
investigator. Primary analysis will be based on IRC determination. For additional data analysis, 
the sponsor will use a modification of a computer algorithm validated for multiple myeloma that 
has been shown to provide consistent review of the data necessary to determine disease 
progression and response according to the response criteria. For CHR, the response criteria 
require subjects to have a negative serum and urine IFE as well as normalization of FLC levels 
and ratio.
9.2.2.
Monoclonal Protein (M-protein) Measurements in Serum and Urine
Blood and 24-hour urine samples for M-protein measurements will be sent to and analyzed by a 
central laboratory. Only 1 serum and one 24-hour urine sample per time point are required by the 
central laboratory to perform the following tests. If the 24-hour urine collection (for UPEP and 
U-IFE) began before informed consent was obtained as part of routine patient care, the sample 
can be used in this study as long as it was sent to the central laboratory for analyses after the 
informed consent was obtained.

Serum M-protein quantitation by electrophoresis (SPEP) and serum immunofixation (S-IFE)

If daratumumab interference is suspected based on SPEP and IFE results, additional reflex 
IFE testing will be performed

Serum free light chain assay

24-hour urine M-protein quantitation by electrophoresis (UPEP) and U-IFE
Blood and 24-hour urine samples will be collected as specified in Table 1. S-IFE and U-IFE test 
and serum free light chain assay will be performed at Screening and Day 1 of every cycle. For 
subjects with VGPR or better and suspected daratumumab interference on serum IFE, a second 
reflex assay using the anti-idiotype monoclonal antibody may be used to confirm daratumumab 
migration on the IFE. Subjects that meet all other response criteria for CHR, and whose positive 
IFE is confirmed to be daratumumab, will be considered complete responders.
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Note: All attempts should be made to determine eligibility of the subject based on the central 
laboratory results of screening blood and urine M-protein measurements. In exceptional 
circumstances, the local laboratory results of blood and urine M-protein measurements or serum 
FLC measurements may be used to determine eligibility, but only if the results are clearly
(eg, 25% or more) above the thresholds for measurability upon consultation with the sponsor.
9.2.3.
Determination of Organ Response
Organ disease that is considered to be quantifiable for response evaluated by the central 
laboratory includes cardiac disease (NT-proBNP, troponin T, and high sensitivity troponin T), 
renal disease (proteinuria, eGFR), and hepatic disease (alkaline phosphatase). Cardiac and liver 
organ response must be monitored by the International Amyloidosis Consensus Criteria 
(Comenzo 2012)7. Renal organ response must be monitored by Palladini criteria 
(Palladini 2014)35. Refer to Table 10.
The cardiac biomarker NT-proBNP will be used to monitor cardiac response. Response is 
defined as a decrease of >30% in NT-proBNP levels and >300 ng/L (NOTE: subjects with 
NT-proBNP <650 ng/L are not assessable for a cardiac NT-proBNP response) compared to 
baseline levels or NYHA class response (>2 class decrease in subjects with NYHA class of 3 or 
4). The cardiac biomarkers (NT-proBNP, troponin T and high sensitivity [HS] troponin T) will 
be evaluated by the central laboratory. Of note, only HS Troponin T will be sent to central 
laboratory in China.
For kidney response, the recent Palladini criteria response is defined as a decrease in proteinuria 
by ≥30% or below 0.5 g/24 hours without renal progression; renal progression is defined as a 
≥25% eGFR decrease (Palladini 2014)35.
For liver response, alkaline phosphatase will be monitored. For hepatic response, a 50% decrease 
in abnormal alkaline phosphatase value is required.
Table 10:
Organ Response and Progression Criteriaa
Organ
Responsed
Progressiond
Hearta
NT-ProBNP response (>30% and >300 ng/L 
decrease in subjects with baseline NT-proBNP 
>650 ng/L) or NYHA class response (>2 class 
decrease in subjects with baseline NYHA class 3 or 
4)
NT-proBNP progression (>30% and 
>300 ng/L increasec) or cTn progression 
(>33% increase) or ejection fraction 
progression (>10% decrease)
Kidneyb
≥30% decrease in proteinuria or drop in proteinuria 
below 0.5 g/24 hours in the absence of renal 
progression.
≥25% decrease in eGFR
Livera
50% decrease in abnormal alkaline phosphatase 
value
50% increase of alkaline phosphatase 
above the lowest value
Abbreviations: eGFR, estimated glomerular filtration rate; NT-proBNP, N-terminal prohormone of brain natriuretic 
peptide; cTn, cardiac troponin; NYHA, New York Heart Association.
a.
Based on Comenzo 2012 consensus criteria (Comenzo 2012)7
b.
Based on Palladini 2014 criteria (Palladini 2014)35
c.
Subjects with progressive worsening renal function cannot be scored for NT-proBNP progression.
d.
Baseline measurement is defined as the closest non-missing measurement taken on or prior to the first study 
treatment administration.
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9.2.4.
Bone Marrow Assessment
Bone marrow biopsy slides will be assessed by IHC for CD38 expression on the plasma cells and 
bone marrow aspirate slides will be used to identify an index clone(s) for baseline 
MRD assessment. MRD assessment has been shown to have prognostic significance in many 
hematological malignancies and may have utility in amyloidosis. In the present study, MRD will 
be assessed in bone marrow aspirates, when feasible, from subjects who achieve CHR.
9.3.
Pharmacokinetics and Immunogenicity
9.3.1.
Evaluations
Samples to assess both the serum concentration (pharmacokinetics) of daratumumab and the 
generation of anti-daratumumab antibodies (immunogenicity) will be obtained from all subjects 
in the safety run-in and in Treatment Arm B according to the Time and Events Schedule 
(Table 1 and Table 2). At specified time points, venous blood samples (5 mL per sample) will be 
collected to determine serum concentration of daratumumab and the serum will be divided into 3 
aliquots (1 aliquot for pharmacokinetic analysis, 1 aliquot for antibodies to daratumumab 
analysis [when appropriate], and 1 aliquot as a backup).
Samples will also be collected from all subjects in the safety run-in and in Treatment Arm B to 
evaluate the immunogenicity of rHuPH20 according to the Time and Events Schedule. At 
specified time points, venous blood samples (5 mL per sample) will be collected and the plasma 
will be divided into 5 aliquots to accommodate immunogenicity screening, confirmatory, and 
titer assays and neutralizing antibody analysis (when appropriate) as well as volume for backup.
The exact dates and times of blood sampling must be documented. Refer to the central laboratory 
manual or equivalent document for sample collection requirements. Collected samples must be 
stored under the specified and controlled conditions for the temperatures indicated in the 
laboratory manual. Samples collected for determining serum concentrations/immunogenicity of 
daratumumab or immunogenicity of rHuPH20 in this study may be retained to address questions 
about drug characteristics that may arise at a later time point.
9.3.2.
Analytical Procedures
Serum samples will be analyzed to determine concentrations of daratumumab or generation of 
antibodies to daratumumab using validated immunoassay methods by or under the supervision of 
the sponsor’s bioanalytical facility.
For the daratumumab immunogenicity assessments, serum samples will be screened for 
antibodies binding to daratumumab and serum titer will also be determined from confirmed 
positive samples. Other immunogenicity analyses (eg, assessment of neutralizing capabilities) 
may be performed to further characterize the immune responses that are generated. For the 
rHuPH20 immunogenicity assessments, plasma samples will be screened for antibodies binding 
to rHuPH20 and will be assessed in confirmatory and titer assays as necessary. Neutralizing 
antibody assessments may also be performed to further characterize immune responses that are 
generated.
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9.3.3.
Pharmacokinetic Parameters
Pharmacokinetic samples to determine serum concentration of daratumumab will be obtained 
from subjects in Treatment Arm B. The pharmacokinetic parameters are defined as:

Sample collected on Day 4 will be nominally classified as Cmax: Maximum observed 
serum concentration

Predose samples will be reported as Ctrough: Trough concentrations
To further describe the PK of daratumumab in amyloidosis, population pharmacokinetic analysis 
of serum concentration-time data of daratumumab may be performed using nonlinear mixed-
effects modeling and may include data from other clinical studies. Details will be provided in a 
population pharmacokinetic analysis plan and results of the analysis will be presented in a 
separate report.
9.3.4.
Immunogenicity Assessments
Serum from venous blood samples collected from all subjects in the safety run-in and Treatment 
Arm B will be assessed for the generation of anti-daratumumab antibodies (immunogenicity) 
according to the Time and Events Schedule. Daratumumab concentration will be evaluated at all 
immunogenicity time points to ensure appropriate interpretation of immunogenicity data. When 
both daratumumab serum concentration and immunogenicity analyses are specified, they will be 
performed on aliquots from the same blood draw and no additional sampling is required. Plasma 
samples will also be collected from all subjects in the safety run-in and Treatment Arm B and 
assessed for antibodies to rHuPH20. 
When an IRR occurs associated with the second daratumumab SC-administration or beyond, 
2 separate blood samples should be obtained, if possible, for determination of antibodies to 
daratumumab and antibodies to rHuPH20. No unscheduled samples need to be collected for 
SC-infusion reactions associated with the first SC-infusion of daratumumab. Daratumumab 
serum concentration will also be determined from the daratumumab SC-infusion reaction sample 
for the purpose of interpreting immunogenicity data. These samples will be stored and evaluated 
if deemed necessary. If the SC-infusion reaction results in treatment discontinuation, then 
subjects should undergo all scheduled safety and efficacy evaluations. Procedures for sample 
collection, preparation, identification, storage, and shipment will be provided in the Laboratory 
Manual or equivalent document. Samples collected for the analysis of daratumumab 
immunogenicity/serum concentration or rHuPH20 immunogenicity may additionally be used to 
evaluate safety or efficacy aspects that address concerns arising during or after the study period 
or for the evaluation of relevant biomarkers by the sponsor or sponsor’s designee.
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations
Data permitting, pharmacokinetic/pharmacodynamic modeling may be performed, to assess the 
relationship between serum concentrations of daratumumab and endpoints of clinical efficacy or 
safety. If these analyses are performed, then the details and results will be presented in a separate 
report.
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9.5.
Biomarkers
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and may 
be deferred or not performed if during or at the end of the study it becomes clear that the analysis 
will have no scientific value, or if there are not enough samples or not enough responders to 
allow for adequate biomarker evaluation. In the event the study is terminated early or shows poor 
clinical efficacy, completion of biomarker assessments is based on justification and intended 
utility of the data. All biomarker assessments will be performed in a central laboratory. Samples 
for biomarker evaluations will be collected as specified in Table 1.
Biomarker evaluations will focus on the evaluation of CD38 expression by IHC on the malignant 
plasma cells from core diagnostic biopsies to determine if CD38 expression correlates with 
response to daratumumab. Bone marrow aspirate will also be obtained to evaluate MRD. 
MRD negativity may be a potential surrogate for HemPFS and OS. Minimal residual disease 
may be monitored in subjects who achieve CHR using next generation sequencing (NGS) or 
similar technologies that utilize malignant plasma cell DNA from bone marrow aspirates. Flow 
cytometry will be performed on peripheral blood to confirm daratumumab mechanism of actions 
in amyloidosis.
Whole blood samples and their derivatives will be obtained for evaluation including but not 
limited to biomarkers related to AL amyloidosis or immune biology. The initial values of these 
parameters and relative changes during therapy may be correlated with the quality and duration 
of clinical response. Biomarker assessments may monitor changes in immune cell 
subpopulations including the determination of frequency and activity of regulatory T cells and 
MDSC as these cells express CD38 and may be involved in immune-regulatory mechanisms of 
daratumumab activity (Krejcik 2016).18 Samples will also be processed to obtain plasma and 
may be analyzed for exploratory biomarkers predictive of response or resistance to therapy.
9.6.
Sample Collection and Handling
The actual dates and times of local sample collection must be recorded in the eCRF or laboratory 
requisition form. If blood samples are collected via an indwelling cannula, then an appropriate 
amount (1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock 
will be removed from the cannula and discarded before each blood sample is taken. Refer to the 
Time and Events Schedule (Table 1 and Table 2) for the timing and frequency of all sample 
collections.
For samples collected for the central laboratory, sample dates and times must be recorded on the 
laboratory requisition form. Further instructions for the collection, handling, storage, and 
shipment of samples are found in the Laboratory Manual. Collection, handling, storage, and 
shipment of samples must be under the specified, and where applicable, controlled temperature 
conditions as indicated in the Laboratory Manual.
9.7.
Medical Resource Utilization
Medical resource utilization data, associated with protocol-driven medical encounters and safety 
monitoring, will be collected in the eCRF by the investigator and study-site personnel for all 
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subjects throughout the study. Specifically, the investigator will document all hospitalizations 
and indicate whether the hospitalization was for a primary cardiac or non-cardiac indication. In 
addition, use of hemodialysis, cardiac assist devices (IABP or LVAD), and solid organ 
transplantation of the kidney or heart will be documented in the eCRF. The use of hemodialysis 
will also be documented in the eCRF.
The Medical Encounters Summary (yes/no) question in the eCRF should be answered at each 
disease assessment (Cycles 1-6 every 28 days, Cycle 7+ and during the post-treatment 
observation phase every 8 weeks), and every 16 weeks during the long-term follow-up phase of 
the study. If the subject has required any additional encounters other than those mandated per 
protocol since the last disease evaluation visit, a Medical Encounters eCRF page must be 
completed.
9.8.
Patient-Reported Outcomes
On the days that PROs are scheduled (see Table 1), the PROs should be administered before any 
other study procedures. If a subject has completed the PRO assessments and dosing is delayed, 
the PRO assessment does not need to be repeated if the assessment occurs ≤4 days before dosing. 
PROs will be administered electronically and collected to understand what trends occur over 
time.
To our knowledge, no validated, disease-specific questionnaires for amyloidosis exist to evaluate 
symptoms and disease-specific HRQOL. Symptoms experienced by patients with amyloidosis 
can vary widely (Lin 2015).23 The EORTC QLQ-C30 (Attachment 8 and Attachment 9) is a 
cancer-specific PRO measure that captures most of the symptoms reported by patients with 
amyloidosis. It 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). Also, 
3 additional items will be used from the EORTC Item Bank (MY20, V28, and PR25) to assess 
symptoms (upper and lower body swelling and neuropathy) reported by patients with 
amyloidosis (Attachment 9, Lin 2015; EORTC website).23 The recall period is 1 week (the past 
week). Administration time for the questionnaire is approximately 15 minutes. The EORTC 
QLQ-C30 has been widely used among cancer patients. Scores are transformed to a 0 to 
100 scale. A high score for the global health status represents high quality of life, a high score for 
a functional scale represents high level of functioning, and a high score for a symptom 
scale/items represent a high level of symptomatology/problems. Reliability, validity, and 
clinically meaningful change of the EORTC QLQ-C30 has been demonstrated in multiple 
myeloma patients (Wisløff 1996, Wisløff 1997).52,51
The EQ-5D-5L (Attachment 10) is a generic measure of health status. For the purposes of this 
study, the EQ-5D-5L will be used to generate utility scores for use in cost-effectiveness analyses. 
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 
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health state) (Herdman 2011).13 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) with higher values representing 
better general health status of the individual. Administration time for the questionnaire is up to 
approximately 10 minutes.
The SF-36v2 Health Survey (Attachment 11) is a generic measure of health status. The SF-36v2 
consists of 36 questions that yield an 8-scale profile of functional health and well-being, as well 
as 2 physical and mental health summary measures and a preference-based health utility index. 
The physical component summary, the MCS, and the 8 domain scores range from zero (0) to 
100, with higher scores representing higher level of functioning. Administration time for the 
questionnaire is approximately 10 minutes. 
9.9.
Safety Evaluations
Safety will be assessed by AEs, laboratory test results, ECGs, echocardiograms, vital sign 
measurements, physical examination findings, and ECOG performance status.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the eCRF. Any clinically significant abnormalities persisting at the end of the 
study/early withdrawal will be followed by the investigator until resolution or until a clinically 
stable endpoint is reached.
Adverse Events
Adverse events (with the exception of progression of AL amyloidosis) will be reported by the 
subject (or, when appropriate, by a caregiver, surrogate, or the subject's legally acceptable 
representative) from the time a signed and dated informed consent is obtained until 30 days 
following the last dose of study treatment. Adverse events will be followed by the investigator as 
specified in Section 12, Adverse Event Reporting. Expected progression of disease should not be 
considered an AE (or SAE). However, if determined by the investigator to be more likely related 
to the study treatment than the underlying disease, the clinical signs or symptoms of progression 
and the possibility that the study treatment is enhancing disease progression, should be reported 
per the usual reporting requirements (see Section 12).
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the Adverse Event section of the eCRF. The laboratory reports 
must be filed with the source documents.
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The following tests will be performed by the local laboratory:
Hematology Panel
-hemoglobin
-platelet count
-white blood cell (WBC) count with absolute 
neutrophils and lymphocytes
- Optional: coagulation studies (PTT, 
PT)
- Optional: Factor X levels 
(recommended if a subject will have 
an invasive procedure or experiences a 
clinically significant bleeding event)
Serum Chemistry Panel
-sodium
-total bilirubin
-potassium
-direct bilirubin if history of Gilbert’s 
syndrome
-aspartate aminotransferase (AST)
-alkaline phosphatase
-alanine aminotransferase (ALT)
-creatinine
-Thyroid-stimulating hormone (TSH) and T4 
(at Screening only and subsequently if 
clinically indicated)
Serum or urine pregnancy testing (serum preferred): Women of childbearing potential only.
HBV Serology
All subjects will be tested locally for hepatitis B surface antigen (HBsAg), hepatitis B surface 
antibody (Anti-HBs), and hepatitis B core antibody (Anti-HBc) at Screening. Additionally, 
subjects ongoing in the Treatment Phase who are within 6 months of starting study treatment 
when Protocol Amendment 2 is implemented will be required to have HBV serology performed 
locally upon signing the updated ICF. If the Hepatitis B serologic status of a subject in the 
daratumumab plus CyBorD arm is unknown, HBsAg, Anti-HBs, and Anti-HBc testing is 
recommended if the subject is still receiving daratumumab or is within 6 months of the last dose.
HBV serology is not required at Screening or for subjects ongoing in the Treatment Phase who 
are within 6 months of starting study treatment if this was performed as part of standard of care 
within 3 months prior to first dose.
Hepatitis B Virus (HBV) DNA Tests
Subjects who tested positive for Anti-HBc or Anti-HBs or both will undergo testing for 
hepatitis B DNA by PCR. Subjects with serologic findings suggestive of HBV vaccination (Anti-
HBs positivity as the only serologic marker) and a known history of prior HBV vaccination do 
not need to be tested for HBV DNA by PCR. During and following study treatment, subjects 
who have history of HBV infection will be closely monitored for clinical and laboratory signs of 
reactivation of HBV as specified in the Time and Events Schedule (Table 1). Where required by 
local law, the results of HBV testing may be reported to the local health authorities.
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At Screening: calcium and eGFR calculated using CKD-EPI equation.
FEV1 Test: Subjects with known or suspected COPD or asthma must have an FEV1 test during 
Screening.
The following tests will be performed by the central laboratory and results made available 
to the site study staff:

NT-proBNP

Troponin and high sensitivity troponin

SPEP, S-IFE

UPEP, U-IFE

Serum free light chains

Serum creatinine (to derive creatinine clearance)

24-hour urine protein

eGFR
Electrocardiogram (ECG)
Electrocardiograms will be performed as specified in the Time and Events Schedule. During the 
collection of ECGs, subjects should be in a quiet setting without distractions (eg, television, cell 
phones). Subjects should rest in a supine position for at least 5 minutes before ECG collection 
and should refrain from talking or moving arms or legs. If blood sampling or vital sign 
measurement is scheduled for the same time point as ECG recording, then the procedures should 
be performed in the following order: ECG(s), vital signs, blood draw.
Transthoracic Echocardiogram (TTE) or Alternative Assessment:
Transthoracic echocardiogram (TTE) will be performed as specified in the Time and Events 
Schedule to assess left ventricular ejection fraction (LVEF) and diastolic dysfunction. Repeat 
TTE may be done during the study if clinically indicated.
Adverse events identified on TTE imaging (decrease in LVEF, for example) should be reported 
in the eCRF. Alternative cardiac assessments including multigated acquisition scan, cardiac 
magnetic resonance imaging (MRI), and cardiac catherization are acceptable methods of 
evaluating LVEF if TTE is not used.
To assess diastolic function, several attributes of the echocardiogram (with units) will be 
captured in the eCRF. These assessments include the following parameters, if available locally:

Left Ventricular Internal Diameter in diastole (LVIDd): (mm)

Left Ventricular Intra-ventricular Septal Thickness: (mm)

Left Ventricular Posterior wall thickness: (mm)

Mitral Valve Inflow E-wave velocity (E): (cm/second)
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
Mitral annular Velocity of Lateral wall (Ea): (cm/second)

E/Ea ratio

Ejection fraction
Vital Signs
Blood pressure, pulse, and temperature will be recorded as specified in the Time and Events 
Schedule. It is recommended that blood pressure measurements be preceded by at least 5 minutes 
of rest in a quiet setting without distractions (eg, television, cell phones).
Weight assessment should be performed at every visit as per the Time and Events Schedule to 
monitor volume overload. Any weight gain should prompt evaluation and if needed, 
management of volume overload.
Physical Examination and ECOG Performance Status
Physical examinations will be performed and ECOG performance status will be assessed as 
specified in Attachment 1. Any clinically significant abnormalities identified during the study 
upon physical examination should be reported as an AE. ECOG performance status will be used 
to evaluate the impact of the disease status on the activities of daily living.
Blood Type, Rh, and Indirect Antiglobulin Testing (IAT)
Blood type, Rh, and IAT should be done before the first dose of daratumumab for subjects in the 
safety run-in and in Treatment Arm B. Subject RBC phenotyping (standard or extended) is an 
alternative option to the IAT test, if locally required. Either method must be completed prior to 
first daratumumab SC-administration.
Daratumumab interferes with the IAT, which is a routine pre-transfusion test performed to 
identify a subject’s antibodies to minor antigens so that suitable donor blood can be given for 
transfusion. Daratumumab does not interfere with ABO/RhD typing. CD38 is expressed at very 
low levels on erythrocytes. Daratumumab binds to the CD38 on erythrocytes, which results in a 
positive IAT (Indirect Coombs Test). This positive result masks the detection of antibodies to 
minor antigens and may prevent or delay blood banks from issuing donor blood for transfusion. 
This effect occurs during daratumumab treatment and for up to 6 months after treatment ends. 
Subjects will receive a patient identification wallet card for the study that includes the blood 
profile (ABO, Rh, and IAT or phenotyping) determined before the first SC-administration of 
daratumumab along with information on the IAT interference for healthcare providers/blood 
banks. Subjects are to carry this card throughout the treatment period and for at least 6 months 
after treatment ends. Blood banks can eliminate the daratumumab interference with IAT by 
treating reagent RBCs with dithiothreitol (Chapuy 2015).2
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
a)
Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or 
genotypically matched units
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b)
Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using dithiothreitol-treated reagent RBCs
Un-crossmatched, 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.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow-up, or has not withdrawn consent for study participation 
before the end of the study (end of study defined in Section 17.9.1).
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study
Discontinuation of Study Treatment
A subject will not be automatically withdrawn from the study if they must discontinue treatment 
before the end of the treatment regimen. The End-of-Treatment visit and Post-Treatment visit 
assessments should continue as specified in the Time and Events Schedule.
A subject’s study treatment must be discontinued if:
1.
The investigator believes that for safety reasons or tolerability reasons (eg, AE), it is in the 
best interest of the subject to discontinue study treatment.
2.
The subject becomes pregnant.
3.
The subject (or the subject's legally acceptable representative) withdraws consent for 
administration of study treatment.
4.
The subject initiates treatment with a prohibited medication.
5.
The subject receives concurrent (non-protocol) treatment for AL amyloidosis (subsequent 
therapy).
6.
The subject experiences unacceptable toxicity, including daratumumab IRRs as described in 
Section 6.2.3. For subjects whose daratumumab treatment is discontinued because of a 
daratumumab-related 
SC-infusion 
reaction, 
they 
may 
continue 
to 
receive 
cyclophosphamide/bortezomib/dexamethasone. 
For 
subjects 
whose 
bortezomib 
is 
discontinued because of a bortezomib-related toxicity (eg, peripheral neuropathy), they may 
continue to receive daratumumab, cyclophosphamide, and dexamethasone.
7.
The subject's dose is held for more than 28 days in Cycles 1 to 6 (or more than 6 weeks from 
Cycle 7) due to toxicity, or if 3 consecutive planned doses are missed for reasons other than 
toxicity (unless agreed upon by the investigator and sponsor to continue).
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8.
The subject meets criteria for MOD-PFS endpoint (See Section 2.2), provided no benefit is 
expected from continuing treatment (see Section 9.1.3.2).
9.
The subject receives autologous stem cell transplant.
10. A subject who experiences a second primary malignancy that cannot be treated by surgery 
or radiotherapy alone must be withdrawn from the study. However, a subject who develops 
a malignancy that can be cured surgically or by radiation therapy may continue to receive 
the assigned study treatment and should continue to be followed for subsequent progression 
of AL amyloidosis.
The primary reason for discontinuation of study treatment is to be recorded in the eCRF. For 
subjects who discontinue study treatment due to meeting MOD-PFS criteria, sites will complete 
a disease progression form and fax the completed form to the sponsor’s medical monitor. If study 
treatment is discontinued for a reason other than disease progression, then disease evaluations 
will continue to be performed as specified in the Time and Events Schedule (Table 1).
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:
1. Lost to follow-up.
2. Withdrawal of consent for any type of follow-up, including overall survival.
3. Death.
4. Sponsor terminates the study.
If a subject is lost to follow-up, every reasonable effort must be made by the study-site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow-up with the subject must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw from the study will not 
be replaced. 
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF. 
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
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11.1.
Subject Information
The primary analysis population will be the intent-to-treat (ITT) population, which will include
all randomized subjects. Safety will be evaluated for the population of all treated subjects. The 
per protocol population is a subset of the ITT population defined as those subjects who have no 
major protocol violations related to inclusion and exclusion criteria. The pharmacokinetic 
analyses will be performed on the pharmacokinetic-evaluable population. Continuous variables 
will be summarized using descriptive statistics such as mean, standard deviation, median, and 
range. Categorical variables will be summarized using frequency and percentage. For 
time-to-event variables, the Kaplan-Meier method will be used for descriptive summaries.
11.2.
Sample Size Determination
The sample size for this study is based on the alternative hypothesis of a 15% improvement in 
overall CHR. Taking an overall CHR rate estimated to be 25% for the CyBorD arm 
(Palladini 2015),38 adding a 15% improvement translates to an overall CHR rate of 40% for the 
CyBorD plus daratumumab arm. Approximately 360 subjects (180 subjects per arm) would 
provide more than 85% power to detect a 15% improvement in overall CHR using a likelihood 
ratio test with a 2-sided alpha of 0.05.
The Post-Treatment phase will continue until 200 MOD-PFS events have been observed. 
Therefore, this study will achieve approximately 80% power to detect a 33% reduction in the risk 
of hematologic progression, MOD or death (hazard ratio [CyBorD plus daratumumab vs 
CyborD] of 0.67) with a log-rank test (2-sided alpha=0.05).
11.3.
Efficacy Analyses
The primary comparison of the 2 randomized treatments will be made with respect to overall 
CHR based on IRC assessment using the Cochran-Mantel-Haenszel (CMH) chi square test in the 
ITT population stratified by cardiac risk (Dispenzieri 2014; Palladini 2016)11,36 (Stages I, II, and 
IIIa), countries that typically offer transplant for patients with AL amyloidosis (List A or List B), 
and renal function (CrCl ≥60 mL/min or CrCl <60 mL/min). A Mantel-Haenszel odds ratio, 
along with its 2-sided 95% confidence interval, will be calculated. All binary secondary 
endpoints will be analyzed using the CMH chi-square test. Analysis of CHR rate at 6 months 
will be performed similarly to the primary endpoint CHR rate.
For time-to-event endpoints (eg, MOD-PFS, HemPFS, OS, etc.), Kaplan-Meier estimates will be 
presented, along with a log-rank test stratified by cardiac risk (Dispenzieri 201411; 
Palladini 201636) (Stages I, II, and IIIa), countries that typically offer transplant for patients with 
AL amyloidosis (List A or List B), and renal function (CrCl ≥60 mL/min or CrCl <60 mL/min) 
comparing the 2 treatment arms. Median along with corresponding 95% CIs will be obtained 
from the Kaplan-Meier estimates. Cox’s regression will be applied to obtain the hazard ratio 
estimate and the corresponding 95% CI.
Organ response/progression analysis will be performed separately for each organ involved at 
baseline, specifically for heart, kidney, and liver. A transient increase in NT-proBNP, troponin T, 
24-hour proteinuria, and alkaline phosphatase, or a transient decrease in eGFR meeting organ 
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progression criteria are not considered for organ progression if it persisted less than 6 months, 
and levels returned to baseline level or better. Descriptive statistics will be provided to 
summarize organ response/progression at 6 months, time to organ response, and time to organ 
progression.
11.4.
Pharmacokinetic Analyses
Pharmacokinetic data will be listed by visit for the pharmacokinetic-evaluable population, 
defined as subjects assigned to Treatment Arm B (CyBorD plus daratumumab) who have 
received at least 1 dose of daratumumab and have at least 1 pharmacokinetic sample 
concentration value after the first SC-administration of daratumumab.
All serum concentrations below the lowest quantifiable concentration in a sample or missing data 
will be labeled as such in the concentration database. Concentrations below the lowest 
quantifiable concentration in a sample will be treated as zero in the summary statistics. All 
subjects and samples excluded from the analysis will be clearly documented in the clinical study 
report.
Serum concentration data collected within specified windows in Treatment Arm B will be 
summarized using descriptive statistics, by visit. All predose samples will be described as 
Ctrough, whereas Cycle 1 Day 4 and Cycle 3 Day 4 serum concentrations will be described as
Cmax.
To further describe the PK of daratumumab in amyloidosis population and to identify covariates 
affecting the PK, pooled population pharmacokinetic analysis may be performed using nonlinear 
mixed-effects modeling and may include data from other studies. If the population 
pharmacokinetic analysis is conducted, then details will be given in a population 
pharmacokinetic analysis plan and the results of the analysis will be presented in a separate 
report.
11.5.
Immunogenicity Analyses
The incidence of antibodies to daratumumab and antibodies to rHuPH20 will be summarized for 
all subjects assigned to Treatment Arm B (CyBorD plus daratumumab) who receive at least 
1 dose of daratumumab and have appropriate samples for detection of antibodies to 
daratumumab or rHuPH20 after their first daratumumab SC-administration. The maximum titers 
of antibodies to daratumumab and rHuPH20 will be summarized for subjects who are positive 
for antibodies to daratumumab and rHuPH20. 
11.6.
Pharmacokinetic/Pharmacodynamic Analyses
To understand the relationship between serum concentrations of daratumumab and biomarkers or 
endpoints of clinical efficacy or safety, additional pharmacokinetic/pharmacodynamic modeling 
may be performed, which will be summarized in a separate report.
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11.7.
Biomarker Analyses
Any biomarker measurements will be listed, tabulated, and where appropriate, plotted. As this is 
an open-label study with an active control treatment, statistical analyses will be done to aid in the 
understanding of results.
Results of biomarker and pharmacodynamic analyses may be presented in a separate report. 
Planned analyses are based on the availability of clinically valid assays and may be deferred if 
emerging study data show no likelihood of providing useful scientific information.
11.8.
Patient-Reported Outcomes
EORTC QLQ-C30 scale and single-item scores, EQ-5D-5L visual analog scale and utility 
values, and SF-36v2 component summary and domain scores will be summarized at each time 
point. Treatment effect will be assessed by change from baseline at each time point summarized 
descriptively by treatment group.
11.9.
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 subjects who experience at least 1 occurrence of the given event will 
be summarized by treatment arm. In addition, comparisons between treatment arms will be 
provided if appropriate.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe or an 
SAE.
Clinical Laboratory Tests
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). Worst toxicity grade during treatment will be presented, according to 
the National Cancer Institute’s Common Terminology for Adverse Events (NCI-CTCAE) 
(version 4.03). A listing of subjects with any laboratory results outside the reference ranges will 
be provided. A listing of subjects with any markedly abnormal laboratory results will also be 
provided.
Electrocardiogram (ECG)
The number and percentage of subjects with normal or abnormal (clinically significant or 
clinically insignificant) 12-lead ECG results will be summarized by treatment arm. 
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Transthoracic Echocardiogram (TTE) or Other Assessment of Cardiac Function
Any changes from baseline TTE measurements (specifically, changes in LVEF and changes in 
diastolic function) will be summarized by treatment arm. Descriptive statistics will be calculated 
for observed values at baseline and change from baseline at each scheduled time point. 
Frequency tabulations of the abnormalities will be made.
Vital Signs
Descriptive statistics of temperature and blood pressure (systolic and diastolic) values, subject 
weight, and changes from baseline will be summarized at each scheduled time point. The 
percentage of subjects with values beyond clinically important limits will be summarized.
Physical Examination and ECOG
Descriptive statistics of baseline values and change from baseline will be summarized at each 
scheduled time point.
11.10. Interim Analysis
Two interim analyses are planned for the randomized study. The first interim will occur after the 
first 30 subjects are treated for at least 1 cycle (CyBorD and CyBorD plus daratumumab). The 
purpose of the first interim analysis is to have a comprehensive evaluation of safety. The second 
interim analysis will occur after at least 180 subjects in total are treated for at least 6 cycles. The 
purpose of the second interim analysis is to evaluate cumulative interim safety and efficacy data. 
Both futility and efficacy stopping rules are built in this interim analysis. The study may be 
stopped due to futility if the overall CHR rate in Treatment Arm B (CyBorD plus daratumumab) 
is the same or worse than Treatment Arm A (CyBorD). The study may be stopped due to 
efficacy if the significance level at this interim analysis to establish the superiority of CyBorD 
plus daratumumab over CyBorD is ≤0.0001 (2-sided). The primary analysis will occur after all 
subjects are treated for at least 6 cycles and the alpha to be spent is 0.04999 (2-sided). 
An IDMC, consisting of 2 clinicians and 1 statistician, will be established to review the interim 
results at the planned interim analyses in the randomized study. After the interim review, they 
will make recommendations regarding any required modification and provide guidance in the 
continuation of the study. The details will be provided in a separate IDMC charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
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12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International Council 
for Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.3.1, All 
Adverse Events, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at-risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
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be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For daratumumab, the expectedness of an AE will be 
determined by whether or not it is listed in the IB. For bortezomib, cyclophosphamide, and 
dexamethasone, please refer to the appropriate product label or SmPC for the expectedness of an 
AE.
Adverse Event Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An AE that is not related to the use of the drug.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time 
is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
The severity assessment for an AE or SAE should be completed using the NCI-CTCAE 
version 4.03. Any AE or SAE not listed in the NCI-CTCAE version 4.03 will be graded 
according to investigator clinical judgment by using the standard grades as follows:
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Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*.
Grade 3 (Severe or medically significant): 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 the AE
Activities of Daily Living (ADL)
*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 subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug. 

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental or occupational exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the Serious Adverse Event page of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All AE and special reporting situations, whether serious or non-serious, will be reported from the 
time a signed and dated ICF is obtained until 30 days after the last dose of study treatment 
(cyclophosphamide, bortezomib, dexamethasone or daratumumab), until the subject withdraws 
consent for study participation, or until the subject starts subsequent therapy, whichever occurs 
first. The only exception is for subjects who have withdrawn informed consent for study 
participation or for subjects who have received additional treatment with therapeutic intent for 
AL amyloidosis within 30 days after the last study treatment administration. For subjects who 
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have received additional treatment with therapeutic intent for AL amyloidosis during the AE 
reporting period, only AEs that are considered to be possibly, probably, or very likely related to 
study drug must be reported (unless the subject has been withdrawn from the study).
Serious adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study treatment, and those that are considered related to the study drug 
within the Follow-up Phase, must be reported using the Serious Adverse Event Form. The 
sponsor will evaluate any safety information that is spontaneously reported by an investigator 
beyond the time frame specified in the protocol.
Anticipated events will be recorded and reported as described in Attachment 12 in countries 
where required. 
Expected progression of disease should not be considered an AE (or SAE). However, if 
determined by the investigator to be more likely related to the study treatment than the 
underlying disease, the clinical signs or symptoms of progression and the possibility that the 
study treatment is enhancing disease progression, should be reported per the usual reporting 
requirements (see Section 12). Death should not be recorded as an AE or SAE, but as the 
outcome of an AE. The AE that resulted in the death should be reported as an SAE. All events 
that meet the definition of an SAE will be reported as SAEs, regardless of whether they are 
protocol-specific assessments.
All AEs, regardless of seriousness, severity, or presumed relationship to study treatment, must be 
recorded using medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). Investigators must record in the eCRF their opinion concerning the relationship of 
the AE to study therapy. All measures required for AE management must be recorded in the 
source document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required). suspected unexpected serious adverse reactions. For anticipated events reported 
as individual SAEs, the sponsor will make a determination of relatedness in addition to and 
independent of the investigator’s assessment. The sponsor will periodically evaluate the 
accumulating data and, when there is sufficient evidence and the sponsor has determined there is 
a reasonable possibility that the 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 according to requirements of the countries in 
which the studies are conducted. 
Subjects (or their designees, if appropriate) must be provided with a “wallet (study) card” and 
instructed to carry this card with them for the duration of the study indicating the following:
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
Subject number

Site number

Study number

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number

Blood type and IAT results (safety run-in and Treatment Arm B only)

Statement, in the local language(s), that the subject is participating in a clinical study
12.3.2.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a physician from the study site, and transmitted to 
the sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by fax.
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject’s participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study treatment or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject’s participation in a study must be reported as an SAE, except hospitalizations 
for the following:

If the subject has not experienced a significant medical event but is hospitalized overnight 
only for observation following SC-administration of daratumumab, then the hospitalization 
should not be reported as an SAE.

Hospitalizations not intended to treat an acute illness or AE (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 
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considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.
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 SAEs and must be reported using the Serious Adverse Event Form. Any 
subject who becomes pregnant during the study must promptly discontinue further study 
treatment. The subject should be referred to a physician experienced in teratology for evaluation 
and advice. Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE 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 DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
The daratumumab SC supplied for this study is a colorless to yellow liquid and sterile concentrate 
of 120 mg/mL as a liquid vial. The study agent should be essentially free of visible particulate 
matter at the time of syringe preparation and drug product administration. Each vial of 
co-formulated daratumumab contains nominal 15 mL (16 mL including overfill to account for 
hold-up volume losses), 10 mM histidine, 300 mM sorbitol, 1 mg/mL methionine, 0.04 % PS20, 
and 2000 U/mL of rHuPH20 at pH 5.6. It will be manufactured and provided under the 
responsibility of the sponsor.
14.2.
Packaging
Daratumumab SC is supplied in glass vials containing daratumumab at a concentration of 
120 mg/mL and rHuPH20 at a concentration of 2000 U/mL (~20 µg/mL). It will be supplied to the 
site/pharmacy as open-label supply.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each 
vial will contain a study-specific label with a unique identification number.
14.4.
Preparation, Handling, and Storage
Daratumumab SC product must be stored in the original carton in a refrigerator at controlled 
temperatures ranging from 2°C to 8°C until it is removed for dose preparation. Study drug must 
not be utilized after the expiry date printed on the label. Daratumumab SC product must be 
protected from light and must not be frozen. Daratumumab SC does not contain preservatives; 
therefore, any unused portion remaining in the vial must be discarded.
Refer to the IPPI for additional guidance on daratumumab SC preparation, handling, and storage.
14.5.
Bortezomib, Cyclophosphamide, and Dexamethasone
Bortezomib may be provided in 3.5 mg single-use vials as a lyophilized powder or as prescribed by 
the investigator. Cyclophosphamide may be provided in 50 mg oral tablets or as prescribed by the 
treating physician. Dexamethasone may be provided in 4 mg oral tablets or as prescribed by the 
treating physician. Bortezomib, cyclophosphamide, and dexamethasone labels will contain 
information to meet the applicable regulatory requirements. 
Bortezomib must be prepared in an aseptic manner according to local standards. Refer to the 
bortezomib, cyclophosphamide, and dexamethasone local prescribing information or the SIPPM 
for further instructions on preparation, handling, and storage.
14.6.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
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according to the sponsor’s instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug, or used returned study drug for destruction, will be documented on the drug return form. 
When the study site is an authorized destruction unit and study drug supplies are destroyed 
on-site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes.
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Study Protocol and Amendments

IB for daratumumab and rHuPH20 

Site Investigation Product Procedures Manual (SIPPM)

Investigational Product Preparation Instructions (IPPI)

Laboratory Manual

IWRS Manual

eCRF Completion Guidelines

Sample Informed Consent Form

PRO Questionnaires and PRO Completion Guidelines

Subject diaries, as needed

Subject wallet card indicating blood type and IAT

Other manuals and guidance documents, as needed
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16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
The primary safety profile of daratumumab is consistent with IRRs. Based on the mechanism of 
action of daratumumab, a potential risk could be infection; therefore, the protocol requires the 
review of hematological laboratory results prior to daratumumab SC-administration. CD38 is 
distributed in erythrocytes and platelets. A significant reduction of platelets was reported in an 
animal study. In a human clinical study of subjects with relapsed or refractory multiple myeloma 
(Study GEN501), thrombocytopenia was also reported. However, safety laboratory monitoring 
did not show a clinically meaningful reduction of platelets, and no bleeding events were 
observed. Safety data from a Phase 3 clinical study (MMY3004) in subjects with relapsed or 
refractory multiple myeloma comparing DVd versus Vd, showed daratumumab may increase 
thrombocytopenia associated with bortezomib-based regimens. However, bleeding events were 
low and the majority of events were minor (<1% of subjects experienced Grade 3 or 4 bleeding 
events). Anemia was also reported in Study GEN501. Free hemoglobin was mildly elevated, but 
other parameters did not support hemolysis. Anemia, all grades and Grade 3 or 4 in the 
MMY3004 study, were similar among the 2 treatment groups. Routine safety laboratory 
measurement of hemoglobin and platelets will be closely monitored in this study.
In the current study with SC-administration, a lower risk of IRRs is expected due to a more 
gradual absorption of daratumumab and encouraging data presented by Usmani and colleagues 
from study MMY1004 (Usmani 2016).46 However, IRRs may still occur and may develop at a 
later time point than previously observed with IV administration (where most IRRs occur within 
24 hours after administration). Therefore, as an extra safety precaution for the safety run-in, a 
staggered enrollment approach will be applied. Furthermore, inpatient observation for at least 
24 hours after the first dose will be implemented for the safety run-in phase. Inpatient 
observation after SC delivery during the randomization phase may be implemented based on 
safety observations collected during the safety run-in. Apart from IRRs, a similar toxicity profile 
is anticipated with SC versus IV administration for anemia, thrombocytopenia, and other 
toxicities based on projected exposures being lower at equivalent doses of SC versus IV 
daratumumab. In this study, local tolerability at the SC-administration site will be closely 
monitored as well.
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential AEs of the study, and provide their consent voluntarily will be enrolled.
The blood volume to be collected for the study is estimated at approximately 25 mL at Screening, 
280 mL during Cycle 1 through Cycle 6, approximately 20 mL every 8 weeks during monotherapy 
treatment (Cycle 7+) and observation phase with an additional 10 mL at Cycle 7 Day 1 and 
Cycle 12 Day 1 and approximately 15 mL at End-of-Treatment visit. The volume of blood to be 
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drawn is considered to be acceptable for subjects participating in a cancer clinical study and also 
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 subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

IB (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator’s curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study, the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:
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
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study treatment 

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent
Each subject (or legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved 
by both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read 
and understand. The informed consent should be in accordance with principles that originated in 
the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
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and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her disease. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that their records 
may be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject (or legally acceptable representative) is authorizing such access, 
which includes permission to obtain information about his or her survival status. It also denotes 
that the subject agrees to allow his or her study physician to recontact the subject for the purpose 
of obtaining consent for additional safety evaluations, and subsequent disease-related treatments, 
if needed.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative’s personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for 
study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
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will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, pharmacodynamics, biomarker, PK, and immunogenicity research is not 
conducted under standards appropriate for the return of data to subjects. In addition, the sponsor 
cannot make decisions as to the significance of any findings resulting from exploratory research. 
Therefore, exploratory research data will not be returned to subjects or investigators, unless 
required by law or local regulations. Privacy and confidentiality of data generated in the future 
on stored samples will be protected by the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years from last patient out (or 
according to local regulations) for additional research. Samples will only be used to understand 
daratumumab, to understand amyloidosis, to understand differential drug responders, and to 
develop tests/assays related to daratumumab and amyloidosis. The research may begin at any 
time during the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.2).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16.1, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate 
document. Except in emergency situations, this contact should be made before implementing any 
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departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form Food and Drug Administration 
[FDA] 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)
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
Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth (as allowed by local regulations). In cases where the subject is not randomized 
into the study, the date seen and date of birth (as allowed by local regulations) will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs and follow-up of AEs; concomitant medication; drug 
receipt/dispensing/return records; study treatment administration information; and date of study 
completion and reason for early discontinuation of study treatment or withdrawal from the study, 
if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
Subject- and investigator-completed scales and assessments designated by the sponsor (EORTC 
QLQ-C30, EQ-5D-5L, SF-36v2 Health Survey) will be recorded directly into an electronic 
device or other tool and will be considered source data.
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site
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
Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
study-specific data fields as determined by the protocol. This data is electronically extracted for 
use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol include 
the eSource system but information collected through eSource 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
Electronic data capture (eDC) will be used for this study. Electronic case report forms are 
provided for each subject in electronic format. Study-site personnel must log in eDC via a secure 
manner - personal password. The individual password must keep confidential for personal use.
The study data will be transcribed by study-site personnel from the source documents onto an 
eCRF according to eCRF completion guideline provided by the sponsor. Data must be entered 
into the eCRFs in English. Study-site personnel must complete the eCRF as soon as possible 
after a subject visit. The eCRFs should be available for review at the next scheduled monitoring 
visit. Worksheets may be used for the capture of some data to facilitate completion of the eCRF. 
Any such worksheets will become part of the subject's source documentation.
All subjective measurements (eg, pain scale information or other questionnaires) shall be 
completed by the same individual who made the initial baseline determinations whenever 
possible. The investigator must verify that all data entries in the eCRFs are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool. The 
investigator or study-site personnel must address the queries and update the eCRF if applicable.
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different ways:

Study-site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Study-site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
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17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRF for accuracy and completeness during 
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
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17.8.
Monitoring
The sponsor will perform remote monitoring during the safety run-in and randomization phases, 
and on-site monitoring visits as frequently as necessary. The monitor will record dates of the 
visits in a study site visit log that will be kept at the study site. The first post-initiation visit will 
be made as soon as possible after enrollment has begun. At these visits, the monitor will compare 
the data entered into the eCRF with the source documents (eg, hospital/clinic/physician’s office 
medical records). The nature and location of all source documents will be identified to ensure 
that all sources of original data required to complete the eCRF are known to the sponsor and 
study-site personnel and are accessible for verification by the sponsor study-site contact. If 
electronic records are maintained at the study site, the method of verification must be discussed 
with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documents will be accessible, and a suitable environment will be provided 
for review of study-related documents. The monitor will meet with the investigator on a regular 
basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The end of the study is defined to be 5 years after the last subject is randomized. The final data 
from the study sites will be sent to the sponsor (or designee) after completion of the final subject 
visit at that study site, in the time frame specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
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17.10. On-Site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding daratumumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomics or exploratory biomarker 
research data, generated as a result of this study, are considered confidential and remain the sole 
property of the sponsor. The investigator agrees to maintain this information in confidence and 
use this information only to accomplish this study, and will not use it for other purposes without 
the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of daratumumab, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a clinical study report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomics or 
exploratory biomarker analyses performed after the clinical study report has been issued will be 
reported in a separate report and will not require a revision of the clinical study report. Study 
subject identifiers will not be used in publication of results. Any work created in connection with 
performance of the study and contained in the data that can benefit from copyright protection 
(except any publication by the investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary 
(multicenter) data and information without approval from the investigator. The investigator has 
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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 18 months after study end 
date, or the sponsor confirms there will be no multicenter study publication. Authorship of 
publications resulting from this study will be based on the guidelines on authorship, such as 
those described in the ICMJE Recommendations for the Conduct, Reporting, Editing and 
Publication of Scholarly Work in Medical Journals, which state that the named authors must 
have made a significant contribution to the conception or design of the work; or the acquisition, 
analysis, or interpretation of the data for the work, and drafted the work or revised it critically for 
important intellectual content; and given final approval of the version to be published; and 
agreed to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.
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malignant M-protein from therapeutic antibody. J Clin Oncol. 2015;(Suppl; Abstr 8590).
30.
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(CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 
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31.
Muchtar E, Dispenzieri A, Leung N, et al. Optimizing deep response assessment for AL amyloidosis using 
involved free light chain level at end of therapy: failure of the serum free light chain ratio. Leukemia. 
2019;33(2):527-531.
32.
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Group. Am J Clin Oncol. 1982;5(6):649-655. 
33.
Overdijk MB, Jansen JH, Nederend M, et al. The therapeutic CD38 monoclonal antibody daratumumab 
induces programmed cell death via Fcγ receptor-mediated cross-linking. J Immunol. 2016;197(3):807-813.
34.
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35.
Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal 
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Palladini G, Merlini G. What is new in diagnosis and management of light chain amyloidosis? Blood. 
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37.
Palladini G, Russo P, Milani P, et al. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone 
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38.
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43.
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44.
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47.
Venner CP, Lane T, Foard D, et al. Cyclophosphamide, bortezomib, and dexamethasone therapy in AL 
amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood. 
2012;119(19):4387-4390.
48.
Wechalekar A, Gillmore JD, Foard D, et al. Evaluation of an early switch to second line chemotherapy in AL 
amyloidosis among patients who fail to achieve a very good partial response to frontline treatment. 13th
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49.
Wechalekar AD, Hawkins PN, Gillmore JD. Perspectives in treatment of AL amyloidosis. Br J Haematol. 
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50.
Weiss BM, Waxman A, Cohen AD, et al. Clinical experience with daratumumab in AL amyloidosis and 
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51.
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Wisløff F, Eika S, Hippe E, et al. Measurement of health-related quality of life in multiple myeloma. Br J 
Hematol. 1996;92(3):604-613.
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ATTACHMENT 1:
ECOG PERFORMANCE STATUS SCALE
Grade ECOG Performance Status 
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
Reference: Oken et al 1982
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ATTACHMENT 2:
DEFINITION OF ORGAN INVOLVEMENT BASED ON 
AMYLOIDOSIS CONSENSUS CRITERIA
Heart
Echo: mean wall thickness >12mm, no other cardiac cause or an 
elevated NT-ProBNP (>332 ng/L) in the absence of renal failure or 
atrial fibrillation
Kidney
24-hour urine protein>0.5 g/day, predominantly albumin
Liver
Total liver span >15 cm in the absence of heart failure or alkaline 
phosphatase >1.5 times institutional upper limit of normal
Nerve
Peripheral: clinical, symmetric lower extremity sensorimotor 
peripheral neuropathy
Autonomic: gastric-emptying disorder, pseudo-obstruction, voiding 
dysfunction not related to direct organ infiltration
Gastrointestinal Tract
Direct biopsy verification with symptoms
Lung
Direct biopsy verification with symptoms
Interstitial radiographic pattern
Soft Tissue
Tongue enlargement, clinical
Arthropathy
Claudication, presumed vascular amyloid
Skin
Myopathy by biopsy or pseudohypertrophy
Lymph node (may be localized)
Carpal tunnel syndrome
(adapted from NCCN Guidelines Version 1.2016)
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ATTACHMENT 3:
NYHA CLASSIFICATION 
Class
Functional Capacity by Class
Objective Assessment*
I
No limitation in physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
No evidence of cardiovascular 
disease.
II
Slight limitation of physical activity. Patient is comfortable
at rest. Ordinary physical activity results in fatigue,
palpitation, dyspnea, or anginal pain.
Objective evidence of minimal
cardiovascular disease.
IIIA
Comfortable at rest. Less than ordinary physical 
activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
Objective evidence of moderately 
severe cardiovascular disease.
IIIB
Comfortable at rest. Shortness of breath with 
performance of activities of daily living 
(dressing, toileting, showering etc).
Objective evidence of severe
cardiovascular disease.
IV
Shortness of breath at rest. Unable to carry on any 
physical activity without discomfort. Signs /Symptoms of
heart failure or anginal syndrome may be present at 
rest. If any physical activity is undertaken, discomfort is 
increased.
Objective evidence of very severe
cardiovascular disease.
* Measures such as EKG, stress test, x-ray, echocardiogram, or radiologic images.
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ATTACHMENT 4:
CONVERSION TABLE FOR GLUCOCORTICOID DOSE
CONVERSION TABLE FOR GLUCOCORTICOSTEROID DOSE FOR METHYLPREDNISOLONE OR 
EQUIVALENT
Generic Name
Oral or Intravenous Dose 
(mg)
Half-life (Biologic) hours
Short-Acting
Hydrocortisone
100
8-12
Intermediate-Acting
Methylprednisolone
20
18-36
Prednisolone
25
18-36
Prednisone
25
18-36
Long-Acting
Dexamethasone
3.75
36-54
Betamethasone 
3
36-54
CONVERSION TABLE FOR GLUCOCORTICOSTEROID DOSE FOR DEXAMETHASONE OR 
EQUIVALENT
Generic Name
Oral or 
Intravenous Dose 
(mg)
Oral or Intravenous 
Dose (mg)
Half-life (Biologic) hours
Long-Acting
Dexamethasone
20
40
36-54
Betamethasone 
16
32
36-54
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ATTACHMENT 5:
CALCULATED CREATININE CLEARANCE AND ESTIMATED 
GLOMERULAR FILTRATION RATE
Cockcroft-Gault formula:
To calculate the subject’s creatinine clearance (CrCl), use the following Cockcroft-Gault 
formula:
CrCl =
(140 - age [in years]) x weight (kg)
(x 0.85 for females)
(72 x serum creatinine [mg/dL])
If the serum creatinine is obtained using the International System of Units (SI) (ie, micromol/L), 
use the following formula to convert SI units to conventional (mg/dL) units (Manual of 
Laboratory & Diagnostic Tests, 2004):
•
serum creatinine (micromol/L) divided by 88.4 = serum creatinine (mg/dL).
Chronic Kidney Disease Epidemiology Collaboration 
Glomerular filtration rate will be calculated according to the CKD-EPI (Levey et al 2009).
For online calculators, please go to https://www.kidney.org/professionals/KDOQI/gfr_calculator .
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ATTACHMENT 6:
GUIDELINE FOR ASTHMA ELIGIBILITY CRITERIA
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ATTACHMENT 7:
BODY SURFACE AREA NOMOGRAM
Body surface area should be calculated using the standard calculation given below. However, the DuBois 
Formula can be used as an alternative to calculate BSA. If a site uses another formula other than the 
standard calculation given below or the DuBois Formula, they must receive approval from the Sponsor to 
use another BSA formula.
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ATTACHMENT 8:
EORTC QLQ-C30
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ATTACHMENT 9: SUPPLEMENTAL ITEMS TO EORTC QLQ-C30 (FROM EORTC 
ITEM BANK)
During the past week:
Module,
Item # 
Not at 
all
A
Little
Quite 
a Bit
Very 
Much
PR25,
Item #46
Have you had swelling in your legs or ankles?
1
2
3
4
OV28,
Item #32
Did you have a bloated feeling in your 
abdomen/stomach?
1
2
3
4
MY-20,
Item #43
Did you have tingling hands or feet?
1
2
3
4
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ATTACHMENT 10: EQ-5D-5L
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ATTACHMENT 11: SF-36V2
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ATTACHMENT 12: ANTICIPATED EVENTS
Anticipated Event
An anticipated event is an AE (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:

Hyperuricemia

Hypercalcemia

Bone diseases

Infection

Bleeding

Hyperviscosity syndrome

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. Any anticipated event that 
meets serious criteria will be reported to the sponsor as described in Section 12.3.2.
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 (SAC)
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 intervention based on a review of the aggregate data 
by arm.
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Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and
threshold to trigger an aggregate analysis of anticipated events will be provided in a separate 
Anticipated Events Safety Monitoring Plan (ASMP).
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ATTACHMENT 13: PROTOCOL 54767414AMY3001 STUDY RISK/BENEFIT 
ASSESSMENT
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ATTACHMENT 14: MAYO CLINICAL CARDIAC STAGING SYSTEM
AMY3001 Clinical Cardiac Stage will be based on 2 biomarker Risk Factors; NT-proBNP and 
high sensitivity cardiac troponin T (hs-cTnT). Central lab NT-proBNP and hs-cTnT should be 
used to determine Clinical Cardiac Stage.
Risk Factors:
•
NT-proBNP: >332 ng/L
•
hs-cTnT: >54 ng/L
Stage definition:
•
Stage 1: no risk factors (Both NT-proBNP and hs-cTnT do not meet above risk factors)
•
Stage 2: one risk factor (NT-proBNP OR hs-cTnT meet above risk factors)
•
Stage 3: 2 risk factors (Both NT-proBNP and hs-cTnT meet above risk factors)
References: Dispenzieri 2014; Palladini 2016
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ATTACHMENT 15: LIST OF CYP3A INDUCERS AND INHIBITORS
CYP3A Inducers
Strong Inducers
≥80% decrease in AUC
Moderate Inducers
50-80% decrease in AUC
Weak Inducers
20-50% decrease in AUC
Avasimibe, carbamazepine, 
phenytoin, rifampin, St. John’s wort
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin 
Amprenavir, aprepitant, armodafinil, 
clobazam, echinacea, pioglitazone, 
prednisone, rufinamide, vemurafenib
Source: Department of Health and Human Services (DHHS) 2012
CYP3A Inhibitors
Strong Inhibitors
≥5-fold increase in AUC or >80% 
decrease in CL
Moderate Inhibitors
≥2 but <5-fold increase in AUC or 
50-80% decrease in CL
Weak Inhibitors
≥1.25 but <2-fold increase in AUC 
or 20-50% decrease in CL
Boceprevir, clarithromycin, 
conivaptan, grapefruit juice, 
indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, 
voriconazole
Amprenavir, aprepitant, atazanavir; 
ciprofloxacin, crizotinib, 
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit juice, 
imatinib, verapamil
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, cimetidine, 
cyclosporine, fluoxetine, 
fluvoxamine, ginkgo, goldenseal, 
isoniazid, lapatinib, nilotinib, oral 
contraceptives, pazopanib, 
ranitidine, ranolazine, 
tipranavir/ritonavir, ticagrelor, 
zileuton
Source: Department of Health and Human Services (DHHS) 2012
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INVESTIGATOR AGREEMENT
PPD
PPD
NCT03201965

SAP_001.pdf: 
1
Approved, Date: 4 May 2020
Janssen Research & Development *
Statistical Analysis Plan
A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in 
Combination with Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) 
Compared With CyBorD Alone in Newly Diagnosed Systemic AL Amyloidosis
Protocol 54767414AMY3001; Phase 3
Amendment 2
JNJ-54767414  (daratumumab)
Status:
Approved
Date:
4 May 2020
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-168413547
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 5
LIST OF IN-TEXT FIGURES ........................................................................................................................ 5
ABBREVIATIONS ........................................................................................................................................ 6
AMENDMENT HISTORY.............................................................................................................................. 8
1.
INTRODUCTION................................................................................................................................ 10
1.1.
Trial Objectives .............................................................................................................................. 10
1.2.
Trial Design .................................................................................................................................... 10
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 13
1.4.
Sample Size Justification ............................................................................................................... 14
1.5.
Randomization and Blinding .......................................................................................................... 14
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 14
2.1.
Study Part ...................................................................................................................................... 14
2.2.
Visit Windows................................................................................................................................. 15
2.3.
Pooling Algorithm for Analysis Centers.......................................................................................... 15
2.4.
Study Treatment and Study Drug .................................................................................................. 15
2.5.
Study Treatment Dosing Date........................................................................................................ 15
2.6.
Treatment Cycle............................................................................................................................. 15
2.7.
Baseline Measurement .................................................................................................................. 15
2.8.
Unique Lab Value........................................................................................................................... 16
2.9.
Imputation of Partial Dates............................................................................................................. 16
2.9.1.
Missing/Partial Adverse Event Onset Date................................................................................. 16
2.9.2.
Missing/Partial Adverse Event End Date.................................................................................... 17
2.9.3.
Partial Concomitant Medication Start/End Date ......................................................................... 17
2.9.4.
Partial AL Amyloidosis Diagnosis Date ...................................................................................... 18
2.9.5.
Partial Subsequent Anti-AL Amyloidosis Therapy Start Date..................................................... 18
2.10.
General Analysis Method............................................................................................................... 18
2.11.
Analysis Sets.................................................................................................................................. 18
2.11.1.
Efficacy Analysis Set(s) .............................................................................................................. 18
2.11.1.1.
Primary Efficacy Analysis Set.................................................................................................. 18
2.11.1.2.
Secondary Efficacy Analysis Set............................................................................................. 19
2.11.1.3.
Safety Analysis Set.................................................................................................................. 19
2.11.1.4.
Pharmacokinetics Analysis Set ............................................................................................... 19
2.11.1.5.
Immune Response-evaluable Analysis Set............................................................................. 19
2.12.
Definition of Subgroups.................................................................................................................. 20
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 20
4.
SUBJECT INFORMATION................................................................................................................ 21
4.1.
Demographics and Baseline Characteristics ................................................................................. 21
4.2.
Disposition Information................................................................................................................... 22
4.3.
Extent of Exposure......................................................................................................................... 22
4.4.
Protocol Deviations ........................................................................................................................ 23
4.5.
Concomitant Medications............................................................................................................... 23
4.6.
Subsequent Non-cross Resistant Anti-plasma Cell Therapy for AL Amyloidosis.......................... 24
5.
EFFICACY ......................................................................................................................................... 24
5.1.
Analysis Specifications................................................................................................................... 25
5.1.1.
Level of Significance................................................................................................................... 25
5.1.2.
Independent Review Committee ................................................................................................ 26
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5.1.3.
Data Handling Rules................................................................................................................... 26
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 26
5.2.1.
Definition..................................................................................................................................... 26
5.2.2.
Estimand..................................................................................................................................... 26
5.2.3.
Analysis Methods........................................................................................................................ 27
5.3.
Major Secondary Endpoints........................................................................................................... 28
5.3.1.
Major Organ Deterioration Progression-Free Survival (MOD-PFS) ........................................... 28
5.3.1.1.
Definition.................................................................................................................................. 28
5.3.1.2.
Estimand.................................................................................................................................. 29
5.3.1.3.
Analysis Methods .................................................................................................................... 29
5.3.1.3.1.
Censoring Rules for MOD-PFS............................................................................................ 30
5.3.1.3.2.
Inverse Probability of Censoring Weighted (IPCW) Analysis .............................................. 30
5.3.1.4.
Sensitivity Analysis of MOD-PFS ............................................................................................ 33
5.3.1.5.
Supplementary Analysis of MOD-PFS .................................................................................... 33
5.3.1.5.1.
Ignore Subsequent Non-Cross Resistant Anti-Plasma Cell Therapy .................................. 33
5.3.1.5.2.
MOD-Event Free Survival (MOD-EFS) ................................................................................ 34
5.3.1.5.3.
Subsequent Non-Cross Resistant Anti-Plasma Cell Therapy as a Time Dependent 
Covariate.............................................................................................................................. 34
5.3.1.5.4.
Censored for Death/PD after Missing More Than One Disease Evaluation........................ 35
5.3.1.5.5.
Exclude Hematologic Progression From MOD-PFS Definition............................................ 35
5.3.2.
Overall Survival (OS).................................................................................................................. 35
5.3.2.1.
Definition.................................................................................................................................. 35
5.3.2.2.
Analysis Methods .................................................................................................................... 35
5.3.3.
Complete Hematologic Response Rate at 6 Months ................................................................. 36
5.3.3.1.
Definition.................................................................................................................................. 36
5.3.3.2.
Analysis Methods .................................................................................................................... 36
5.3.4.
Hematologic VGPR or better Rate ............................................................................................. 36
5.3.4.1.
Definition.................................................................................................................................. 36
5.3.4.2.
Analysis Methods .................................................................................................................... 37
5.3.5.
Time to Hematologic Response ................................................................................................. 37
5.3.5.1.
Definition.................................................................................................................................. 37
5.3.5.2.
Analysis Methods .................................................................................................................... 37
5.3.6.
Duration of Hematologic Response............................................................................................ 37
5.3.6.1.
Definition.................................................................................................................................. 37
5.3.6.2.
Analysis Methods .................................................................................................................... 38
5.4.
Other Efficacy Endpoints................................................................................................................ 38
5.4.1.
Hematologic PFS (HemPFS)...................................................................................................... 38
5.4.1.1.
Definition.................................................................................................................................. 38
5.4.1.2.
Analysis Methods .................................................................................................................... 39
5.4.2.
Time to Subsequent Non-cross Resistant Anti-plasma Cell Therapy ........................................ 39
5.4.2.1.
Definition.................................................................................................................................. 39
5.4.2.2.
Analysis Methods .................................................................................................................... 39
5.4.3.
Time to iFLC<ULN, iFLC≤20 mg/L and Time to dFLC<10 mg/L Response.............................. 40
5.4.3.1.
Definition.................................................................................................................................. 40
5.4.3.2.
Analysis Method ...................................................................................................................... 40
5.4.4.
Organ Response......................................................................................................................... 40
5.4.4.1.
Cardiac/Renal/Liver Response Rate at 6 Months ................................................................... 40
5.4.4.1.1.
Definition .............................................................................................................................. 40
5.4.4.1.2.
Analysis Methods ................................................................................................................. 40
5.4.4.2.
Time to Cardiac/Renal/Liver Response................................................................................... 41
5.4.4.2.1.
Definition .............................................................................................................................. 41
5.4.4.2.2.
Analysis Methods ................................................................................................................. 41
5.4.5.
Organ Progression...................................................................................................................... 41
5.4.5.1.
Cardiac/Renal/Liver Progression Rate at 6 Months ................................................................ 41
5.4.5.1.1.
Definition .............................................................................................................................. 41
5.4.5.1.2.
Analysis Methods ................................................................................................................. 41
5.4.6.
Time to Cardiac/Renal/Liver Progression................................................................................... 42
5.4.6.1.
Definition.................................................................................................................................. 42
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5.4.6.2.
Analysis Methods .................................................................................................................... 42
5.4.6.3.
Analysis Methods .................................................................................................................... 42
5.5.
Patient-Reported-Outcome (PRO)................................................................................................. 42
5.5.1.
Definition..................................................................................................................................... 43
5.5.2.
Analysis Methods........................................................................................................................ 43
5.6.
Subgroup Analysis of Efficacy Endpoints ...................................................................................... 45
6.
SAFETY............................................................................................................................................. 45
6.1.
Adverse Events .............................................................................................................................. 45
6.1.1.
Overview of TEAEs..................................................................................................................... 46
6.1.2.
All TEAEs.................................................................................................................................... 46
6.1.3.
Toxicity Grade 3 or 4 TEAEs ...................................................................................................... 46
6.1.4.
Study Treatment-Related TEAEs ............................................................................................... 46
6.1.5.
Serious Adverse Events (SAEs)................................................................................................. 46
6.1.6.
TEAEs Leading to Cycle Delays or Dose Modifications............................................................. 46
6.1.7.
TEAEs Leading to Discontinuation of Any Study Treatment...................................................... 47
6.1.8.
TEAEs Leading to Discontinuation of Study Treatment ............................................................. 47
6.2.
Deaths............................................................................................................................................ 47
6.2.1.
All Deaths ................................................................................................................................... 47
6.2.2.
Death Due to TEAEs .................................................................................................................. 47
6.3.
Adverse Events of Clinical Interest ................................................................................................ 47
6.3.1.
Infusion-Related Reactions (IRR)............................................................................................... 47
6.3.2.
Local Injection Site Reactions (LISR) ......................................................................................... 48
6.3.3.
Infections and Infestations.......................................................................................................... 48
6.3.4.
Herpes Zoster Reactivation ........................................................................................................ 48
6.3.5.
Hepatitis B Virus Reactivation .................................................................................................... 48
6.3.6.
Peripheral Neuropathies............................................................................................................. 48
6.3.7.
Cardiac Disorders ....................................................................................................................... 49
6.3.8.
Renal and Urinary Disorders ...................................................................................................... 49
6.3.9.
Hepatobiliary Disorders .............................................................................................................. 49
6.3.10.
Hemorrhage Events.................................................................................................................... 49
6.3.11.
Second Primary Malignancies .................................................................................................... 49
6.4.
Adverse Events by Subgroups....................................................................................................... 49
6.5.
Clinical Laboratory Tests................................................................................................................ 50
6.6.
Vital Signs and Physical Examination Findings ............................................................................. 50
6.7.
Transthoracic Echocardiogram (TTE) or Other Assessment of Cardiac Function ........................ 50
6.8.
Electrocardiogram.......................................................................................................................... 50
6.9.
Other Safety Parameters ............................................................................................................... 51
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 51
7.1.
Pharmacokinetics........................................................................................................................... 51
7.1.1.
Sampling Timepoints .................................................................................................................. 51
7.1.2.
Pharmacokinetic Parameters ..................................................................................................... 51
7.1.3.
Analysis Methods........................................................................................................................ 51
7.2.
Immunogenicity.............................................................................................................................. 52
7.2.1.
Sampling Timepoints .................................................................................................................. 52
7.2.2.
Analysis Methods........................................................................................................................ 52
7.3.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 52
8.
BIOMARKER..................................................................................................................................... 52
9.
PHARMACOGENOMIC ANALYSES................................................................................................ 53
10.
MEDICAL RESOURCE UTILIZATION.............................................................................................. 53
REFERENCES............................................................................................................................................ 54
ATTACHMENT 1:
HEMATOLOGIC PD AND RESPONSE ALGORITHM............................................. 55
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ATTACHMENT 2:
GUIDELINES FOR SUBSEQUENT THERAPY........................................................ 62
ATTACHMENT 3:
COUNTRIES THAT TYPICALLY OFFER STEM CELL TRANSPLANT: 
LIST A OR LIST B............................................................................................................................. 63
ATTACHMENT 4:
INDEPENDENT REVIEW COMMITTEE................................................................... 64
ATTACHMENT 5:
ADDITIONAL EXPLORATORY ANALYSIS TO SUPPORT HEMAR...................... 65
LIST OF IN-TEXT TABLES
Table 1:
Subgroup Analyses of Efficacy and Safety Endpoints.............................................................. 20
Table 2:
MOD-PFS Event and Censoring Method.................................................................................. 30
Table 3:
Hematologic PFS Event and Censoring Method...................................................................... 38
Table 4:
Time to Cardiac/Renal/Liver Progression Event and Censoring Method................................. 42
LIST OF IN-TEXT FIGURES
Figure 1:
Schematic Overview of the Safety Run-In................................................................................ 11
Figure 2:
Schematic Overview of the Randomized Study ....................................................................... 12
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ABBREVIATIONS
AE
Adverse event
AL amyloidosis
Light chain amyloidosis
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
CHR
Complete hematologic response
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMH
Cochran-Mantel-Haenszel
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
CPR
Cardiac progression rate
CR
Complete response
CRF
Case report form
CRR
Cardiac response rate
CTCAE 
Common Terminology Criteria for Adverse Events
CSR
Clinical Study Report
CyBorD
Cyclophosphamide, bortezomib and dexamethasone
dFLC
Difference between involved and uninvolved free light chains
DPS
Data presentation specification
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eGFR
Estimated glomerular filtration rate
EORTC QLQ
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire
EQ-5D-5L
European Quality of Life Five Dimensions Questionnaire
FEV1
Forced Expiratory Volume in 1 second
FLC
Free light chain
HemPFS 
Hematologic progression-free survival 
HBV
Hepatitis B virus
IA
Interim analysis
IDMC 
Independent Data Monitoring Committee
iFLC
Involved free light chain
IRC
Independent review committee
ITT
Intent-to-treat
IWRS
Interactive web response system
LDH
Lactate dehydrogenase
LLOQ
Lower limits of quantification 
LPR
Liver progression rate
LRR
Liver response rate
MedDRA
Medical Dictionary for Regulatory Activities
M-protein
Monoclonal protein, monoclonal paraprotein
MOD
Major organ deterioration
MOD-PFS
Major organ deterioration-progression-free survival
MRD
Minimal residual disease
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse
NR
No response
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
ORR
Overall response rate
OrRR
Organ response rate
OS
Overall survival
PD
Progressive disease
PFS 
Progression-free survival
PR
Partial response
PRO
Patient-reported outcome
rHuPH20
Recombinant hyaluronidase PH20
RPR
Renal progression rate
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RRR
Renal response rate
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation 
SF-36v2
36-Item Short Form Survey version 2
SOC
System organ class
SPEP
Serum protein electrophoresis
TEAEs
Treatment-emergent adverse events
TTOCP
Time to cardiac progression
TTOLP
Time to liver progression
TTORP
Time to renal progression
TNT
Time to next treatment
ULN
Upper limit of normal
UPEP
Urine protein electrophoresis
VGPR
Very good partial response
WBC
White blood cells
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AMENDMENT HISTORY
SAP version 
Issue Date
Original SAP 
06Aug2018
Amendment 1
16Sep2019
Amendment 2
27Mar2020
This full study statistical analysis plan (SAP) has been revised. The rational for the amendment
and description of the changes are provided below.
Amendment -2 
Rational for the amendment
Based on FDA comments that dyspnea at rest for at least 3 consecutive days as a clinical manifestation 
of cardiac failure has subjective nature, it was requested to exclude from MOD-PFS definition. In 
addition, FDA has concern about patients who received subsequent treatment in the absence of 
hematologic progression or major organ deterioration
Summary of Changes:
Dyspnea at rest for at least 3 consecutive days as a clinical manifestation of cardiac failure was 
excluded from MOD-PFS primary analysis
The primary analysis of MOD-PFS will employ inverse probability of censoring weights 
(IPCW) method to adjust estimates of a treatment effect in the presence of subsequent non-
cross resistant anti-plasma cell therapy.
Added sensitivity analysis and supplementary analysis for MOD-PFS 
Added time to iFLC≤ 20 mg/L response
Minor edit changes for clarifications
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Amendment -1 (16Sep2019)
Rationale for the amendment
The primary endpoint, complete hematological response (CHR) rate and key secondary endpoints of 
major organ deterioration free survival (MOD-PFS) and overall survival (OS) remain the same. In the 
original plan, a progression-free survival (PFS) endpoint (defined as hematologic progression, or cardiac, 
kidney or liver progression, or death, whichever comes first) was planned.  Considering that there is no 
literature currently available to assess for clinical meaningfulness of aggregate PFS as an endpoint in AL 
amyloidosis treatment, separate analyses will be conducted for hematological PFS and organ-based 
progression.  In the revised plan, the PFS analysis will be specific to hematologic PFS (defined as 
hematologic progression, or death, whichever comes first). Additional landmark analysis on organ 
response and progression has been added for appropriate interpretation of results and meaningful 
comparison to existing literature. In addition, supportive analysis has been added as appropriate (e.g., 
analysis on iFLC and dFLC, time to PR or better and additional subgroups). Further editorial changes 
were made throughout the document for clarification.
Summary of changes: 
PFS analysis will be specific to hematologic PFS and moved to exploratory endpoint. PFS 
endpoint was removed from statistical hierarchical testing
Added organ response and progression 6-month landmark analysis for each involved organ
Added t(11:14) and high risk of cytogenetic subgroup
Added time to and duration of PR or better response
Added Time to iFLC<ULN and Time to dFLC<10 mg/dL response
Replaced time to organ progression with time to cardiac progression, time to renal progression 
and time to liver progression
Added attachments of hematologic PD and response computerized algorithm and additional 
exploratory analysis to support HEMAR.
Minor edit changes for clarifications
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for the planned analyses for study JNJ-54767414AMY3001.
1.1.
Trial Objectives
Primary Objective
The primary objective is to evaluate the efficacy of daratumumab plus CyBorD compared with CyBorD 
alone, in terms of overall complete hematologic response in the treatment of newly diagnosed AL 
amyloidosis patient. 
Secondary Objectives
The secondary objectives are:

To evaluate the clinically observable endpoints for major organ deterioration (MOD-PFS) following 
treatment with daratumumab in combination with CyBorD compared with CyBorD alone

To evaluate the following efficacy measures following treatment with daratumumab in combination 
with CyBorD compared with CyBorD alone:
–
Organ response rate (OrRR)
–
Overall survival (OS)
–
Time to and duration of response

To evaluate fatigue, mental functioning, and health-related quality of life following treatment with 
daratumumab in combination with CyBorD compared with CyBorD alone

To assess the safety and tolerability of daratumumab when administered in combination with CyBorD

To assess the pharmacokinetics of daratumumab and the immunogenicity of daratumumab and 
rHuPh20

To explore minimal residual disease status in AL amyloidosis patients as a surrogate for PFS and OS 
or as a biomarker for relapse
1.2.
Trial Design
This is a randomized, open-label, active-controlled, multicenter Phase 3 study in subjects with 
newly diagnosed amyloid light chain amyloidosis. Approximately 360 subjects will be randomized 
in a 1:1 ratio to receive either CyBorD or CyBorD in combination with daratumumab (Dara 
SC+CyBorD). The randomization will be balanced by using randomly permuted blocks and will 
be stratified by cardiac stage (Stage I, II, and IIIa), countries that typically offer transplant for 
patients with AL amyloidosis (List A or List B), and renal function (CrCl ≥60 mL/min or 
CrCl <60 mL/min). 
Adult subjects age 18 and older with newly diagnosed AL amyloidosis are eligible for the study. 
Diagnosis will be based on histopathological or electron microscopy criteria, one or more organs 
need to be affected, and disease must be measurable (by serum monoclonal protein or free light 
chain criteria). Eligible subjects will have an ECOG performance score of 0, 1, or 2 and adequate 
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organ function as defined in the protocol. Key exclusion criteria include previous or current 
diagnosis of symptomatic multiple myeloma, evidence of significant cardiovascular conditions, 
any form of non-AL amyloidosis, or planned stem cell transplant during first 6 cycles of protocol 
therapy. Subject participation will include a Screening Phase, a Treatment Phase, a Post-Treatment 
Observation Phase, and a Long-term Follow-up Phase.
Given the potential safety concern with regards to the use of IV daratumumab in the AL 
amyloidosis population (ie, volume overload), this study will utilize the daratumumab SC co-
formulation. Although the risk of volume overload is predicted to be lower with SC daratumumab 
than with IV infusion, patients with newly diagnosed AL amyloidosis may still develop adverse 
events attributable to hypervolemia (for example, dyspnea, peripheral edema, etc) secondary to 
amyloid-induced cardiac or renal insufficiency. Additionally, SC daratumumab has not been 
co-administered with CyBorD. Therefore, prior to the start of the randomized portion of the study, 
a safety run-in will be conducted (Figure 1). Dosing of these subjects will be staggered so that no 
subject will receive their first dose sooner than 48 hours after the previously enrolled subject. 
Safety evaluation will be performed by the sponsor (and external academic hematologists) after at 
least 10 subjects have received at least 1 cycle of treatment. If no safety signal is observed, 
particularly in regard to volume overload, the randomized portion of the study will begin.
Figure 1:
Schematic Overview of the Safety Run-In
Subjects in the safety run-in will continue all scheduled assessments and contribute to the overall 
safety evaluation of the daratumumab in combination of CyBorD. However, these subjects will 
not be included in the overall efficacy assessment which will be based on the randomized subject 
population.
For subjects randomized to Dara SC+CyBorD, study drug (daratumumab) at fixed dose 1800 mg 
will be administered subcutaneously on weekly basis for the first 8 weeks (2 cycles), then every 
2 weeks for 4 cycles (Cycles 3-6), and then every 4 weeks until progression of disease or start of 
subsequent therapy, or a maximum of 2 years from the start of the study (Figure 2). For all 
daratumumab administrations, subjects will receive preinfusion medications to prevent
infusion-related reactions. For the background (CyBorD) therapy, both treatment groups will 
receive up to 6 cycles (24 weeks) of CyBorD treatment. 
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Subjects will receive 300 mg/m2 cyclophosphamide (maximum weekly dose 500 mg) as an oral or 
IV weekly dose and 1.3 mg/m2 bortezomib as an SC injection weekly (Days 1, 8, 15, and 22) in 
every 28-day cycle for a maximum of 6 cycles.
Dexamethasone will be administered at a total dose of 40 mg weekly (ie, Days 1, 8, 15, 22). On 
days of daratumumab dosing, subjects in Dara SC+CyBorD will receive 20 mg on the day of 
daratumumab dosing as premedication and 20 mg on the day after daratumumab dosing. On weeks 
that daratumumab is not administered, or for subjects randomized to CyBorD, dexamethasone is 
to be given 40 mg weekly on a single day or divided into 2 days. For subjects who are older than 
70 years, underweight (BMI <18.5), have hypervolemia, poorly controlled diabetes mellitus, or 
prior intolerance/adverse event to steroid therapy, the dexamethasone dose may be administered 
at a dose of 20 mg weekly.
Figure 2:
Schematic Overview of the Randomized Study
Throughout the study, evaluation of disease response and progression will be conducted in 
accordance with the consensus guidelines for the conduct and reporting of clinical trials in 
systemic light-chain amyloidosis (Comenzo 2012)2 and renal response and progression criteria by 
(Palladini 2014)3. In addition, recently published guidelines on response assessment will be taken 
into consideration when determining complete hematologic response (Manwani 2018, 
Muchtar 2019, Sidana 2019).6, 7, 10 A blinded Independent Review Committee (IRC) consisting of 
3 experts in plasma cell disorders will evaluate and adjudicate responses. 
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Disease evaluations will be performed by a central laboratory (unless otherwise specified) 
according to the Time and Events Schedules until disease progression as defined by the MOD-PFS 
endpoint is documented, death, withdrawal of consent for study participation, or the end of study, 
whichever occurs first. Disease evaluations scheduled for study treatment days should be collected 
before study drug is administered. For free light chain assessment, M-protein, and immunofixation 
measurements in serum and 24-hour urine, the investigator will use results provided by the central 
laboratory. Subjects with positive serum IFE and confirmed daratumumab IFE interference, that 
meet all other clinical criteria for complete hematologic response (CHR), will be considered to be 
in a CHR. 
Safety evaluations in this study will include adverse events, laboratory test results, 
electrocardiogram (ECGs), echocardiograms, vital sign measurement, physical examination 
findings and Eastern Cooperative Oncology Group (ECOG) performance status.
The primary endpoint of this study is overall complete hematologic response rate. The major 
secondary endpoints include MOD-PFS and OS. Analysis of the primary endpoint will be 
performed after all subjects have been treated for at least 6 cycles. The post-treatment phase will 
continue until 200 MOD-PFS events have been observed. The end of the study is defined to be 5 
years after the last subject is randomized.
Two interim analyses are planned for this study. The first interim analysis is a pre-specified safety 
analysis and will occur after the first 30 subjects complete at least 1 cycle of treatment. The second 
interim analysis will be conducted for cumulative safety and efficacy and will occur after 
180 subjects have been treated for at least 6 cycles. In addition to the 2 interim analyses, the IDMC 
will also review serious adverse event data at regular intervals during the study (i.e., after first 
interim analysis, and then approximately every 6 months).
1.3.
Statistical Hypotheses for Trial Objectives
The primary efficacy endpoint is the overall complete hematologic response rate (CHR). The null 
hypothesis (H0) is that there is no difference in overall CHR rate between Dara SC+CyBorD and
CyBorD alone in subjects with newly diagnosed AL amyloidosis.
The null hypotheses (H0) of no difference between the two treatment groups (Dara SC+ CyBorD
and CyBorD) are evaluated for the following major secondary endpoints: 
MOD-PFS
OS
These secondary hypotheses are to be tested in a sequential order as specified above. The details 
of the testing procedure are specified in Section 5.1.1.
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1.4.
Sample Size Justification
The sample size for this study is based on the alternative hypothesis of a 15% improvement in 
overall CHR rate. Taking an overall CHR rate estimated to be 25% for the CyBorD arm 
(Palladini 2015),4 adding a 15% improvement translates to an overall CHR rate of 40% for the 
Dara SC+CyBorD arm. Approximately 360 subjects (180 subjects per arm) would provide more 
than 85% power to detect a 15% improvement in overall CHR rate using a likelihood ratio test 
with a 2-sided alpha of 0.05. 
The post-treatment observation phase will continue until 200 MOD-PFS events have been 
observed. Therefore, this study will achieve approximately 80% power to detect a 33% reduction 
in the risk of hematologic progression, major organ deterioration or death (hazard ratio [Dara SC 
+CyBorD vs. CyborD] of 0.67) with a log-rank test (2-sided alpha=0.05).
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Subjects will be randomly assigned to 1 
of 2 treatment groups based on a computer-generated randomization schedule prepared by vendor 
under the supervision of the sponsor. The randomization will be balanced by using randomly 
permuted blocks and will be stratified by cardiac stage (Stage I, II, and IIIa), countries that 
typically offer transplant for patients with AL amyloidosis (List A or List B), and renal function 
(CrCl ≥60 mL/min or CrCl <60 mL/min). Country List A contains the countries that typically offer 
stem cell transplant while country List B contains the countries that do not offer stem cell transplant 
for patients with AL amyloidosis. After 6 cycles of study treatment, some subjects may receive 
stem cell transplant if recommended by the investigator. To minimize the imbalance in 
randomization among these patients, this country list variable is included as one of the stratification 
factors. The interactive web response system (IWRS) will assign a unique treatment code, which 
will dictate the treatment assignment and matching study treatment kit for the subject. The 
requestor must use his or her own user identification and personal identification number when 
contacting the IWRS and will then give the relevant subject details to uniquely identify the subject. 
As this is an open-label study, blinding procedures are not applicable.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Study Part
In general, data collected in the study will be summarized and presented separately for Part 1 
(safety run-in) and Part 2 (randomization). The start date for Part 1 is the date of the first study 
agent administration and the start date for Part 2 is date of randomization. In Part 1, limited analysis 
and summary tables such as subject disposition, demographic and baseline disease characteristics, 
disease response, and AE will be provided. For subjects randomized in Part 2, the data summaries 
and planned analyses are detailed in the rest of Sections of the SAP. Note that the analysis methods 
and definition rules applied in Part 2 analysis will be similarly applied to Part 1 analysis.
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2.2.
Visit Windows
For analyses of data by cycle, if data are collected by date (e.g., AE onset), the corresponding study 
evaluations will be assigned to actual sequential cycles, which are derived from the study treatment 
administration data. The start date of a particular cycle is defined as the date of the first scheduled 
dose of any component of the study treatment, and the end date of a cycle is the start date of the 
next cycle minus 1. For the last cycle, the end date is defined as the end of treatment visit date or 
the minimum of last study treatment date plus 30 days or subsequent anticancer therapy minus 1 
day, if the end of treatment visit date is not available.  
In general, if data (e.g., laboratory and vital sign etc.) are collected by cycle, the nominal cycle 
will be used to summarize data. However, due to possible cycle delays, assessment performed in 
the same cycle may not be well aligned in time scale for different subjects. To address this, 
by-week windowing rules may be applied in the overtime data summary by study week.
2.3.
Pooling Algorithm for Analysis Centers
All participating centers in the study will be pooled together for analyses.
2.4.
Study Treatment and Study Drug  
In this study, study treatment refers to cyclophosphamide, bortezomib, dexamethasone, and 
daratumumab. Study drug refers to daratumumab. 
2.5.
Study Treatment Dosing Date 
Study treatment dosing date is the date on which a subject actually received study treatment (partial 
or complete) and will be recorded in the study treatment administration dataset.
For subjects who receive Dara SC+CyBorD treatment, the first study treatment date is defined as 
the earliest date of non-zero dose of the following administration: bortezomib, cyclophosphamide, 
dexamethasone or daratumumab. The last study treatment date is defined as the latest date of non-
zero dose of the following administration: bortezomib, cyclophosphamide, dexamethasone or
daratumumab.
For subjects who receive CyBorD treatment, the first study treatment date is defined as the earliest 
date of non-zero dose of the following administration: bortezomib, cyclophosphamide, or 
dexamethasone. The last study treatment date is defined as the latest date of non-zero dose of the 
following administration: bortezomib, cyclophosphamide, or dexamethasone.
2.6.
Treatment Cycle 
A subject is considered as treated in a cycle if he/she receives any nonzero dose of bortezomib, 
cyclophosphamide, dexamethasone or daratumumab in that cycle.
2.7.
Baseline Measurement
Baseline measurement is defined as the closest non-missing measurement taken on or prior to the 
first study treatment administration.
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2.8.
Unique Lab Value 
In general, in instances when there are multiple records at a given visit date for lab parameters 
associated with disease assessment, the following rules will be applied to select the unique lab 
value for analysis: a) multiple records from both central and local lab, central lab value always 
takes precedence over local lab value; b) multiple records from central lab, select the latest value 
as the unique lab value; c) multiple records from local lab, select the latest lab value as the unique 
lab value.   
2.9.
Imputation of Partial Dates
Unless specified otherwise, no data imputation will be applied for missing safety and efficacy 
evaluations. For analysis and reporting purpose, missing or partial date in adverse event (AE onset 
date; AE end date), concomitant therapies (start date; end date), AL amyloidosis diagnosis (date of 
diagnosis), and subsequent anti-amyloidosis therapy (start date) data domain will be imputed. 
2.9.1.
Missing/Partial Adverse Event Onset Date
If the onset date of an adverse event is missing completely or partially, the following imputation 
rules will be used.

When month and year are present and the day is missing,

If the onset month and year are the same as the month and year of first study treatment, 
the day of first study treatment or the day-component of the AE end date (possibly 
imputed) is imputed, whichever is earlier

If the onset month and year are not the same as the month and year of first study treatment, 
then the first day of the month is imputed

When only a year is present or no components of the onset date are present, 

If the onset year is the same as the year of first study treatment. If AE end date is available
and is prior to first study treatment, the day and month of AE end date are imputed.
Otherwise, the day and month of first study treatment are imputed

If the onset year is different from the year of first study treatment, the 1st of January is 
imputed

If the onset date is completely missing, the date of first study treatment is imputed as the 
onset date.
No imputation will be done for partial or missing AE onset time. 
If AE onset date needs imputation, but the AE onset time is available, the AE onset time will be 
dropped in the imputed AE onset date/time variable.
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2.9.2.
Missing/Partial Adverse Event End Date
If the end date of an adverse event is missing completely or partially, the following imputation 
rules will be used.

If month and year are present and the day of the month is missing, the last day of the 
month is imputed. 

If only a year is present, the 31st of December is used. 

If the imputed date is later than the date of death (if available), the date of death will be 
used as the imputed date instead.
No imputation will be done for partial or missing AE end time. 
If AE end date needs imputation, but the AE end time is available, the AE end time will be dropped 
in the imputed AE end date/time variable.
2.9.3.
Partial Concomitant Medication Start/End Date
In case of partially missing concomitant medication start/end dates, the following imputation rules 
will be applied. If the date is completely missing, no imputation will be performed.

If only the day is missing, the 15th day of the month will be used

If both the day and month are missing, the 30th of June will be used
If the medication was taken prior to study start, and the imputed start date is after first treatment 
date, further adjust the imputed start date as the day prior to first dosing date; If the medication 
was taken after study start, and the imputed start date is prior to first dosing date, further adjust the 
imputed start date as first dosing date. Also adjust the imputed medication end date so that it is on 
or after first dosing date. 
After applying above adjusting method, if it results in medication start date that is after 
medication end date, the medication start date needs re-adjustment as follows:
If medication start date was imputed, then adjust as follows: 

Impute the same month and year as medication end date if the non-imputed date parts are 
the same 

Impute the first day of the month as medication start day 
If medication end date was imputed, then re-adjust medication end date to be the same as the 
medication start date if the corresponding non-imputed date parts match the medication start 
date. 
Also adjust the imputed medication end date so that it is on or after first dosing date. 
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2.9.4.
Partial AL Amyloidosis Diagnosis Date
For partial date of original AL amyloidosis diagnosis, the following imputation rules will apply:

If only day is missing, the 15th day of the month will be imputed 

If both month and day are missing, the 30th of June will be imputed

If year is missing, no imputation will be applied
If the imputed AL amyloidosis diagnosis date is after first treatment date, further adjust the imputed 
diagnosis date as the day prior to first dosing date.
2.9.5.
Partial Subsequent Anti-AL Amyloidosis Therapy Start Date
If the year or month of subsequent anticancer therapy start date is missing or no components of 
the start date are present, no imputation will be performed.  
If only the day-component is missing, the following steps apply: 

If the month and year of the start date are the same as the month and year of last dosing 
date, the day of last dosing date or the day-component of the stop date of subsequent 
anticancer therapy is imputed, whichever is earlier. 

If the start month and year are not the same as the month and year of last dosing date, the 
first day of the month is imputed.
No imputation will be applied for missing or partial subsequent anticancer therapy end date. 
2.10.
General Analysis Method
In general, continuous variables will be summarized using descriptive statistics (n, mean [SD] 
median, and range). Categorical variables will be summarized using frequency and percentage
(n [%]).  The Kaplan-Meier method will be used for descriptive summaries for time-to-event 
variables. For the calculation of time-to-event and duration-of-event variables, the difference 
between the start date and the end date plus 1 day will be used.
2.11.
Analysis Sets
The following analysis sets are defined in this study. 
2.11.1.
Efficacy Analysis Set(s)
2.11.1.1.
Primary Efficacy Analysis Set
The primary efficacy analysis set will be the intent-to-treat (ITT) population, which is defined as 
subjects who have been randomly assigned to the Dara SC+CyBorD or CyBorD arm. Analyses 
of the primary endpoint overall CHR rate, secondary endpoints, including time-to-event variables 
(e.g., MOD-PFS, and OS), and demographic and baseline characteristic etc. will be based on this 
population.
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2.11.1.2.
Secondary Efficacy Analysis Set
Secondary efficacy analysis sets are defined as follows:

Hematologic response-evaluable: is defined as subjects who have a confirmed diagnosis 
of AL amyloidosis and measurable disease at baseline or screening visit. In addition, 
subjects must have received at least 1 administration of study treatment and have at least 
1 post- baseline disease assessment.
Supplementary analysis of CHR rate and VGPR or better rate will be based on this population.
If >95% randomized subjects are hematologic response-evaluable, these supplementary
analyses may be omitted.

Cardiac response-evaluable is defined as subjects with baseline NT-proBNP value 
≥650 ng/L or baseline NYHA class 3 or 4. In addition, subjects must have received at 
least 1 administration of study treatment and have at least one post-baseline
NT-proBNP measurement (if baseline NT-proBNP ≥650 ng/L) or NYHA function 
evaluation (if baseline NYHA class 3 or 4)

Renal response-evaluable is defined as subjects with baseline urine protein >0.5 g/day. 
In addition, subjects must have received at least 1 administration of study treatment 
and have at least one post-baseline urine protein (g/day) measurement

Liver response-evaluable is defined as subjects with baseline abnormal alkaline 
phosphatase value (i.e., >1.5*ULN). In addition, subjects must have received at least 1 
administration of study treatment and have at least one post-baseline alkaline 
phosphatase measurement
2.11.1.3.
Safety Analysis Set
Safety analysis set is defined as subjects who have received at least 1 administration of any study 
treatment (partial or complete). This population will be used for all safety analyses. The safety 
analyses grouping will be according to treatment received.
2.11.1.4.
Pharmacokinetics Analysis Set
Pharmacokinetics analysis set will be pharmacokinetics-evaluable population: is defined as 
subjects assigned to Dara SC+CyBorD arm who received at least 1 administration of daratumumab 
and have at least 1 pharmacokinetic sample concentration value after the first infusion. All 
pharmacokinetics analyses are based on the pharmacokinetic evaluable population.
2.11.1.5.
Immune Response-evaluable Analysis Set
Immune response-evaluable: is defined as subjects assigned to Dara SC+CyBorD arm who 
received at least 1 administration of daratumumab and had appropriate serum samples for 
detection of antibodies to daratumumab or rHuPH20 (i.e., subjects with at least 1 immunogenicity 
sample obtained after their first daratumumab administration). This analysis set will be used for 
immunogenicity related analyses.
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2.12.
Definition of Subgroups 
In general, the following pre-specified subgroup (Table 1) analyses are to be performed for the 
primary efficacy endpoint, major secondary endpoints: MOD-PFS and OS, and safety endpoints. 
Additional subgroup analyses may be performed for selected efficacy and/or safety endpoints, 
which are described in later sections.
Table 1:
Subgroup Analyses of Efficacy and Safety Endpoints
Subgroup
Definition
Analysis Type
Sex
Male, Female
E, S
Age
<65 years, 65 years
E, S
Race
White, Asian, Others
E, S
Baseline weight
≤ 65 kg, >65 to 85 kg, >85 kg
E, S
Baseline Cardiac stage
I, II, and IIIa/IIIb
E
Countries that typically offer transplant 
for patients with AL amyloidosisa
List A, List B
E
Baseline renal function (CrCl)≥60 
mL/min or CrCl <60 mL/min))
≥60 mL/min; <60 mL/min
E, S
Cardiac involvement at baseline
Yes, No
E, S
Baseline Renal stage
I, II, III
E
Baseline Alkaline phosphataseb
Abnormal, normal 
E
Achieve dFLC responsec
Yes, No
E
t(11:14) by FISH
Abnormal, normal
E
High-risk 
del 17p, t(4;14), t(14;16)
E
Baseline ECOG performance score
0, ≥1
E
a List A = countries that typically offer transplant; List B = countries that typically not offer transplant.
b Abnormal is defined as alkaline phosphatase value at baseline >1.5ULN. 
c dFLC response is defined as >50% reduction in the dFLC.
E: efficacy (CHR, MOD-PFS, OS); S: TEAE.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
Two interim analyses are planned for this study.  The first interim will occur after the first 
30 subjects are treated for at least 1 cycle in each arm. The purpose of the first interim analysis is 
to have a comprehensive evaluation of safety. The second interim analysis will occur after at least 
180 subjects in total have been treated for at least 6 cycles. The purpose of the second interim 
analysis is to evaluate cumulative interim safety and efficacy data. Both futility and efficacy 
stopping rules are built in this interim analysis. The study may be stopped due to futility if the 
complete hematologic response rate in Dara SC+CyBorD arm is the same or worse than CyBorD 
arm. The study may be stopped due to efficacy if the significance level at this interim analysis to 
establish the superiority of Dara SC+CyBorD over CyBorD is less than or equal to 0.0001 (2-
sided). The primary analysis will occur after all subjects are treated for at least 6 cycles and the 
alpha to be spent is 0.04999 (2-sided) by a user defined alpha spending function.
An IDMC, consisting of 2 clinicians and 1 statistician, will be established to review the interim 
results at the planned interim analyses. After the interim review, the IDMC will make 
recommendations regarding any required modification and provide guidance on the continuation 
of the study. The details will be provided in a separate IDMC charter.
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4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Unless specified otherwise, all demographic and baseline characteristics variables will be 
summarized for the ITT population. No statistical comparisons between the 2 treatment groups are 
planned. 
The distribution of subject enrollment will be presented for each treatment group according to 
region and country. Subjects who did not meet study inclusion/exclusion criteria will be listed by 
subject ID, treatment group, and specific criteria not met. 
Subject demographic and baseline characteristic variables: age, sex, ethnicity, race, weight (kg), 
height (cm), body surface area (m2), and ECOG performance status will be summarized by 
treatment group and overall. 
Baseline amyloid disease characteristics will be summarized and tabulated by treatment group and 
overall. The baseline disease characteristics include time since initial AL amyloidosis diagnosis 
(months), type of AL amyloidosis (IgG, IgA, IgD, IgE, IgM, bioclonal) by immunofixation test, 
light chain type (kappa, lambda), type of measurable disease (serum M-protein, serum FLC, serum 
FLC + serum M-protein), t(11;14) by FISH (abnormal, normal), and standard-risk vs. high-risk 
cytogenetic abnormalities (del 17p, t(4;14), t(14;16)). 
Baseline organ characteristics will also be summarized by treatment group and overall. Organ 
characteristics includes cardiac stage (I, II, IIIa/IIIb) based on Mayo Cardiac Staging System, 
NYHA classification (I, II, IIIA), renal stage (I, II, III) and chronic kidney disease (CKD) stages 
based on published staging criteria (Palladini 2014)3, organ involvement (heart, kidney, liver, 
gastrointestinal track, lung, PNS, ANS, and soft tissue), and number of organ involvement 
(1, 2, ≥3 organs; median with range).
Disease related hematologic biomarkers (bone marrow plasma cell (%), iFLC and dFLC) at 
baseline will be summarized for all subjects, by descriptive statistics. Organ related biomarkers
will be summarized for all subjects and subjects with specific organ involvement, respectively. 
These biomarkers include NT-proBNP, cardiac troponin T (cTnT), HS cardiac troponin T 
(Hs-cTnT), proteinuria, creatinine, eGFR, albumin, alkaline phosphatase, and LVEF, etc. 
A descriptive summary of selected hematology (i.e, hemoglobin, neutrophils, platelet, and WBC)
and chemistry (i.e., AST, ALT, alkaline phosphatase, total bilirubin, creatinine clearance, 
estimated glomerular filtration rate [eGFR]) laboratory analytes at baseline will be provided for 
each treatment group and overall. In addition, baseline toxicity grade of each selected laboratory 
analyte in hematology and chemistry panel will be summarized by treatment group using 
frequency. 
Medical history collected at baseline or screening visit will be summarized by system-organ class 
and preferred term for each treatment group and overall. 
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A summary of stratification factors (cardiac stage (Stage I, II, and IIIa), countries that typically 
offer transplant for patients with AL amyloidosis (List A or List B), and renal function 
(CrCl ≥60 mL/min or CrCl <60 mL/min) used in the randomization based on IWRS will be 
provided to evaluate if randomization process is appropriately executed in the study.  
4.2.
Disposition Information
An overview of subject disposition by treatment group will be provided. The overview includes a 
summary of total number of subjects who are randomized to each treatment group, the number and 
percentage of subjects who are randomized but not treated, and the number and percentage of 
subjects who are treated in each treatment group. For all treated subjects (defined as subjects who 
have received at least 1 administration of any study treatment), the number and percentage of 
subjects who discontinued study treatment including reason for discontinuation as indicated in the 
“Treatment Disposition” CRF page will be summarized. 
According to study design, after a maximum of 6 cycles of CyBorD treatment, subjects who are 
assigned to Dara SC+CyBorD arm can continue to receive daratumumab monotherapy, if they 
have not progressed or received subsequent anti-plasma cell therapy. Therefore, to evaluate study 
treatment discontinuation during treatment period for both groups, the number and percentage of 
subjects who discontinued study treatment during Cycles 1-6 will also be provided. 
Similar summaries will be presented for all randomized subjects who discontinued from study 
participation. 
4.3.
Extent of Exposure
Extent of exposure to study treatments will be summarized through the following variables: 
number of treatment cycles, duration of study treatment, total dose administered, dose intensity, 
relative dose intensity, and number of subjects with cycle delay and dose modification etc. These
summaries will be based on safety analysis set and presented by treatment group. 
The number and percentage of subjects treated within each cycle will be summarized. The 
maximum number of treatment cycles received for each subject will be summarized by frequency 
and descriptive statistics.
Duration of study treatment, defined as the number of days from the date of the first administration
of study treatment to the date of the last administration of study treatment, will be summarized. 
Number of Daratumumab injections and duration of 1st, 2nd and subsequent injections will be 
summarized.
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Descriptive statistics for number of daratumumab administrations will be provided for Dara 
SC+CyBorD arm. The total dose administered for each study treatment (i.e, daratumumab [mg], 
cyclophosphamide [mg/m2], bortezomib [mg/m2], and dexamethasone [mg] or dex-equivalent if 
other steroid is used) will be summarized overall, by treatment cycle, by daratumumab treatment 
frequency (i.e. weekly [Cycles 1-2], biweekly [Cycles 3-6] and monthly [Cycles 7+]).
The dose intensity, which is defined as the sum of total dose administered in all cycles divided by 
the number of treatment cycles, will be calculated for each study treatment and summarized 
accordingly.
The relative dose intensity (%) defined as the ratio of total actual dose received and total planned 
dose will be calculated for each study drug and summarized using descriptive statistics.
The number of subjects with cycle delays or dose modifications (dose delays, dose skipping, or 
dose reduction) including reasons (AE or other) for cycle delays or dose modifications, will be 
reported. In addition, a summary of study treatment dose modifications by cycle will be provided. 
4.4.
Protocol Deviations
Major protocol deviations will be summarized based on ITT analysis set by the following types of 
deviation for each treatment group:

Entered but did not satisfy inclusion/exclusion criteria

Developed withdrawal criteria but not withdrawn

Received wrong treatment or incorrect dose

Received an excluded concomitant treatment

Efficacy assessment deviation

Other – protocol non-compliance
A listing of subjects with major protocol deviations including subject ID, type of deviation, and 
reasons for deviation will be provided. 
Deviations specific to the COVID-19 pandemic will be presented by listing and narratives as 
appropriate.
4.5.
Concomitant Medications
Concomitant medications collected beginning with signing of the ICF and ending 30 days after the 
last dose of the last study treatment or until the start of subsequent anticancer treatment, if earlier, 
will be summarized by therapeutic class, pharmacologic class, and drug name for each treatment 
group. 
A similar summary of pre-infusion medication and post-infusion medication will be provided for 
Dara SC+CyBorD arm according to the CRF pages the medications are collected on. 
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In addition, systemic steroids and prophylactic antiviral medication use during the study will be 
tabulated by therapeutic class, pharmacologic class, and drug name, respectively. 
4.6.
Subsequent Non-cross Resistant Anti-plasma Cell Therapy for AL 
Amyloidosis
Non-cross resistant anti-plasma cell therapy for AL Amyloidosis is defined as any anti-plasma cell 
agent not included in the original protocol assigned treatment. For example, for subjects assigned 
to arm A who receives subsequent lenalidomide and bortezomib combination therapy, 
lenalidomide treatment will be considered as subsequent non-cross resistant, anti-plasma cell 
therapy. However, for subjects assigned to arm A who continues to receive cyclophosphamide, 
bortezomib and dexamethasone (CyBorD) or any component of cyclophosphamide, bortezomib 
and dexamethasone (e.g. bortezomib alone), subjects will not be considered as receiving 
subsequent, non-cross resistant, anti-plasma cell therapy.       
Subsequent non-cross resistant anti-plasma cell therapy for AL Amyloidosis recorded during the 
study will be summarized and presented by therapeutic class, pharmacologic class and drug name 
for each treatment group. In AL amyloidosis disease setting, subsequent non-cross resistant, anti-
plasma cell therapy could start earlier in some subjects prior to observation of hematologic 
progression, therefore, the summary will also be presented for a) subjects who initiated subsequent
non-cross anti-plasma cell therapy prior to hematologic progression; b) subjects who initiated 
subsequent non-cross anti-plasma cell therapy on or after hematologic progression.
For subjects who received at least one line of subsequent non-cross anti-plasma cell therapy, the 
number of lines of subsequent therapy will be calculated for each subject and summarized by 
treatment group through frequency and descriptive statistics. In addition, their overall best 
hematologic and organ response to subsequent anti-plasma cell therapy will be summarized. 
Additionally, hematologic and organ response to first subsequent non-cross resistant anti-plasma 
cell therapy will be tabulated. The reasons for initiation of first subsequent non-cross resistant anti-
plasma cell therapy will be provided. 
Please refer to Section 5.4.2 for analysis of time to non-cross resistant anti-plasma cell therapy for 
AL Amyloidosis. 
5.
EFFICACY
Evaluation of disease response and progression will be conducted in accordance with the 
“Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain 
amyloidosis (Comenzo 2012)”2 and renal response and progression criteria by (Palladini 2014)3
(hereafter referred to as consensus guidelines). In addition, recently published guidelines on 
response assessment will be taken into consideration when determining complete hematologic 
response (Manwani 2018, Muchtar 2019, Sidana 2019).6, 7, 10
The primary efficacy analysis will be conducted based on independent review committee (IRC)
assessment of disease response and progression. Sensitivity analysis of hematologic response, 
which response and progression are evaluated by the sponsor using a computerized algorithm, will 
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be performed. The detailed documentation of the computer algorithm can be found in Attachment 
1. Additionally, analysis will also be carried out for selected efficacy endpoints based on 
investigator assessment.
5.1.
Analysis Specifications
5.1.1.
Level of Significance
All statistical hypothesis tests and 95% confidence interval presented will be 2-sided. 
The primary hypothesis (i.e., hypothesis on overall CHR rate) is to be tested at the 0.05 significance 
level (overall). No alpha spending will be given at the first interim analysis, because the purpose 
of this interim analysis is to evaluate safety and no analysis will be performed for efficacy 
endpoints. The alpha to be spent at the second interim analysis (approximately180 subjects are 
treated for at least 6 cycles), is 0.0001(2-sided). If the observed two-sided p-value is smaller than 
this significance level, the superiority of Dara SC+CyBorD versus CyBorD with respect to overall 
CHR will be established, therefore, the primary hypothesis will not be re-tested at any subsequent 
timepoints. Otherwise, the primary hypothesis will be tested again at the planned primary analysis 
(after all subjects are treated for at least 6 cycles) with alpha to be spent is 0.04999 (2-sided) by a 
user defined alpha spending function.
By the time of second interim analysis, it is estimated that there will be a very limited number of 
events for major secondary endpoints of MOD-PFS and OS. Therefore, only descriptive analysis 
will be conducted without formal hypothesis testing. Formal hypothesis testing of these major 
secondary endpoints will be conducted at the planned primary analysis and/or when approximately 
200 MOD-PFS events are observed according to group-sequential rules as defined in the 
following.
If the testing of the primary endpoint of overall CHR rate is statistically significant, the following 
major secondary endpoints ordered below will be sequentially tested at the planned primary
analysis, each with an overall two-sided alpha of 0.05, by utilizing a hierarchical testing approach 
as proposed by Tang and Geller (1999) that strongly controls Type I error rate. The major 
secondary endpoints are ordered as follows:
1) MOD-PFS
2) OS
The significance level at the planned primary analysis will be determined by the alpha-spending 
function specific to that endpoint. For MOD-PFS and OS endpoints, the O’Brien-Fleming alpha-
spending function as implemented by the Lan-DeMets method will be used.

For MOD-PFS, the exact information fraction at primary analysis is to be determined by 
the observed number of events divided by total planned MOD-PFS events. The exact 
significance level is to be determined per the O’Brien-Fleming alpha spending function.

For OS, the information fraction at primary analysis is to be determined by the observed 
number of death events divided by total projected death events by the time of final OS 
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analysis. According to published data (Palladini, Blood 2015)4, 55% of subjects with newly 
diagnosed AL Amyloidosis treated with CyBorD were projected to survival 5 years. 
Assuming that Dara SC+CyBorD may reduce the risk of death (hazard ratio=0.75) by 25%, 
it is estimated that by the time of final OS analysis, approximately a total of 156 death 
events are projected to be observed.
If the null hypothesis for MOD-PFS endpoint fails to be rejected at the planned primary analysis, 
then OS will not be tested until the next analysis timepoint (e.g., MOD-PFS analysis). If the null 
hypothesis for MOD-PFS endpoint is rejected at the planned primary analysis, it will remain 
rejected and will not be re-tested at final OS analysis.
5.1.2.
Independent Review Committee
Hematologic response and progression, organ response and progression will be adjudicated by an 
Independent Review Committee (IRC). Details of this part can be found in Attachment 4.
5.1.3.
Data Handling Rules
There is no imputation planned for missing efficacy endpoints.
5.2.
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the overall complete hematologic response (CHR) rate.
5.2.1.
Definition
Complete hematologic response will be assessed by the independent review committee (IRC) and 
is based on consensus guidelines (Comenzo 2012)2 and defined as negative serum and urine 
immunofixation, and normalization of FLC levels and FLC ratio.
During the conduct of this trial, it became apparent that there are limitations to the 
(Comenzo 2012)2 guidelines based on deeper understanding of disease biology and outcomes 
(Manwani 2018, Muchtar 2019, Sidana 2019)6, 7, 10 that effect the definition of a complete 
hematologic response.
 
 
 
The overall CHR rate is the proportion of subjects who achieve a CR confirmed by a subsequent 
assessment during or after the study treatment. Subjects with positive serum IFE and confirmed 
daratumumab IFE interference, that meet all other clinical criteria for CR will be considered CHR.  
5.2.2.
Estimand
The primary estimand for this study is defined by the following components:

Treatment: 
CCI
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
Dara SC+CyBorD for up to 6 cycles followed by dara monotherapy until PD or 
start of subsequent non-cross resistant, anti-plasma cell therapy, or a maximum of 
2 years from the start of the treatment

CyBorD for up to 6 cycles followed by observation 

Population: subjects with newly diagnosed AL amyloidosis

Endpoint: overall complete hematologic response (CHR)

Intercurrent event: 

Treatment discontinuation

Start of subsequent non-cross resistant, anti-plasma cell therapy for AL 
Amyloidosis without hematologic progression

Measure of intervention: odds ratio of overall CHR rate
Two different strategies are used to account for the intercurrent events. 

Disease assessments after subsequent non-cross resistant, anti-plasma cell therapy will be 
ignored for a subject who started subsequent non-cross resistant, anti-plasma cell therapy 
for AL Amyloidosis (while on treatment strategy). 

Treatment discontinuation will be ignored (treatment policy strategy). 
Note: please refer to Section 4.6 for the definition of non-cross resistant anti-plasma cell therapy 
for AL Amyloidosis. 
5.2.3.
Analysis Methods
The main analysis for the primary endpoint overall CHR rate will be based on IRC-assessed CHR. 
Overall CHR rate will be calculated for each treatment group based on the ITT population. The 
corresponding 
95% 
exact 
confidence 
interval 
(CI)
will 
be 
provided.
Stratified 
Cochran-Mantel-Haenszel (CMH) test will be used to test treatment difference in the proportion 
of subjects who achieved an overall CHR. The CMH estimate of odds ratio and its 95% CI and 
p-value for testing treatment difference will be reported. Stratification factors used in the analysis 
include cardiac stage (Stage I, II, and IIIa), countries that typically offer transplant for patients 
with AL amyloidosis (List A or List B), and renal function (CrCl ≥60 mL/min or 
CrCl <60 mL/min).
Subgroup analyses of CHR rate will be performed for pre-specified subgroups as described in 
Section 2.12.
A sensitivity analysis that target the primary estimand will be performed. The sensitivity analysis 
will be based on investigator assessed CR and computerized algorithm derived CR, respectively.
Same analysis approach as for the main analysis will be implemented. 
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In addition, three planned supplementary analyses will be conducted. These are considered 
supplementary analyses as they inherently change the estimand. According to the ICH E9 
addendum9 recommendations, only one component per analysis is changed at a time.
a) Changes the target variable to CHR based on computer algorithm without confirmation by 
Comenzo (2012) with clarifications to CR criteria (i.e., negative serum and urine 
immunofixation and iFLC<ULN), the rest of the estimand remain the same
b) Changes the target variable to CHR based on computer algorithm without confirmation by 
Comenzo (2012) with clarifications to CR criteria (i.e., negative serum and urine 
immunofixation and iFLC<ULN and normalization of FLC ratio), the rest of the estimand 
remain the same 
c) Changes which strategy is employed for the intercurrent event of subsequent non-cross 
resistant, anti-plasma cell therapy. If there is a disease assessment that demonstrates CHR 
before PD after the start of subsequent non-cross resistant, anti-plasma cell therapy, the 
subject will be considered as a responder (treatment policy strategy)
5.3.
Major Secondary Endpoints
The major secondary endpoints included in formal hierarchical hypothesis testing are MOD-PFS 
and OS. Other secondary endpoints include CHR at 6 months, hematologic VGPR or better rate, 
time to hematologic response, and duration of hematologic response. Except for time to and 
duration of hematologic response, analyses will be performed based on ITT set unless specified 
otherwise.
5.3.1.
Major Organ Deterioration Progression-Free Survival (MOD-PFS)
5.3.1.1.
Definition
MOD-PFS event is defined as one of the following clinically observable incidences:
a) Death
b) Major organ deterioration defined as

Clinical Manifestation of Cardiac Failure:
Defined as need for cardiac transplant, left ventricular assist device (LVAD), or 
intra-aortic balloon pump (IABP)

Clinical Manifestation of Renal Failure:
Defined as the development of end-stage renal disease (need for hemodialysis or 
renal transplant)
c) Development of hematologic PD as per consensus guidelines by IRC
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MOD-PFS is defined as duration from the date of randomization to either hematologic progression, 
or major organ deterioration (clinical manifestation of cardiac failure or renal failure), or death, 
whichever occurs first.
5.3.1.2.
Estimand
The estimand corresponding to the major secondary endpoint MOD-PFS for this study is defined 
by the following components:

Treatment: 

Dara SC+CyBorD for up to 6 cycles followed by dara monotherapy until PD or 
start of subsequent non-cross resistant, anti-plasma cell therapy, or a maximum of 
2 years 

CyBorD for up to 6 cycles followed by observation 

Population: subjects with newly diagnosed AL amyloidosis

Endpoint: MOD-PFS 

Intercurrent event: 

Treatment discontinuation 

Start of subsequent non-cross resistant, anti-plasma cell therapy for AL 
Amyloidosis before hematological PD or major organ deterioration or death

Measure of intervention: hazard ratio (HR) 
Different strategies are used to account for the intercurrent events. 

Treatment discontinuation will be ignored (treatment policy strategy)

For intercurrent event of subsequent non-cross resistant, anti-plasma cell therapy for AL 
Amyloidosis before hematological PD or major organ deterioration or death, hypothetical 
strategy will be implemented. i.e., had subsequent, non-cross resistant, anti-plasma cell 
therapy not been available to subjects 
Note: please refer to Section 4.6 for the definition of non-cross resistant anti-plasma cell therapy 
for AL Amyloidosis.  
5.3.1.3.
Analysis Methods
According to study design, a subject with suboptimal hematologic response or worsening organ 
function may switch to subsequent non-cross resistant, anti-plasma cell therapy before 
hematologic PD or major organ deterioration, which may impact or interfere with the evaluation 
of endpoint MOD-PFS. To adjust for confounding impact of subsequent, non-cross resistant anti-
plasma cell therapy on MOD-PFS, the primary analysis of MOD-PFS will employ inverse 
probability of censoring weight (IPCW, Robins and Finkelstein, 2000)11 method to adjust 
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estimates of a treatment effect in the presence of subsequent non-cross resistant, anti-plasma cell 
therapy.
5.3.1.3.1.
Censoring Rules for MOD-PFS
Subjects who received subsequent non-cross resistant, anti-plasma cell therapy before 
hematological PD or major organ deterioration or death will be censored at the last disease 
assessment before start of subsequent non-cross resistant, anti-plasma cell therapy.
Subjects who withdraw consent from the study before MOD-PFS event will be censored at the last 
disease assessment before withdrawal of consent to study. 
Subjects who are lost to follow-up before MOD PFS event will be censored at the last disease 
assessment before subjects are lost to follow-up. 
Subjects who don’t experience MOD-PFS event and are still alive at the cutoff date for analysis 
will be censored at the last disease assessment. 
Subjects without any post-baseline disease assessment will be censored at randomization.
Determination of dates of MOD-PFS event and dates for censoring is summarized in Table 2 as 
follows.
Table 2:
MOD-PFS Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
Hematologic PD or clinical 
manifestation of cardiac failure or 
clinical manifestation of renal failure
prior to start of subsequent, non-cross 
resistant, anti-plasma cell therapy
Earliest date of any of these 3 events
MOD-PFS 
event
Death prior to start of subsequent, non-
cross resistant, anti-plasma cell therapy
Date of death
MOD-PFS 
event
No post-baseline clinical evaluation of 
MOD-PFS
Randomization
Censored
No MOD-PFS events
Date of last clinical evaluation of MOD-PFS 
endpoint
Censored
Other (e.g., withdrawal of consent to 
study participation, lost to follow-up,
start of subsequent, non-cross resistant, 
anti-plasma cell therapy etc.)
Date of last clinical evaluation of MOD-PFS 
endpoint prior to censoring situation
Censored
5.3.1.3.2.
Inverse Probability of Censoring Weighted (IPCW) Analysis
The primary analysis of MOD-PFS will be based on IRC event assessment for the ITT population.
The number and percentage of subjects who have a MOD-PFS event or are censored including 
reasons for censoring will be reported. The detailed breakdown of events by each component 
(hematologic PD, major organ deterioration or death) will also be provided. 
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The primary treatment comparison of the distribution of overall MOD-PFS will be based on 
inverse probability of censoring weighted (IPCW, Robins and Finkelstein, 2000)11 log-rank test to 
adjust for potential dependent censoring due to switching to subsequent non-cross resistant, anti-
plasma cell therapy. Due to expected small number of MOD-PFS events at the primary analysis, 
the distribution comparison of MOD-PFS for the 2 treatment groups will be based on unstratified 
IPCW log-rank test (i.e. score test from unstratified IPCW weighted cox-proportional hazard 
model). The p-value from the unstratified IPCW log-rank test will be reported. Hazard ratio and 
its 95% confidence interval will be estimated using a unstratified weighted Cox proportional 
hazards model with treatment as the sole explanatory variable. Inverse probability of censoring 
weighted Kaplan-Meier curves will be plotted by treatment group. At the final MOD-PFS analysis
(i.e., when approximately 200 MOD-PFS events have been observed), a stratified MOD-PFS 
analysis including stratified IPCW log-rank test, stratified weighted Cox proportional hazards 
model with treatment as the sole explanatory variable will be performed.
Time-dependent stabilized weights will be calculated for each subject at time (t) by estimating the 
conditional probability of having remained uncensored (i.e., not switching to subsequent non-cross 
resistant, anti-plasma cell therapy) until time t given baseline covariates, divided by the estimated 
conditional probability of having remained uncensored until time t given baseline and time-
dependent covariates.
The conditional probability of the subject having remained uncensored (i.e., not switching to 
subsequent non-cross resistant, anti-plasma cell therapy) until time t will be estimated based on 
the treatment specific fits of a Cox proportional hazards model for switching to subsequent non-
cross resistant, anti-plasma cell therapy. Subjects who receive subsequent non-cross resistant, anti-
plasma cell therapy without experiencing a MOD-PFS event or before experiencing a MOD-PFS 
event will be considered as an event for treatment switching,  with event date as  the start date of 
subsequent non-cross resistant anti-plasma cell therapy; Subjects who receive subsequent non-
cross resistant, anti-plasma cell therapy after experiencing a MOD-PFS event will be censored at 
time of the MOD-PFS event. Subjects who don’t receive subsequent non-cross resistant, anti-
plasma cell therapy at the cutoff date for analysis will be censored at the last disease assessment.
The following baseline covariates and time-dependent prognostic factors for MOD-PFS and 
switching to subsequent non-cross resistant, anti-plasma cell therapy will be taken into 
consideration.   
Baseline covariates

Age (<65, >=65)

Sex (Male, Female)

Race (White, Others)

ECOG Performance Score (0, >=1)

Countries that typically offer transplant 
for patients with AL amyloidosis (List A: 
countries that typically offer transplant or 
List B: countries that typically not offer 
transplant)

Baseline dFLC
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
Baseline iFLC

Type of FLC (kappa, lambda)

Number of organ involvement (<2, vs 
>=2)

Cardiac involvement (Y, N)

Cardiac stage (Stage I, II, and IIIa/IIIb),

Renal involvement (Y, N)

Renal function (CrCl ≥60 mL/min or 
CrCl <60 mL/min)

Renal Stage (I, II, III)
Time varying covariates

dFLC

iFLC level 

PR status 

CR status

Worsening in hematologic response 
criterion from best achieved status

Alkaline Phosphate

eGFR

Proteinuria level

NT-proBNP

Progression of organ disease (Heart, 
Kidney and Liver) as defined in protocol 
Table 10 by laboratory values

Organ response (Heart, Kidney and Liver) 
as defined in protocol Table 10 by 
laboratory values

Interaction of organ function (protocol 
Table 10) and hematologic response (PR 
or better)

Interaction of organ function (protocol 
Table 10), hematologic response (PR or 
better) and treatment cycle (<=6 vs >6).

Exposure to study treatment (study drug 
discontinued or not)
Variable selection methods will be used to increase modelling stability and to restrict the number 
of covariates and time-dependent prognostic factors in the model to the ones that best fit both 
MOD-PFS data and switching to subsequent non-cross resistant, anti-plasma cell therapy based on
stratified Cox proportional hazard model with treatment group as the only stratification factor.
Transformations to continuous lab variables will be implemented where necessary, to increase 
stability of the modelling approach (e.g. log-transformation for dFLC and iFLC values and 
(baseline) adjustments for individual effects). Missing time-varying covariate observations will be 
imputed by the last available assessment prior to missingness. 
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Any missing conditional probabilities (numerator / denominator) in the calculation of weights will 
be set to 1. To increase stability of the final IPCW weights, these will be truncated to the 2.5% and 
97.5% quantile of the calculated weights. 
The robustness and impact of the variable selection, modelling and weighting approach on the 
estimates will be evaluated by means of sensitivity IPCW analysis, including:

Inclusion of all covariates and time-dependent prognostic factors into the calculation of 
weights.

Calculation of weights without applying stabilizing transformations to time-varying 
prognostic factors.

Calculation of weights using logistic regression for modelling time to initiation of 
subsequent non-cross resistant, anti-plasma cell therapy.
5.3.1.4.
Sensitivity Analysis of MOD-PFS 
Three planned sensitivity analyses that target the estimand for MOD-PFS will be performed. 
a.
MOD-PFS based on investigator assessed hematologic PD. Same analysis approach as for 
the primary analysis (IPCW method) will be implemented
b. MOD-PFS based on IRC assessment by using naïve censoring method (i.e., censoring 
subjects at the last disease assessment before start of subsequent non-cross resistant, anti-
plasma cell therapy)
Stratified log-rank test and stratified Cox’s regression model with treatment as the 
sole explanatory variable will be used to estimate treatment effect (i.e. hazard ratio 
and its 95% confidence interval)
c.
Unstratified analysis of MOD-PFS based on IRC assessment by using naïve censoring 
method
Log-rank test and Cox’s regression model with treatment as the sole explanatory 
variable will be used to estimate treatment effect (i.e. hazard ratio and 95% CI)
5.3.1.5.
Supplementary Analysis of MOD-PFS
Supplementary analyses including other strategies for intercurrent events of subsequent non-cross
resistant, anti-plasma cell therapy such as treatment policy strategy (no censoring at start
subsequent non-cross resistant, anti-plasma cell therapy) and composite strategy (subsequent non-
cross resistant, anti-plasma cell therapy will be treated as a MOD-PFS event) will be performed.
5.3.1.5.1.
Ignore Subsequent Non-Cross Resistant Anti-Plasma Cell Therapy 
The MOD-PFS defined in Section 5.3.1.1 will be analyzed by using treatment policy strategy to 
handle intercurrent event of subsequent non-cross resistant, anti-plasma cell therapy, in other 
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words, if a subject receives subsequent non-cross, anti-plasma cell therapy prior to hematologic 
progression or major organ deterioration, the subject will not be censored at the last disease 
assessment before start of subsequent non-cross, anti-plasma cell therapy.
The primary treatment comparison of the distribution of overall MOD-PFS will be based on a 
stratified log-rank test. The p-value from a stratified log-rank test will be reported.  Hazard ratio 
and its 95% confidence interval will be estimated based on a stratified Cox’s regression model 
with treatment as the sole explanatory variable. Stratification factors used in the analyses include 
cardiac stage (Stage I, II, and IIIa), countries that typically offer transplant for patients with AL 
amyloidosis (List A or List B), and renal function (CrCl ≥60 mL/min or CrCl <60 mL/min).
5.3.1.5.2.
MOD-Event Free Survival (MOD-EFS)
MOD-EFS is a supplementary analysis to MOD-PFS by implementing composite strategy to the 
intercurrent event of subsequent non-cross resistant, anti-plasma cell therapy for AL Amyloidosis. 
MOD-EFS is defined as hematologic PD, major organ deterioration, initiation of any subsequent 
non-cross resistant, anti-plasma cell therapy, or death, whichever comes first.
The primary treatment comparison of the distribution of overall MOD-EFS will be based on a 
stratified log-rank test. The p-value from a stratified log-rank test will be reported.  Hazard ratio 
and its 95% confidence interval will be estimated based on a stratified Cox’s regression model 
with treatment as the sole explanatory variable. Stratification factors used in the analyses include 
cardiac stage (Stage I, II, and IIIa), countries that typically offer transplant for patients with AL 
amyloidosis (List A or List B), and renal function (CrCl ≥60 mL/min or CrCl <60 mL/min).
Additionally, MOD-EFS analysis based on IRC assessed subsequent non-cross resistant, anti-
plasma cell therapy event will be performed.  
5.3.1.5.3.
Subsequent Non-Cross Resistant Anti-Plasma Cell Therapy as a Time 
Dependent Covariate 
A time-dependent Cox proportional-hazards model with subsequent non-cross resistant, anti-
plasma cell therapy as a time dependent covariate will be performed for MOD-PFS. 
This time dependent Cox proportional-hazards regression model included three variables: 
1.
Treatment group, 
2.
A time dependent covariate (an indicator function for each subject, taking the value of 0 from 
randomization to start of subsequent non-cross resistant, anti-plasma cell therapy, and 1 
thereafter), and 
3.
The interaction term of the above 2 variables. 
This analysis will evaluate treatment effect before and after any subsequent non-cross resistant, 
anti-plasma cell therapy. 
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5.3.1.5.4.
Censored for Death/PD after Missing More Than One Disease 
Evaluation
A supplementary analysis of MOD-PFS based on computer algorithm by censoring for death or 
hematologic progression after missing more than one consecutive disease evaluation will be 
performed in a similar manner as described in Section 5.3.1.5.1.
The MOD-PFS definition used in the supplementary analysis is similar to that defined in 
Section 5.3.1.1, except for death or hematologic progression after missing more than one 
consecutive disease evaluation. For any MOD-PFS (death or hematologic progression) event, if 
the event date and the latest date of scheduled disease evaluation (includes serum M-protein, urine 
M-protein, and serum FLC) immediately preceding the event differs more than 2.5 cycles, which 
indicates that subject missed at least one scheduled disease evaluation, then this event will not be 
considered as a MOD-PFS event in the supplementary analysis. Instead, the subject will be 
censored at the date of last disease evaluation (includes serum M-protein, urine M-protein, and 
serum FLC) prior to the MOD-PFS event originally identified.
Note that for subjects with missing disease assessments due to impact of COVID-19, the window 
rules may be adjusted, accordingly.
5.3.1.5.5.
Exclude Hematologic Progression From MOD-PFS Definition 
A supplementary analysis of MOD-PFS with adjusted MOD-PFS definition excluding 
hematologic progression from MOD-PFS will be performed in the same manner as described in 
Section 5.3.1.5.1.
In addition to analysis described in Section 5.3.1, a 6-month landmark analysis may be conducted 
to explore the correlation between MOD-PFS and CHR at 6 months. The Kaplan-Meier MOD-
PFS curve will be plotted by hematologic response.
5.3.2.
Overall Survival (OS)
5.3.2.1.
Definition
Overall survival (OS) is measured from the date of randomization to the date of the subject’s death. 
Subjects who are lost to follow-up will be censored at the time of lost to follow-up. Subjects who 
are still alive at the clinical cut-off date for the analysis will be censored at the last known alive 
date. The date of last known alive will be determined by the maximum collection/assessment date 
from among selected data domains within the clinical database.
5.3.2.2.
Analysis Methods
OS will be analyzed for the ITT population. The Kaplan-Meier method will be used to estimate 
the distribution of OS for each treatment group. Median OS with 95% CI will be provided. In
addition, the number and percentage of subjects who had died or were censored will be reported. 
The Kaplan-Meier OS curve will also be plotted by treatment group.  
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Due to expected small number of death events at the planned final analysis, the distribution of OS 
for the 2 treatment groups will be compared based on an unstratified log-rank test. A p-value from 
an unstratified log-rank test will be reported. Hazard ratio and its 95% confidence interval will be 
estimated based on an unstratified Cox’s regression model with treatment as the sole explanatory 
variable.
A summary of reasons for censoring of overall survival will be provided.
At the final OS analysis, a stratified OS analysis will be performed. Stratification factors that are 
used in the analyses include cardiac stage (Stage I, II, and IIIa), countries that typically offer 
transplant for patients with AL amyloidosis (List A or List B), and renal function
(CrCl ≥60 mL/min or CrCl <60 mL/min). In addition, 4 and 5-year survival rates will be reported.
As described in Section 5.3.1.3, subsequent non-cross resistant, anti-plasma cell therapy are 
permitted to start before hematologic progression in this disease setting. A large number of subjects 
who receive subsequent anti-plasma cell therapy may confound the analysis of overall survival. At 
the final OS analysis, exploratory analysis may be performed that adjust for the effect of treatment 
switch on overall survival.
A 6-months landmark analysis may be conducted to explore the correlation between OS and CHR
at 6 months. The Kaplan-Meier OS curve will be plotted by hematologic response. 
5.3.3.
Complete Hematologic Response Rate at 6 Months
5.3.3.1.
Definition
CHR rate at 6 months is defined as the proportion of subjects who achieve a complete hematologic 
response at 6 months (i.e., initial or confirmation is within 6 +/- 1 months).  
5.3.3.2.
Analysis Methods
The primary analysis for CHR rate at 6 months will be based on IRC-assessed CHR. A sensitivity 
analysis of CHR rate at 6 months based on investigator assessment and computerized algorithm
will be performed to evaluate the robustness of CHR rate at 6 months. In addition, CHR without 
confirmation rules applied by the computerized algorithm will also be explored.  
Analysis of CHR rate at 6 months will be performed similarly as the primary endpoint CHR rate.
In addition, CHR rate at 12 months and 18 months may be provided.
5.3.4.
Hematologic VGPR or better Rate
5.3.4.1.
Definition
Hematologic VGPR or better rate is defined as the proportion of subjects who achieve confirmed 
a hematologic CR or VGPR.
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5.3.4.2.
Analysis Methods
The primary analysis for hematologic VGPR or better rate will be based on IRC-assessed response. 
Hematologic response assessed by investigator will be used as supportive evidence.
Hematologic VGPR or better rate will be analyzed similarly as the primary endpoint CHR rate. 
5.3.5.
Time to Hematologic Response
5.3.5.1.
Definition
Time to hematologic response analysis will be based on IRC-assessed response, the analysis
includes time to CHR, time to VGPR or better and time to PR or better response.

Time to CHR is defined as the time between the date of randomization and the first efficacy 
evaluation that the subject has met all criteria for hematologic CR.

Time to hematologic VGPR or better is defined as the time between the date of 
randomization and the first efficacy evaluation that the subject has met all criteria for 
hematologic VGPR or CR.

Time to hematologic PR or better response is defined as the time between the date of 
randomization and the first efficacy evaluation that the subject has met all criteria for 
hematologic PR or VGPR or CR. 
5.3.5.2.
Analysis Methods
For subjects who achieve a hematologic CR, descriptive statistics will be provided to summarize 
time to CHR. 
The similar analysis will be performed for subjects who achieve a hematologic VGPR or better or 
hematologic PR or better response.
5.3.6.
Duration of Hematologic Response
5.3.6.1.
Definition
Duration of hematologic response analysis will be based on IRC assessed response, the analysis
includes duration of CHR, duration of VGPR or better response and duration of PR or better 
response.

Duration of CHR is defined for subjects with CHR as the time from the date of initial 
documentation of CHR to the date of first documented evidence of hematologic
progressive disease. For subjects who have not progressed, data will be censored at the last 
disease assessment.

Duration of hematologic VGPR or better is defined for subjects with hematologic VGPR 
or better as the time from the date of initial documentation of hematologic VGPR or better 
to the date of first documented evidence of hematologic progressive disease. For subjects 
who have not progressed, data will be censored at the last disease assessment.

Duration of hematologic PR or better response is defined as the time from the date of 
initial documentation of hematologic PR or VGPR or CR to the date of first documented 
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evidence of hematologic progressive disease. For subjects who have not progressed, data 
will be censored at the last disease assessment.
5.3.6.2.
Analysis Methods
For subjects who achieve a hematologic CR, median duration of CHR with 95% CI will be 
estimated based on the Kaplan-Meier method for each treatment group. The Kaplan-Meier curves 
will be plotted by treatment group.
No formal statistical comparison of duration of CHR between the treatment groups will be made.
The similar analysis will be performed for subjects who achieve a hematologic VGPR or better or 
hematologic PR or better response.
5.4.
Other Efficacy Endpoints
5.4.1.
Hematologic PFS (HemPFS)
5.4.1.1.
Definition
Hematologic PFS is defined as the time from the date of randomization to the date of hematologic 
progression assessed by IRC, or death due to any cause, whichever occurs first. Subjects who 
withdraw consent from the study before hematologic progression will be censored at the last 
hematologic assessment before withdrawal of consent to study. Subjects who are lost to follow-up 
will be censored at the last hematologic assessment before subjects are lost to follow-up. Subjects 
who don’t have a HemPFS event and are still alive at the cutoff date for analysis will be censored 
at the last hematologic assessment. Subjects without any post-baseline hematologic assessment 
will be censored at randomization.
Determination of dates of hematologic PFS event and dates for censoring is summarized in 
Table 3 as follows.
Table 3:
Hematologic PFS Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
Hematologic PD per consensus 
guidelines
Earliest date of progression
HemPFS event
Death 
Date of death
HemPFS event
No post-baseline hematologic disease 
assessment
Randomization
Censored
No hematologic PFS events
Date of last clinical evaluation hematologic 
disease assessment
Censored
Other (e.g., withdrawal of consent to 
study participation, lost to follow-up 
etc.)
Date of last clinical evaluation hematologic 
disease assessment
Censored
According to study design, for subjects with suboptimal hematologic response or worsening organ 
function, subsequent non-cross resistant, anti-plasma cell therapy for AL amyloidosis are 
permitted to start before hematologic progression in this disease setting, to evaluate overall 
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treatment effect, the hematologic PFS will not be censored at the starting of subsequent non-cross 
resistant, anti-plasma cell therapy.
5.4.1.2.
Analysis Methods
Analysis of HemPFS will be based on IRC assessment for the ITT population. The Kaplan-Meier 
method will be used to estimate the distribution of overall HemPFS for each treatment group. The 
median HemPFS with 95% CI will be provided. In addition, the number and percentage of subjects 
who had a HemPFS event or were censored will be reported. The Kaplan-Meier PFS curve will 
also be plotted by treatment group.  
The primary treatment comparison of the distribution of overall HemPFS will be based on a 
stratified log-rank test. The p-value from a stratified log-rank test will be reported.  Hazard ratio 
and its 95% confidence interval will be estimated based on a stratified Cox’s regression model 
with treatment as the sole explanatory variable. Stratification factors used in the analyses include 
cardiac stage (Stage I, II, and IIIa), countries that typically offer transplant for patients with AL 
amyloidosis (List A or List B), and renal function (CrCl ≥60 mL/min or CrCl <60 mL/min). 
Sensitivity analysis of HemPFS based on investigator assessment will be performed in a similar 
manner.
5.4.2.
Time to Subsequent Non-cross Resistant Anti-plasma Cell Therapy 
5.4.2.1.
Definition
Time to subsequent non-cross resistant, anti-plasma cell therapy is defined as the time from the 
date of randomization to the start date of subsequent non-cross resistant, anti-plasma cell therapy. 
Death due to PD without start of subsequent non-cross resistant, anti-plasma cell therapy will be 
considered as an event. Subjects who withdraw consent to study or are lost to follow-up or die due 
to causes other than disease progression will be censored at the date of death or the last date known 
to be alive. 
5.4.2.2.
Analysis Methods
The Kaplan-Meier method will be used to estimate the distribution of time to subsequent non-cross 
resistant, anti-plasma cell therapy for the ITT population. Median time to subsequent non-cross 
resistant, anti-plasma cell therapy with 95% CI will be tabulated for each treatment group. In 
addition, a Kaplan-Meier curve for time to subsequent non-cross resistant, anti-plasma cell therapy 
will be plotted. The hazards ratio and its 95% CI will be obtained through a stratified Cox’s 
regression model with treatment as the sole explanatory variable. Treatment comparison will be 
made via a stratified log-rank test.
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5.4.3.
Time to iFLC<ULN, iFLC≤20 mg/L and Time to dFLC<10 mg/L
Response
5.4.3.1.
Definition
Time to iFLC<ULN response is defined as the time from the date of randomization to the date of 
the first disease evaluation that subject’s iFLC level reduction to less than ULN, confirmed by a 
subsequent assessment.
Time to iFLC≤20 mg/L response is defined as the time from the date of randomization to the date 
of the first disease evaluation that subject’s iFLC level reduction to less than or equal to 20 mg/L, 
confirmed by a subsequent assessment. 
Time to dFLC<10 mg /dL (“stringent dFLC response”) response is defined as the time from the 
date of randomization to date of the first disease evaluation that subject’s dFLC level reduction to 
less than10 mg/dL, confirmed by a subsequent assessment.
5.4.3.2.
Analysis Method
For subjects who achieve iFLC<ULN, iFLC≤ 20 mg/L or dFLC<10 mg/L (“stringent dFLC 
response) response, descriptive statistics will be provided to summarize time to iFLC<ULN, 
iFLC≤ 20 mg/L and time to dFLC<10 mg/L, respectively.
5.4.4.
Organ Response 
Organ response analysis will focus on individual organ involved at baseline, specifically for heart, 
kidney and liver. Organ response is defined using consensus guideline (refer to Section 5 of the 
SAP) and organ response requires confirmation by a subsequent assessment.
5.4.4.1.
Cardiac/Renal/Liver Response Rate at 6 Months
5.4.4.1.1.
Definition
Cardiac response rate (CRR) at 6 months is defined as the proportions of cardiac response-
evaluable subjects (defined in Section 2.10 of the SAP) who achieved cardiac response at 6 months
(i.e., initial or confirmation is within 6 +/- 1 months).
Similarly, renal response rate (RRR) and liver response rate (LRR) at 6 months will be defined in 
the same manner. 
5.4.4.1.2.
Analysis Methods
CRR at 6 months will be calculated for each treatment group based on the cardiac response-
evaluable population. The corresponding 95% exact CI will be provided.
Stratified Cochran-Mantel-Haenszel (CMH) test will be used to test treatment difference in the 
proportion of subjects who achieved cardiac response at 6 months. The CMH estimate of odds 
ratio and its 95% CI and p-value for testing treatment difference will be reported. Stratification 
factors used in the analysis include cardiac stage (Stage I, II, and IIIa), countries that typically 
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offer transplant for patients with AL amyloidosis (List A or List B), and renal function 
(CrCl ≥60 mL/min or CrCl <60 mL/min).
The similar analysis will be performed for RRR at 6 months and LRR at 6 months. In addition, 
CRR, RRR and LRR at 12 months and 18 months may be provided.
Additionally, a total number of subjects who achieve overall organ response during the study will 
be reported for each specific organ. 
5.4.4.2.
Time to Cardiac/Renal/Liver Response
5.4.4.2.1.
Definition
Time to cardiac response is defined as the time between the date of randomization and the first 
efficacy evaluation at which the subject has cardiac response. 
A similar definition will be defined for time to renal and time to liver response. 
5.4.4.2.2.
Analysis Methods
For subjects who are in cardiac response-evaluable population and achieve a cardiac response, 
descriptive statistics will be provided to summarize time to cardiac response. 
A similar analysis will be performed on time to renal response and time to liver response, if 
applicable. 
5.4.5.
Organ Progression 
Organ progression analysis will focus on each organ involved at baseline, specifically for heart, 
kidney and liver. Organ progression is defined using consensus guideline (refer to Section 5 of the
SAP). A transient increase in NT-proBNP, and AP or transient decrease in eGFR meeting organ 
progression criteria are not considered for organ progression if this persisted <6 months and levels 
returned to baseline level or better.8
5.4.5.1.
Cardiac/Renal/Liver Progression Rate at 6 Months
5.4.5.1.1.
Definition
Cardiac progression rate (CPR) at 6 months is defined as the proportions of cardiac response-
evaluable subjects (defined in Section 2.10 of the SAP) who experienced cardiac progression at 6 
months (i.e., initial or confirmation is within 6 +/- 1 months).
Renal progression rate (RPR) and liver progression rate (LPR) at 6 months will be defined in a 
similar fashion.
5.4.5.1.2.
Analysis Methods
CPR at 6 months will be calculated for each treatment group based on the cardiac response-
evaluable population. The corresponding 95% exact CI will be provided.
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The similar analysis will be performed for RPR and LPR at 6 months. 
5.4.6.
Time to Cardiac/Renal/Liver Progression
5.4.6.1.
Definition
Time to cardiac progression (TTOCP) is defined as the time from the date of randomization to the 
date of cardiac progression. Subjects who withdraw consent from the study before cardiac
progression will be censored at the last cardiac assessment before withdrawal of consent to study. 
Subjects who are lost to follow-up will be censored at the last cardiac assessment before subjects 
are lost to follow-up. Subjects who don’t have cardiac progression and are still alive at the cutoff 
date for analysis will be censored at the last cardiac assessment. Subjects without any post-baseline 
cardiac assessment will be censored at randomization.
Time to renal progression (TTORP) and time to liver progression (TTOLP) will be defined in a 
similar manner as time to cardiac progression.
Determination of dates of time to cardiac/renal/liver progression event and dates for censoring is 
summarized in Table 4 as follows.
Table 4:
Time to Cardiac/Renal/Liver Progression Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
Cardiac/renal/liver PD per consensus 
guidelines
Earliest date of progression 
event
No post-baseline organ disease 
assessment
Randomization
Censored
No events
Date of last clinical evaluation of organ disease 
assessment
Censored
Other (e.g., withdrawal of consent to 
study participation, lost to follow-up 
etc.)
Date of last clinical evaluation of organ disease 
assessment
Censored
5.4.6.2.
Analysis Methods
5.4.6.3.
Analysis Methods
Analysis of TTOCP will be based on the cardiac-evaluable population. The Kaplan-Meier method 
will be used to estimate the distribution of overall TTOCP for each treatment group. The median 
TTOCP with 95% CI will be provided. The Kaplan-Meier PFS curve will also be plotted by 
treatment group.  
Analysis of time to renal and liver progression will be performed in a similar manner.
5.5.
Patient-Reported-Outcome (PRO)
Patient-reported-outcome (PRO) will be evaluated in this study through the following 3 
instruments:  EORTC QLQ-C30 with 4 supplemental questions from the EORTC item bank, 
EQ-5D-5L and SF-36. Scoring for each instrument will be done based on the instrument developer 
guidelines. No imputation will be done for the PRO data.
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On the days that PROs are scheduled, the PROs should be administered before any other study 
procedures. If a subject has completed the PRO assessments and dosing is delayed, the PRO 
assessment does not need to be repeated if the assessment occurs ≤4 days before dosing.
5.5.1.
Definition
The EORTC QLQ-C30 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 (the past week). A higher score represents a higher (“better”) level of functioning, 
or a higher (“worse”) level of symptoms.
The EQ-5D-5L is a generic measure of health status. For purposes of this study, the EQ-5D-5L 
will be used to generate utility scores for use in cost effectiveness analyses. 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). 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 of the individual (but scoring by the UK 
algorithm allows for values less than 0).
The SF-36 Health Survey is a generic measure of health status. The SF-36 consists of 36 questions 
that yield an eight-scale (physical functioning, role-physical, bodily pain, general health, vitality, 
social functioning, role-emotional, and mental health) profile of functional health and well-being, 
as well as 2 physical and mental health summary measures and a preference-based health utility 
index. The physical component summary (PCS), the mental component summary (MCS), and the 
8 domain scores range from zero (0) to 100, with higher scores representing higher level of 
functioning.
5.5.2.
Analysis Methods
Analysis of PRO data will be performed on ITT analysis set. For subjects with multiple 
records at the same visit, the closest one to the visit date will be selected as the scheduled 
assessment.
At each time point for analysis, the number and percentage of PRO instrument assessment forms 
that are expected, received and missing will be tabulated by treatment group. The missing PRO 
assessments are defined as the expected number of assessments for a visit minus the actual 
number of assessments received for that visit, the expected number of assessments per visit will 
be determined by subject-level study completion status.
Key PRO endpoints
The PRO endpoints are secondary and not part of the statistical hierarchy. Type 1 error control 
will not be applied to PRO data.
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
EORTC-QLQ-C30: fatigue; global health status/quality of life subscale

SF-36v2: MCS

EQ-5D-5L utility score and VAS
Descriptive statistics will be provided for all PRO endpoints at each time point, by treatment group. 
In addition, the above summaries will also be tabulated by hematologic response (responder vs. 
non-responder). Line plot of mean with standard error over time will be displayed by treatment 
group.
For the key PRO endpoints, time to worsening and time to improvement will be derived. A 
distribution-based method will be used to define worsening/improvement in scores, i.e., half 
standard deviation away from the mean score at baseline combining both treatment groups. Time 
to worsening/improvement will be summarized using descriptive statistics and estimated using 
Kaplan-Meier methods. The hazard ratio and its associated 95% confidence interval (CI) will be 
calculated based on the stratified Cox proportional hazards model by the stratification factor at 
randomization. Death due to disease progression will be considered as worsening. Subjects who 
have not met the definition of worsening will be censored at the last PRO assessment. Subjects 
without baseline assessment or post-baseline assessment will be censored at date of randomization.
A mixed effects model with repeated measures analysis will be conducted estimating change from 
baseline at each time point up to Cycle 6 (Week 24) between two treatments. ITT subjects who 
have a baseline value and at least one post-baseline value are included in the analysis. Change 
from baseline will be fitted to a mixed effects model including subjects as a random effect, and 
baseline value, treatment group, time in week, treatment-by-time interaction, and stratification 
factors as fixed effects. 
Other PRO endpoints
These include other EORTC-QLQ-C30 scales and single items: 

functional scales: physical, role, cognitive, emotional, and social

multi-item symptom scales: pain, nausea and vomiting

single-item symptom scale: dyspnea, loss of appetite, insomnia, constipation, diarrhea,
and financial difficulties

additional single items to EORTC-QLQ-C30: swelling in legs or ankles, bloated feeling 
in abdomen/stomach, tingling hands or feet, dizzy
SF-36vs scales: 

physical functioning, role-physical, bodily pain, general health, vitality, social 
functioning, role-emotional and mental health

physical component summary (PCS)
The change from baseline at each time point will be summarized descriptively by treatment group. 
Line plot of mean with standard error over time may be displayed by treatment group.
Time to worsening/improvement and mixed effect model analysis, as described for the key PRO 
endpoints, may be performed as appropriate.
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5.6.
Subgroup Analysis of Efficacy Endpoints
Subgroup analysis of the primary endpoint CHR, major secondary endpoints of MOD-PFS and 
OS based on pre-specified subgroups defined in Section 2.12 will be conducted to investigate the 
consistency of the treatment effect across subgroups.
6.
SAFETY
Safety assessment will be evaluated through AEs, clinical hematology and chemistry laboratory 
tests, ECGs, Transthoracic Echocardiogram (TTE), vital sign measurements, physical examination 
findings, and ECOG performance status. Safety analyses will be based on the safety population 
and presented by the treatment received.
6.1.
Adverse Events
All adverse events whether serious or non-serious, will be reported from the time a signed and 
dated ICF is obtained until 30 days after the last dose of study treatment, until the subject 
withdraws consent for study participation, or until the subject starts subsequent anti-plasma cell
therapy, whichever occurs first. AEs will be recorded in standard medical terminology and graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE), Version 4.03. For AE reporting, the verbatim term used in the CRF by 
investigators to identify adverse events will be coded using the latest version of Medical Dictionary 
for Regulatory Activities (MedDRA) coding dictionary. 
Unless otherwise specified, at each level (e.g., system organ class and/or preferred term) of subject 
summarization in reporting the incidence of the AE, a subject is counted once if one or more events 
were recorded.  For summarizing new onset events, all event records of the same preferred term 
from the same subject are to be linked by the onset date and the end date. If an event is followed 
by another event of the same preferred term with an onset date (or date/time) the same as or 1 day 
(or 1 minute if applicable) after the end date (or date/time) of the previous record and any features 
of the adverse event (i.e.: toxicity grades/seriousness/action taken) are different between these two 
records, these 2 records should be linked together and considered as 1 event.
All summaries of AEs will be based on treatment-emergent adverse events (TEAEs).  TEAEs are 
defined as any AE that occurs after start of the first study treatment through 30 days after the last 
study treatment; or the day prior to start of subsequent anticancer therapy, whichever is earlier; or 
any AE that is considered drug-related (very likely, probably, or possibly related) regardless of the 
start date of the event; or any AE that is present at baseline but worsens in toxicity grade or is 
subsequently considered drug-related by the investigator.  
The incidence of TEAEs will be summarized overall, by MedDRA system organ class (SOC) and 
preferred term, by toxicity grade, and by relationship to study treatment administration. No toxicity 
grade or AE relationship will be imputed when missing. Specifically, the following AE summaries 
will be presented by treatment group:
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6.1.1.
Overview of TEAEs 
An overview of TEAEs reported through the study will be provided for each treatment group.  The 
overview will include summaries of subjects with TEAEs, TEAEs related to study treatment, 
TEAEs of maximum toxicity grade of 1 to 5, SAEs, TEAEs leading to discontinuation of any study 
treatment. 
A similar overview of TEAEs (new onsets) will be presented by treatment cycle.
6.1.2.
All TEAEs 

Incidence of TEAEs by MedDRA SOC and preferred term 

Most commonly reported (>10%) TEAE by MedDRA SOC and preferred term

Most commonly reported (>10%) TEAE by MedDRA preferred term
A similar summary of incidence of TEAEs by MedDRA SOC and preferred term will be presented 
by treatment cycle.
6.1.3.
Toxicity Grade 3 or 4 TEAEs

Incidence of toxicity grade 3 or 4 TEAEs, by MedDRA SOC and preferred term 

List of subjects with any toxicity grade 3 or 4 TEAEs 

Most commonly reported (>5%) grade 3 or 4 TEAE by MedDRA SOC and preferred term

Most commonly reported (>5%) grade 3 or 4 TEAE by MedDRA preferred term
A similar summary of incidence of toxicity grade 3 or 4 will be presented by treatment cycle.
6.1.4.
Study Treatment-Related TEAEs  

Incidence of TEAEs considered by the investigator to be related to study treatment, by 
MedDRA SOC, preferred term and relationship to study treatment 

Incidence of TEAEs with toxicity grade 3 or 4 considered by the investigator to be related 
to study treatment, by MedDRA SOC and preferred term and relationship to study 
treatment
6.1.5.
Serious Adverse Events (SAEs) 

Incidence of treatment-emergent SAEs, by MedDRA SOC and preferred term

Incidence of treatment-emergent SAEs considered by the investigator to be related to study 
treatment, by MedDRA SOC, preferred term and relationship to treatment

List of subjects with any treatment-emergent SAEs
A similar summary will be presented by treatment cycle.
6.1.6.
TEAEs Leading to Cycle Delays or Dose Modifications 
Incidence of TEAEs leading to treatment cycle delays or dose modifications will be summarized 
by MedDRA SOC and preferred term. The summaries will be presented by all grades and grade 3 
or 4 for each treatment. This table will include TEAEs leading to cycle delays or at least 1 of study 
treatments dose modifications, the dose modifications include dose delays, dose skipping, or dose 
reduction (applicable to cyclophosphamide, bortezomib and dexamethasone). 
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6.1.7.
TEAEs Leading to Discontinuation of Any Study Treatment
A summary of number of subjects who discontinued any study treatment because of 1 or more 
TEAEs by MedDRA system-organ class and preferred term will be provided. The summaries will 
be presented by all grades and grade 3 or 4 for each treatment group. The AEs leading to 
discontinuation of any study treatment are based on AEs recorded in the AE CRF page with an 
action taken of drug withdrawal for any study treatment.
A list of subjects who discontinued any study treatment will be provided.
6.1.8.
TEAEs Leading to Discontinuation of Study Treatment
A summary of number of subjects who discontinued study treatment because of 1 or more TEAEs 
by MedDRA system-organ class and preferred Term will be provided. The summaries will be 
presented by all grades and grade 3 or 4 for each treatment group. This table includes AEs leading 
to discontinuation of all study treatment for those subjects indicated as having discontinued study 
treatment due to an adverse event on the end of treatment CRF page.
6.2.
Deaths
6.2.1.
All Deaths
A summary of all deaths and cause of death will be tabulated overall and by treatment group. 
Specifically, the number of subjects who died during the study will be summarized for the ITT 
population. The primary cause of death collected on CRF page will be reported. If the primary 
cause of death reported is a TEAE, the number of subjects who have a treatment related AE and 
unrelated AE will be further reported. Similar summaries will be presented for subjects who died 
within 30 days of last study treatment dose and within 60 days of first study treatment dose, 
respectively. 
A listing of subjects who died during the study will be provided.
6.2.2.
Death Due to TEAEs
The number of subjects who died due to treatment-emergent adverse events will be summarized 
by preferred term and relationship to study treatment for each treatment group. The TEAEs 
included in this table are AEs with outcome death or toxicity grade 5 recorded in the AE CRF 
page. 
A listing of subjects who died due to treatment-emergent adverse events will be provided.  
6.3.
Adverse Events of Clinical Interest
6.3.1.
Infusion-Related Reactions (IRR)
Subjects with any IRR associated with daratumumab administration will be summarized by 
MedDRA system-organ class and preferred term. The summaries will be presented by all grades, 
grade 3, 4, and 5. In addition, the total number of subjects with IRR in more than 1 infusion will 
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be reported. Additionally, the timing of IRR associated with daratumumab administration will be 
evaluated through a summary of IRR by event onset time.  
A listing of subjects with grade 3 or higher treatment-emergent infusion-related reactions 
associated with daratumumab administration will be provided. In addition, subjects with 
treatment-emergent infusion-related reactions results in discontinuation of daratumumab will be 
listed.  
6.3.2.
Local Injection Site Reactions (LISR)
Subjects with any local injection site reaction associated with daratumumab administration will be 
summarized by MedDRA system-organ class and preferred term. The summaries will be presented 
by all grades, grade 3, 4, and 5. In addition, the total number of subjects with IRSR in more than 
1 infusion will be reported. Additionally, the timing of IRSR associated with daratumumab 
administration will be evaluated through a summary of IRSR by event onset time.  
A listing of subjects with grade 3 or higher treatment-emergent IRSR associated with 
daratumumab administration will be provided. In addition, subjects with treatment-emergent IRSR 
resulting in discontinuation of daratumumab will be listed.
6.3.3.
Infections and Infestations
Infections and infestations refer to adverse events with Body System/Organ Class of infections 
and infestations. A summary of number of subjects with 1 or more toxicity grade 3 or 4 
treatment-emergent infections and infestations by MedDRA preferred term and relationship to 
treatment will be provided. In addition, incidences of grade 3 or 4 treatment-emergent infections 
and infestation will be summarized by MedDRA preferred term and treatment cycle.
Time to first onset of infections/infestations event may be explored. 
6.3.4.
Herpes Zoster Reactivation
The incidence of all and grade 3 or 4 herpes zoster reactivation events will be presented by 
MedDRA higher level term and preferred term for each treatment group. 
6.3.5.
Hepatitis B Virus Reactivation 
Reactivation of hepatitis B refers to the abrupt increase in hepatitis B virus (HBV) replication in a 
subject with inactive or resolved hepatitis B. The number of subjects with HBV history and 
incidence of HBV reaction events will be descriptive summarized, if applicable. 
A list of subjects with HBs (HB virus core antibody, HB virus surface antibody, HB virus surface 
antigen, and HBV viral load) test will be provided for safety population.
6.3.6.
Peripheral Neuropathies
Peripheral neuropathies (PNs) refer to adverse events with high level term (HLT) of peripheral 
neuropathies NEC. Incidences of PNs will be summarized by MedDRA high level term and 
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preferred term. The summaries will be presented by all grades and grade 3 or 4 for each treatment 
group.
6.3.7.
Cardiac Disorders
Incidences of all grades and grade 3 or 4 treatment-emergent cardiac disorders by MedDRA high 
level term and preferred term will be provided for each treatment group. Cardiac disorders refer to 
adverse events with Body System/Organ Class of cardiac disorders. 
6.3.8.
Renal and Urinary Disorders
Incidences of all grades and grade 3 or 4 treatment-emergent renal and urinary disorders by 
MedDRA high level term and preferred term will be provided for each treatment group. Renal and 
urinary disorders refer to adverse events with Body System/Organ Class of renal and urinary 
disorders.
6.3.9.
Hepatobiliary Disorders
Incidences of all grades and grade 3 or 4 treatment-emergent hepatobiliary disorders by MedDRA 
high level term and preferred term will be provided for each treatment group. Hepatobiliary 
disorders refer to adverse events with Body System/Organ Class of hepatobiliary disorders.
6.3.10.
Hemorrhage Events
Hemorrhage events refer to the adverse events defined by Standardized MedDRA Queries (SMQ) 
with the first subcategory SMQ of hemorrhage terms (exclude laboratory terms). Incidences will
be summarized by MedDRA system-organ class and preferred term. The summaries will be 
presented by all grades and maximum toxicity grade for each treatment group.
6.3.11.
Second Primary Malignancies
A listing of subjects who reported second primary malignancies during the study will be provided. 
This listing will include diagnosis, study day of diagnosis, recurrence of a prior existing 
malignancy (yes, no) and pathology diagnosis (biopsy, aspirate etc.) etc. information whenever a 
second primary malignancy is observed. In addition, cumulative study treatment exposure, and 
whether subjects received subsequent anticancer therapy (yes, no) information will also be 
presented in the listing.   
6.4.
Adverse Events by Subgroups
The following subgroup analysis of adverse events will be performed based on subgroups specified 
in Section 2.12.

Overview of TEAEs

All TEAEs

Toxicity grade 3 or 4 TEAEs

SAEs  
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6.5.
Clinical Laboratory Tests
Descriptive statistics (mean, standard deviation, median, range) will be used to summarize 
observed laboratory values and change from baseline in observed value at each scheduled visit for 
each treatment group. Line plot of mean with standard error for each laboratory analyte over time 
will be displayed by treatment group. The laboratory analyte to be analyzed includes:

Hematology panel: hemoglobin, WBC, platelet count, neutrophils and lymphocytes

Chemistry panel: sodium, potassium, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, alkaline phosphatase, and creatinine

Cardiac biomarker: NT-proBNP, troponin and high sensitivity troponin
The worst toxicity grade in hematology and chemistry during the treatment will be summarized by 
treatment group and toxicity grade. Shift tables from baseline to worst toxicity grade during the 
treatment will be provided for each laboratory analyte listed above. These tables will summarize 
the number of subjects with each baseline CTC grade and changes to the maximum CTC grade.  
6.6.
Vital Signs and Physical Examination Findings
Temperature and blood pressure measurements at each scheduled treatment administration day
will be summarized by descriptive statistics. In addition, change from baseline in each vital sign 
will be summarized at each measured visit.
Similar analyses will be performed for weight at each scheduled treatment administration day. 
Post-baseline physical examination findings were collected as AEs, and therefore will not be 
summarized.
6.7.
Transthoracic Echocardiogram (TTE) or Other Assessment of Cardiac 
Function
Echocardiogram will be performed at screening visit, Cycle 7 Day 1 and when clinically indicated, 
and the End-of-Treatment (if before Cycle 7 Day 1) visit. Any changes from baseline TTE 
measurements (specifically, changes in LVEF and changes in diastolic function) will be 
summarized by treatment group. Descriptive statistics will be calculated for observed values at 
baseline and change from baseline at each scheduled time point.
6.8.
Electrocardiogram
Electrocardiogram will be collected at screening visit and the End-of-Treatment visit.
The number and percentage of subjects with normal or abnormal (clinically significant or clinically 
insignificant) 12-lead ECG results will be summarized.  
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6.9.
Other Safety Parameters
6.9.1.
ECOG Performance Score
ECOG performance status, which evaluates the effect of the disease status on the activities of daily
living, will be assessed. Descriptive statistics will be used to summarize ECOG performance status 
at each measured visit for each treatment group. Meanwhile, shift table from baseline to each post 
baseline visit and to worst ECOG performance score will be provided.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
Unless specified otherwise, descriptive statistics (e.g., number of observations, mean, standard 
deviation, median, and range) will be used to summarize pharmacokinetics and pharmacodynamics 
data. In addition, coefficient variation and geometric mean will be provided in the pharmacokinetic 
concentration summary. 
7.1.
Pharmacokinetics
7.1.1.
Sampling Timepoints 
For subjects assigned to Dara SC+CyBorD, blood samples to assess serum concentration 
(pharmacokinetics) of daratumumab will be obtained at Cycle 1 Day 1, Day 4 (± 1 day), Day 8, 
Cycle 2 Day 1, Cycle 3 Day 1, Day 4 (±1 day), Cycle 7 Day 1, Cycle 12 Day 1, End-of-Treatment 
(Post-Treatment Week 4) and Post-Treatment Week 8. On a daratumumab dosing day, blood 
samples need to be collected before (up to 2 hours but not after the start of infusion) and 
immediately after (up to 2 hours but not before the end of infusion) daratumumab administration.
7.1.2.
Pharmacokinetic Parameters
The pharmacokinetic parameters are defined as: 

Minimum observed concentration (Cmin) - the concentration observed immediately before 
infusion.

Maximum observed concentration (Cmax) – the concentration observed after the end of 
infusion 
For daratumumab, the pharmacokinetic evaluations include Cmin and Cmax.  If sufficient data are 
available, then other pharmacokinetic parameters may be calculated.
7.1.3.
Analysis Methods
Pharmacokinetic analyses will be performed on the pharmacokinetic-evaluable population. All 
serum concentrations below the lowest quantifiable concentration or missing data will be labeled 
as such in the concentration data presentation. Concentrations below the lowest quantifiable 
concentration will be treated as zero in the summary statistics. All subjects and samples excluded 
from the analysis will be clearly documented in the study report.
Descriptive statistics will be used to summarize daratumumab serum concentrations at each 
sampling time point specified in Section 7.1.1. Line plot of mean (±SD) daratumumab serum 
concentrations over time will be provided.
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The Cmax and Cmin will be determined based on visual inspection of the serum concentration data. 
If sufficient data are available, population pharmacokinetic analysis of serum concentration-time 
data of daratumumab may be performed using nonlinear mixed-effects modeling. If population 
pharmacokinetic analysis is conducted, it may include data from other clinical studies; details will 
be provided in a population pharmacokinetic analysis plan and results will be presented in a 
separate report.
7.2.
Immunogenicity 
7.2.1.
Sampling Timepoints
Samples to assess the generation of antibodies to daratumumab (immunogenicity)/ rHuPh20 will 
be obtained from all subjects in the Dara SC+CyBorD arm at Day 1 predose of Cycle 1, 2, 3, 7 12, 
End-of-Treatment (Post-Treatment Week 4) and 8 weeks after last dose of dara (Post-Treatment 
Week 8). When an IRR occurs associated with the second daratumumab administration or beyond, 
2 separate blood samples should be obtained, if possible, for determination of antibodies to 
daratumumab and antibodies to rHuPH20. No unscheduled samples need to be collected for 
infusion reactions associated with the first infusion of daratumumab.
7.2.2.
Analysis Methods
The incidence of antibodies to daratumumab (immunogenicity)/ rHuPh20 will be summarized for 
all subjects who receive a dose of daratumumab and have appropriate samples for detection of 
antibodies to daratumumab/ rHuPh20. In addition, subjects who are positive for antibodies to 
daratumumab/ rHuPh20 will also be listed.
7.3.
Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, other pharmacokinetic/pharmacodynamic modeling may be 
performed, including exploring the relationship between serum concentrations of daratumumab 
and endpoints of clinical efficacy. If analysis is conducted, details and results of the analysis will 
be presented in a separate report.
8.
BIOMARKER 
Biomarker studies are designed to identify markers predictive of response (or resistance) to 
daratumumab. Planned analyses are based on the availability of clinically valid assays and may be 
deferred if emerging study data show no likelihood of providing useful scientific information. 
Results of biomarker analyses may be presented in a separate report.
Biomarker evaluations in this study will focus on the evaluation of CD38 expression by IHC on 
the malignant plasma cells from core diagnostic biopsies to determine if CD38 expression 
correlates with response to daratumumab. Bone marrow aspirate will also be obtained to evaluate 
minimal residual disease (MRD). Minimal residual disease may be monitored in subjects who 
achieve CHR using next generation sequencing (NGS) or similar technologies which utilize 
malignant plasma cell DNA from bone marrow aspirates.
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As MRD was an exploratory objective without a mandatory sample collected, the MRD analysis 
will be based on MRD evaluable subset, which is defined as subjects who have both baseline and 
post-baseline MRD (with negative, positive or indeterminate result) samples taken.
Descriptive statistics for values and changes from baseline at each scheduled visit for PD 
biomarkers such as T cells, CD38+ MDSCs and Tregs will be provided. Box plots of T cells, 
CD38+ MDSCs and Tregs over time will be presented. 
Exploratory analysis may be conducted to explore minimal residual disease status in AL 
amyloidosis patients as a surrogate for PFS and OS or as a biomarker for relapse.
9.
PHARMACOGENOMIC ANALYSES
Bone marrow aspirate from subjects in both treatment groups will be used for pharmacogenomic 
evaluation to allow the identification of genetic factors that may influence the pharmacodynamics, 
efficacy, safety, or tolerability of daratumumab.
Pharmacogenomic analysis results will be presented in a separate report.
10.
MEDICAL RESOURCE UTILIZATION 
Medical resource utilization will be descriptively summarized by treatment group. Frequencies of 
hospitalization, outpatient visits, type of hospitalization or outpatient visit, reasons for 
hospitalization or outpatient visit, durations of hospitalization or outpatient visit, types of adverse 
events if involved, blood product transfusions, antibiotic use, and other concomitant medication 
will be calculated and tabulated.  
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REFERENCES
1.
Tang DI, Geller NL. Closed testing procedures for group sequential clinical trials with multiple endpoints. 
Biometrics. 1999;55(4):1188-1192.
2.
Comenzo RL, Reece D, Palladini G, et al. Consensus guidelines for the conduct and reporting of clinical trials 
in systemic light-chain amyloidosis. Leukemia 2012; 26:2317-2325.
3.
Palladini G, Hegenbart, Ute, et al. A staging system for renal outcome and early markers of renal response to 
chemotherapy in AL amyloidosis. Blood 2014; Volume 124: 2325-2332.
4.
Palladini G, Sachchithananthan S, Milani P, et al. A European collaborative study of cyclophosphamide, 
bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood 
2015;126(5):612-615.
5.
Wechalekar A, Gillmore JD, Foard D, Rannigan L, et al. Evaluation of an early switch to second line 
chemotherapy in AL amyloidosis among patients who fail to achieve a very good partial response to frontline 
treatment. 13th International Symposium on Amyloidosis, Groningen, Netherlands 2012; p70. 
http://www.amyloid.nl/Files/Abstract_Book_ISA_2012.pdf.
6.
Manwani R et al. Achieving a difference in involved and uninvolved light Chains (dFLC) of less than 10mg/L 
is the new goal of therapy in systemic AL Amyloidosis: analysis of 916 patients treated upfront with 
Bortezomib-based therapy. Blood 2018; 132 (suppl) 3262; 
7.
Muchtar E et al. Optimizing deep response assessment for AL amyloidosis using involved free light chain level 
at end of therapy: failure of the serum free light chain ratio. Leukemia 2019; 33; 527-531.
8.
Eli Muchtar et al. Depth of organ response in AL amyloidosis is associated with improved survival: grading 
the organ response criteria. Leukemia 2018; 32: 2240-2249
9.
ICH E9 (R1) addendum on estimands and sensitivity 5 analysis in clinical trials to the guideline on statistical 
principles for clinical trials. 30 August 2017, EMA/CHMP/ICH/436221/2017 Committee for Human 
Medicinal Products
10.
Surbhi Sidana, Angela Dispenzieri, et al. Revisiting complete response in light chain amyloidosis. Leukemia 
26 November 2019.
11.
James M. Robins and Dianne M. Finkelstein. Correcting for Noncompliance and Dependent Censoring in an 
AIDS Clinical Trial with Inverse Probability of CensoringWeighted (IPCW) Log-Rank Tests. September 2000, 
Biometrics 56, 779-788
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ATTACHMENT 2:
GUIDELINES FOR SUBSEQUENT THERAPY
Guidelines for Subsequent Therapy
Response after 
six cycles of initial therapy
Action taken
Hematologic Response (PR or better) with 
stable/improved major organ function
Observation or daratumumab monotherapy 
until disease progression
Hematologic Response (PR or better) with 
worsening major organ function
Subsequent therapy may be considered
Hematologic Non-Response or disease 
progression with stable/improved organ 
function 
Subsequent therapy may be considered
Hematologic Non-Response or disease 
progression with worsening organ function
Subsequent therapy recommended
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ATTACHMENT 3:
COUNTRIES THAT TYPICALLY OFFER STEM CELL
TRANSPLANT: LIST A OR LIST B
List A (Patients typically offered transplant) 
Australia 
Brazil 
Canada 
Germany 
Hungary 
Italy 
Japan 
The Netherlands
Poland
Romania
S. Korea
Spain
Sweden
Turkey
UK
US
List B (Patients Not typically offered transplant)
Belgium
China
Denmark
France
Greece
Israel
Mexico
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ATTACHMENT 4:
INDEPENDENT REVIEW COMMITTEE
Independent Review Committee
The independent review committee (IRC) will be composed of three physicians with expertise and 
clinical experience in the diagnosis and management of AL Amyloidosis. However, they will not 
have direct involvement in the conduct of the study. The IRC members will perform an 
independent review of data from all randomized subjects. The primary purpose of the IRC review 
will be to provide an independent determination of PD (hematologic and organ progression, 
respectively) and response (hematologic and organ response, respectively) and ensure consistent 
evaluation of PD and response for all subjects in this study.
The review performed by the IRC will be independent of the investigator’s disease response 
assessments performed during the study. The IRC will not be provided with the identification of 
the study site, or treatment group. The three IRC members will be given a subject profile that 
includes hematologic and organ (cardiac, renal and liver) information, and a worksheet to 
determine and record the development of PD as well as response per visit date, confirmed 
hematologic response, confirmed organ response for each organ. In addition, the reason for 
development of PD will be recorded. 
For each subject, the overall IRC-assessed response and PD and corresponding time at each disease 
evaluation will be determined based on a majority (2/3) quorum. For response at a disease 
evaluation that IRC has a different assessment, every effort will be taken to resolve any difference
among 3 IRC members, and ensure at least 2 IRC members to have the same response evaluation. 
if there is no resolution, the IRC chair will decide.
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ATTACHMENT 5:
ADDITIONAL EXPLORATORY ANALYSIS TO SUPPORT 
HEMAR
1.
DEFINITION OF SUBGROUPS
Subgroup analyses will be performed using the criteria listed below to determine whether the 
treatment effect is consistent among subgroups. Analyses will be conducted for the ITT population 
and for the following subgroups:

For subjects who received transplant as subsequent therapy

For subjects who achieve CRR

For subjects who achieve RRR

For subjects who achieve LRR

For subjects who reached CHR as their best response

For subjects who reached VGPR as their best response

For subjects who had baseline ECOG of 1

For subjects who had baseline ECOG of 2

For subjects who achieved MRD negativity (10-4, 10-5 and 10-6)
Subgroup analyses will be performed if data warrants.
2.
TIME-TO-EVENT ENDPOINTS FOR SUBGROUP ANALYZES
Kaplan-Meier estimates will be used to estimate distribution of time to event by treatment group
based on all ITT population. Data will be calculated and summarized with descriptive statistics. 
The following time-to-event endpoints will be analyzed by pre-defined subgroups as defined in 
section 2.12 and in section 1 above:

MOD-PFS

HemPFS

OS
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2.1.
Subgroup Analysis by Center for CHR Rate, MOD-PFS, HemPFS, OS and 
EQ-5D and EORTC QLQ C30
3.
EXPOSURE ADJUSTED INCIDENCE RATES (EAIR)
3.1.
Restriction on the first event
The analysis restricts on the occurrence of the first event per patient and ignores the existence of 
later (multiple) events as these cannot be assumed to occur independent of previous events 
(e.g.: patients suffering from infections may have in general a higher risk of having other 
complications and may even have a higher risk of getting other infections). The occurrence of 
multiple events is subject to another analysis considering the absolute number of adverse events 
per patient.
For these reasons the EAIR should be interpreted as 'rate until the first event occurs'. Rates 
estimated from several patients can be averaged on the level of a preferred term (PT), of a system 
organ class (SOC), or on a global level (see below).
The interpretation of EAIRs is simple and consistent on the preferred-term level only, and can be 
expressed as "Average number of TEAEs per preferred-term emerging per person-month of 
exposure". 
The aforementioned considerations apply in the same way to EAIRs estimated on the global level: 
when EAIRs are collapsed into the global estimate (first analyses), the estimate can be interpreted 
as the "Average number of TEAEs emerging per person-month and PT", because estimation has 
been performed on a 'per PT'-basis (per average or typical PT among all PTs).
Comparing EAIRs on the level of the SOC or on the global level involves data destruction because 
a patient's information is reduced to the first TEAE only (and possibly to a TEAE of marginal 
relevance among many TEAEs with higher clinical relevance).
The EAIR analysis focuses on the 'speed' by which TEAEs emerge. The analysis restricts on the 
first event of a patient because independence of TEAEs cannot be assumed. The necessity to 
restrict on the first event entails considerable data destruction when deriving SOC-specific EAIRs 
or the EAIR on a global level. To overcome this, the 'per PT'-analysis, which is reported in both 
Tables identically, is preferable. 
Comparing EAIRs between the analyses outlined below on a SOC-specific or a global level 
demonstrates that the 'per PT'- method makes the interpretation of results more difficult.  However, 
it can be suggested that this method provides a more robust approach when the two treatment 
groups are to be compared on a SOC-specific or global level. A t-Test like comparison of PT-
specific estimates between the two treatment groups may provide a more robust, comprehensive 
and easy-to-communicate way of visualizing and comparing results.
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3.2.
Duration of exposure: censored & non-censored
The incidence rate for a patient is derived from the duration of exposure to treatment of that patient. 
When averaging incidence rates, a patient's duration of exposure is given either A) by the time 
when the event has occurred (non-censored data), or B) by the total duration of treatment in case 
the patient does not show the adverse event in question (censored data). Depending on whether a 
patient has an adverse event or not, the duration of exposure enters the denominator in its 
non-censored or censored form, respectively. 
3.3.
Incidence rate per patient
The incidence rate for a specific event of a patient i is the reciprocal of time t when the first event 
occurs:
 =

 .
3.4.
Average EAIR
The EAIR averaged over all patients is
 =
∑



∑



,
whereby 
a) a TEAE enters the sum in the nominator unweighted (TEAEi =1, otherwise TEAEi =0), and
b) the duration of exposure enters the denominator as described before:  =
    if occurring (non-censored data)
,- ./0,1  0,1 if no event occurs (censored data) .
3.5.
EAIRs on the level of a SOC and on the global level on a ‘per-PT’ basis
3.5.1.
Average EAIR per PT
The EAIR for a specific PT is an average over all patients, i.e.
3 =
∑
45,


∑
45,


, 
whereby the number of TEAEs and durations of exposure enter the nominator and the 
denominator.
3.5.2.
Average EAIR per SOC
The average EAIR per SOC considers the first event of each patient within the SOC.  The 
denominator includes the exposure time of each adverse event of all PTs within the SOC, per 
patient, i.e.
789 = ∑
789, ∑

45,
: 3; <=> 789
3?
:
?
, 
where TEAESOC,i is the first event per patient per SOC and tPT,i is the exposure time for a specific 
preferred term of a given patient. 
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Note: This EAIR is an incidence rate per average (or typical) preferred term in that SOC (cf. 3.6.1). 
3.5.3.
Average EAIR on a global level
The average EAIR on a global level only considers the first event per patient across all events.  The 
denominator includes the exposure times of all PTs, i.e.
@ABCDA = ∑
 ∑

45,
: 3;
3?
:
?
, 
where TEAEi is the first event of a patient overall and the tPT,i‘s are PT-specific exposure times of 
that patient.
Note: This EAIR is an incidence rate per average (or typical) preferred term. 
3.6.
Second analyses
3.6.1.
Average EAIR per PT
The EAIR for a specific PT is an average over all patients as described before, i.e.
3 =
∑
45,


∑
45,


, 
whereby the number of TEAEs and durations of exposure enter the nominator and the 
denominator.
3.6.2.
Average EAIR per SOC
The average EAIR per SOC considers the first event per patient per SOC only, and only one (the 
corresponding) exposure time in the denominator (confer before, where the denominator in the 
EAIRSOC depends on the number of PTs per SOC):
789 =
∑
EFG,


∑
EFG,


, 
Note: This EAIR is an incidence rate per SOC. 
3.6.3.
Average EAIR on a global level
The average EAIR on a global level considers the overall first event per patient only, and only one 
(the corresponding) exposure time in the denominator (confer before, where the denominator in 
the EAIRSOC depends on the overall number of PTs):
@ABCDA =
∑



∑



, 
whereby TEAEi represents the first TEAE among all TEAEs of patient i and ti as before (time when 
TEAE occurs (non-censored data) or total duration of treatment if no event occurs (censored data))
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4.
ADDITIONAL TIME TO EVENT ANALYSES
In case of different exposure times, time adjustment for AE is necessary. Hazard Ratio and 
Kaplan-Meier curves will be conducted including number of patients at risk for the following 
safety endpoints: 

Any TEAE 

Any Serious TEAE

Any TEAE leading to death

Any Grade 3 or 4 TEAE

Any Grade 3 or higher TEAE

Any TEAE leading to treatment discontinuation
Detailed description by preferred term:

TEAEs by preferred term with prevalence>=10%/

Grade 3 or 4 TEAEs preferred term with prevalence>=5%

Grade 3 or higher TEAEs by preferred term prevalence>=5%

Serious TEAEs preferred term with prevalence>=2%

TEAEs leading to treatment discontinuation preferred term with prevalence>=1%

TEAE leading to death preferred term without prevalence cut-off
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