Clinical trial NCT03836053
Conditions: Relapsed and/or Refractory Multiple Myeloma
Sponsor: Amgen
Start date: 2019-03-04; Completion date: 2022-04-21
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To confirm the maximum tolerated dose (MTD) from the BI 836909 trial of 400 mcg/d, given as 28-day continuous intravenous infusion in patients with relapsed and/or refractory multiple myeloma, to test the 600 mcg/d dose, given as a 28-day continuous iV infusion.

Detailed description:
Cohort 1 will consist of 10 subjects dosed at 400 mcg/d. Cohort 2 will consist of 10 subjects dosed at 600 mcg/d. All doses will be given as a 28-day continuous IV infusion, followed by a 2 week treatment-free interval, until subject experiences disease progression as per International Myeloma Working Group (IMWG) criteria.

Arms: arm 1: Single Arm Design
Interventions: intervention 1: AMG 420
Intervention descriptions: intervention 1: 28 day continuous Intravenous infusion of either 400 mcg/d or 600 mcg/d followed by 2 treatment free weeks

Protocol documents:
Prot_000.pdf: 
Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 1 of 169 
CONFIDENTIAL 
 
 
Title Page 
Protocol Title: 
A Phase 1b Multicenter, Open-label, Expansion Study 
to Assess the Safety and Efficacy of AMG 420 in 
Subjects With Relapsed and/or Refractory Multiple 
Myeloma 
Short Protocol Title: 
A Phase 1b Study to Assess AMG 420 in Subjects 
with Relapsed and/or Refractory Multiple Myeloma 
Protocol Number: 
20160370 
Investigational Product: 
AMG 420 
Trade Name 
Not applicable 
Sponsor 
Name of Sponsor: 
Amgen Inc 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320  
Telephone Number: 
+1 (805) 447 1000 
Key 
Sponsor 
Contact 
Name: 
 PhD 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320  
Telephone Number: 
Email Address: 
 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number: 
Email Address: 
 
EudraCT Number: 
2018‐002879‐17 
NCT Number: 
NCT03836053 
Protocol Date: 
Document Version 
Date 
Original 
15 August 2018 
Amendment 1 
11 October 2018 
Amendment 2 
12 December 2018 
Amendment 3 
22 May 2019 
Amendment 4 
20 May 2020 
Amendment 5 
17 September 2021 
Version/Date: 
Data Element Standards Version 
6.1 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures. 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 2 of 169 
CONFIDENTIAL 
 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 3 of 169 
CONFIDENTIAL 
 
 
Investigator’s Agreement: 
I have read the attached protocol amendment entitled A Phase 1b Multicenter, 
Open-label, Expansion Study to Assess the Safety and Efficacy of AMG 420 in Subjects 
With Relapsed and/or Refractory Multiple Myeloma,dated 17 September 2021, and 
agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by:  me 
(including, if applicable, my spouse or legal partner and dependent children) and my 
subinvestigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
_______________________________ 
Signature 
_______________________________ 
____________________________ 
Name of Investigator  
 
 
Date (DD Month YYYY) 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
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CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Synopsis ................................................................................................. 10 
2. 
Study Schema and Schedule of Activities ............................................................. 17 
2.1 
Study Schema ........................................................................................... 17 
2.2 
Schedule of Activities ................................................................................ 18 
3. 
Introduction ........................................................................................................... 28 
3.1 
Study Rationale ......................................................................................... 28 
3.1.1 
Target Rationale ........................................................................ 28 
3.1.2 
Target Population Rationale ...................................................... 29 
3.2 
Background ............................................................................................... 29 
3.2.1 
Disease ..................................................................................... 29 
3.2.2 
Amgen Investigational Product Background:  
AMG 420 ................................................................................... 31 
3.2.2.1 
Nonclinical Pharmacology ....................................... 32 
3.2.2.2 
Pharmacokinetics .................................................... 34 
3.2.2.3 
Toxicology ............................................................... 35 
3.2.2.4 
Clinical Experience With Other BiTE® 
Antibody Constructs and AMG 420 ......................... 37 
3.3 
Benefit/Risk Assessment ........................................................................... 39 
3.3.1 
Therapeutic Context .................................................................. 40 
3.3.2 
Key Benefits .............................................................................. 40 
3.3.3 
Key Risks  ................................................................................. 40 
3.3.3.1 
Risks ....................................................................... 41 
4. 
Objectives, Endpoints and Hypotheses ................................................................. 42 
4.1 
Objectives and Endpoints .......................................................................... 42 
4.2 
Hypotheses ............................................................................................... 45 
5. 
Study Design ........................................................................................................ 45 
5.1 
Overall Design .......................................................................................... 45 
5.1.1 
Phase 1b (Monotherapy Dose Confirmation) ............................. 45 
5.2 
Number of Subjects ................................................................................... 46 
5.2.1 
Replacement of Subjects ........................................................... 47 
5.2.2 
Number of Sites ......................................................................... 47 
5.3 
End of Study ............................................................................................. 47 
5.3.1 
End of Study Definition .............................................................. 47 
5.3.2 
Study Duration for Subjects ....................................................... 47 
5.4 
Justification for Investigational Product Dose (AMG 420) .......................... 48 
5.5 
Patient Input on Study Design ................................................................... 48 
6. 
Study Population .................................................................................................. 48 
6.1 
Inclusion Criteria ....................................................................................... 48 


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CONFIDENTIAL 
 
 
6.2 
Exclusion Criteria ...................................................................................... 49 
6.3 
Subject Enrollment .................................................................................... 52 
6.4 
Screen Failures ......................................................................................... 53 
7. 
Treatments ........................................................................................................... 54 
7.1 
Treatment Procedures............................................................................... 54 
7.1.1 
Investigational Product:  AMG 420 ............................................ 54 
7.1.1.1 
AMG 420 Dosage Formulation ................................ 54 
7.1.1.2 
AMG 420 Dosage, Administration, and 
Schedule ................................................................. 54 
7.1.1.3 
MRD-based Extended Treatment-free 
Interval .................................................................... 55 
7.1.1.4 
Dosing Instructions .................................................. 55 
7.1.1.5 
Drug Accountability ................................................. 58 
7.1.2 
Non-investigational Products ..................................................... 58 
7.1.3 
Medical Devices ........................................................................ 58 
7.1.4 
Other Protocol-required Therapies ............................................ 58 
7.1.4.1 
Glucocorticoid Premedication .................................. 58 
7.1.4.2 
CRS Treatment ....................................................... 59 
7.1.5 
Other Treatment Procedures ..................................................... 59 
7.1.6 
Product Complaints ................................................................... 59 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 60 
7.1.8 
Vaccines .................................................................................... 60 
7.2 
Method of Treatment Assignment ............................................................. 60 
7.3 
Blinding ..................................................................................................... 60 
7.4 
Dose Modification ...................................................................................... 61 
7.4.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 61 
7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 62 
7.4.2.1 
Amgen Investigational Product:  AMG 420 .............. 62 
7.4.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 79 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 79 
7.6 
Treatment Compliance .............................................................................. 79 
7.7 
Treatment of Overdose ............................................................................. 79 
7.8 
Prior and Concomitant Treatment ............................................................. 80 
7.8.1 
Prior Treatment ......................................................................... 80 
7.8.2 
Concomitant Treatment ............................................................. 80 
7.8.2.1 
Supportive Care ...................................................... 81 
7.8.2.2 
Treatment of Myeloma Bone Disease, 
Hypercalcemia, Pain, and Renal Failure.................. 81 
7.8.2.3 
Bone Disease Therapy ............................................ 81 
7.8.2.4 
Intravenous Immunoglobulin Treatment .................. 81 


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7.8.2.5 
Growth Factors ........................................................ 81 
7.8.2.6 
Infections ................................................................. 82 
7.8.2.7 
Tumor Lysis Syndrome ........................................... 82 
8. 
Discontinuation Criteria ......................................................................................... 83 
8.1 
Discontinuation of Study Treatment........................................................... 83 
8.2 
Discontinuation From the Study ................................................................ 84 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 85 
8.2.2 
Reasons for Removal From Study ............................................. 85 
8.3 
Lost to Follow-up ....................................................................................... 85 
9. 
Study Assessments and Procedures .................................................................... 86 
9.1 
General Study Periods .............................................................................. 86 
9.1.1 
Screening, Enrollment and/or Randomization ............................ 86 
9.1.2 
Treatment Period ....................................................................... 87 
9.1.3 
End of Treatment ....................................................................... 88 
9.1.4 
Safety Follow-up ........................................................................ 88 
9.1.5 
Long-term Follow-up .................................................................. 88 
9.1.6 
End of Study .............................................................................. 89 
9.2 
Description of General Study Assessments and Procedures ..................... 89 
9.2.1 
General Assessments ............................................................... 89 
9.2.1.1 
Informed Consent .................................................... 89 
9.2.1.2 
Demographics ......................................................... 89 
9.2.1.3 
Medical History ........................................................ 89 
9.2.1.4 
Physical Examination .............................................. 90 
9.2.1.5 
Physical Measurements .......................................... 90 
9.2.1.6 
Performance Status................................................. 90 
9.2.2 
Efficacy Assessments ................................................................ 90 
9.2.2.1 
Blood and Bone Marrow .......................................... 90 
9.2.2.2 
SPEP, UPEP, and Tumor Assessment.................... 90 
9.2.2.3 
Serum Free Light Chain .......................................... 91 
9.2.2.4 
Quantitative Immunoglobulin ................................... 91 
9.2.2.5 
Beta-2 Microglobulin................................................ 91 
9.2.2.6 
Skeletal Survey/Plasmacytoma 
Assessments ........................................................... 91 
9.2.2.7 
Minimal Residual Disease ....................................... 92 
9.2.3 
Safety Assessments .................................................................. 93 
9.2.3.1 
Adverse Events ....................................................... 93 
9.2.3.2 
Vital Signs ............................................................... 96 
9.2.3.3 
Electrocardiograms (ECGs) ..................................... 96 
9.2.3.4 
Vital Status .............................................................. 97 
9.2.3.5 
Other Safety ............................................................ 97 
9.2.4 
Clinical Laboratory Assessments ............................................... 97 


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9.2.4.1 
Pregnancy Testing .................................................. 98 
 
 ..................... 98 
9.2.5 
Pharmacokinetic Assessments ................................................ 100 
9.2.6 
Pharmacodynamic Assessments ............................................. 100 
 
............................................... 100 
 
 ................................................... 101 
9.2.9 
Biomarker Development .......................................................... 101 
10. 
Statistical Considerations .................................................................................... 102 
10.1 
Sample Size Determination ..................................................................... 102 
10.2 
Analysis Sets, Subgroups, and Covariates .............................................. 102 
10.2.1 
Analysis Sets ........................................................................... 102 
10.2.2 
Covariates ............................................................................... 102 
10.2.3 
Subgroups ............................................................................... 102 
10.2.4 
Handling of Missing and Incomplete Data ................................ 103 
10.3 
Adaptive Design ...................................................................................... 103 
10.4 
Statistical Analyses ................................................................................. 104 
10.4.1 
Planned Analyses .................................................................... 104 
10.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................. 104 
10.4.1.2 
Primary Analysis ................................................... 104 
10.4.1.3 
Final Analysis ........................................................ 104 
10.4.2 
Methods of Analyses ............................................................... 104 
10.4.2.1 
General Considerations ......................................... 104 
10.4.2.2 
Efficacy Analyses .................................................. 105 
10.4.2.3 
Safety Analyses .................................................... 105 
10.4.2.4 
Other Analyses ...................................................... 107 
11. 
References ......................................................................................................... 108 
12. 
Appendices ......................................................................................................... 112 
12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms .................... 113 
12.2 
Appendix 2.  Clinical Laboratory Tests .................................................... 118 
12.3 
Appendix 3.  Study Governance Considerations ..................................... 120 
Committee(s) .......................................................................................... 120 
Regulatory and Ethical Considerations .................................................... 121 
Recruitment Procedures .......................................................................... 122 
Informed Consent Process ...................................................................... 122 
Data Protection/Subject Confidentiality ................................................... 124 
Publication Policy .................................................................................... 124 
Investigator Signatory Obligations ........................................................... 125 
Data Quality Assurance ........................................................................... 125 
Source Documents .................................................................................. 127 
Study and Site Closure............................................................................ 128 


Product:  AMG 420 
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Compensation ......................................................................................... 128 
12.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 129 
Definition of Adverse Event ..................................................................... 129 
Definition of Serious Adverse Event ........................................................ 130 
Recording Adverse Events and Serious Adverse Events ........................ 131 
Evaluating Adverse Events and Serious Adverse Events ........................ 132 
Reporting of Serious Adverse Event ........................................................ 133 
12.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 139 
Definition of Females of Childbearing Potential ....................................... 139 
Collection of Pregnancy Information ........................................................ 141 
Collection of Lactation Information .......................................................... 142 
12.6 
Appendix 6.  Sample Storage and Destruction ........................................ 145 
12.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 147 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other 
Protocol-required Therapies Due to Potential 
Hepatotoxicity.......................................................................... 147 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 148 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 149 
12.8 
Appendix 8.  International Working Group Response Criteria for 
Multiple Myeloma (IMWG-URC) .............................................................. 151 
12.9 
Appendix 9.  Clarification on Eligibility Criteria:  Definition of 
Relapsed or Refractory Disease and Line of Treatment .......................... 154 
12.10 Appendix 10.  Medications That May Cause QTc Prolongation ............... 155 
12.11 Appendix 11.  Schedule of Activities in Case of Requirement for 
Dose Step ............................................................................................... 158 
12.12 Appendix 12.  Cairo-Bishop Clinical Tumor Lysis Syndrome 
Definition and Grading............................................................................. 163 
12.13 Appendix 13.  Performance Status According to Eastern 
Cooperative Oncology Group (ECOG) Scale .......................................... 165 
12.14 Appendix 14.  Protocol-specific Anticipated Serious Adverse 
Events ..................................................................................................... 166 
12.15 Appendix 15.  Peripheral Neuropathy Assessment .................................. 167 
 
List of Tables 
Table 2-1.  Phase 1b Screening and Treatment Cycle 1 (With No Dose Step) .............. 18 
Table 2-2.  Phase 1b Treatment Cycle 2, 3, and Following to End of Study ................... 23 


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Table 3-1.  Key Safety Risks for AMG 420 .................................................................... 41 
Table 5-1.  Rules for Holding Enrollment in Phase 1b .................................................... 46 
Table 7-1.  Infusion Interruptions/Permanent Discontinuations and 
Management of Adverse Events Including Dose Reductions .................. 66 
Table 7-2.  Additional Guidance on Infusion Interruptions/Permanent 
Discontinuations and Management of Adverse Events 
Including Dose Reductions ..................................................................... 70 
Table 7-3.  Grading and Management of Cytokine Release Syndrome.......................... 75 
Table 12-1.  Analyte Listing ......................................................................................... 119 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 148 
Table 12-3.  Medications That May Cause QTc Prolongation ...................................... 155 
Table 12-4.  Phase 1b Screening and Treatment Cycle 1 With Dose Step .................. 158 
Table 12-5.  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome 
(TLS) .................................................................................................... 163 
Table 12-6.  Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and 
Grading................................................................................................. 164 
 
List of Figures 
Figure 2-1.  Study Schema for Monotherapy Dosing ..................................................... 17 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form ..................................................................................................... 134 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet .................................... 143 
 


Product:  AMG 420 
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1. 
Protocol Synopsis 
Protocol Title:  A Phase 1b Multicenter, Open-label, Expansion Study to Assess the 
Safety and Efficacy of AMG 420 in Subjects With Relapsed and/or Refractory Multiple 
Myeloma 
Short Protocol Title:  A Phase 1b Study to Assess AMG 420 in Subjects with Relapsed 
and/or Refractory Multiple Myeloma 
Study Phase:  1b 
Indication:  Relapsed and/or Refractory Multiple Myeloma 
Rationale 
Patients who have relapsed and/or refractory multiple myeloma (RRMM) and are 
refractory to proteasome inhibitors (PIs) and immunomodulatory drugs experience poor 
prognosis despite recent advances in treatment.  AMG 420 is being developed as 
another treatment option by targeting the B-cell maturation antigen (BCMA, TNFRSF17, 
CD269) because of its function in promoting plasma cell survival, highly restricted 
expression in cells of the B-cell lineage, and elevated expression in malignant plasma 
cells.  This study will further establish the safety and tolerability, as well as evaluate the 
efficacy, of AMG 420. 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Phase 1b 
Primary 
 
Establish the safety and tolerability of 
AMG 420 at dose levels of 400 g/day 
and 600 g/day in subjects with 
relapsed and/or refractory multiple 
myeloma (RRMM)   
 
Dose-limiting toxicities (DLTs), 
treatment-emergent adverse events, 
treatment-related adverse events, and 
changes in vital signs, 
electrocardiograms (ECGs), and 
clinical laboratory tests 
Key Secondary 
• 
Estimate overall response rate (ORR) 
and duration of response (DOR) of 
AMG 420 in subjects with RRMM 
 
ORR 
 
DOR 
 
Evaluate the rate of minimal residual 
disease (MRD)-negativity at the time 
of CR 
 
MRD negativity at the time of CR 


Product:  AMG 420 
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Objectives 
Endpoints 
Secondary 
 
Establish the safety and tolerability of 
AMG 420 in subjects with 
extramedullary relapsed multiple 
myeloma 
 
DLTs, treatment-emergent adverse 
events, treatment-related adverse 
events, and changes in vital signs, 
ECGs, and clinical laboratory tests 
 
Characterize the pharmacokinetics 
(PK) of AMG 420 when administered 
as 4-week continuous intravenous 
(cIV) infusion 
 
AMG 420 PK parameters including, 
but not limited to, half-life (t1/2), 
clearance, and apparent Css 
 
Evaluate other measures of 
anti-myeloma activity of AMG 420 in 
subjects with RRMM: 
 
Time to response  
 
Progression-free survival (PFS) 
 
Overall survival (OS) 
 
Best overall response (BOR) 
 
Efficacy parameters according to 
International Myeloma Working Group 
(IMWG) response criteria, per 
investigator assessment: 
 
Time to response  
 
PFS  
 
OS 
 
BOR 
 
Hypotheses 
A safe and tolerable dose of AMG 420 will have evidence of anti-tumor activity in 
patients with RRMM as measured by the rate of overall response. 
The overall response rate (ORR) according to International Myeloma Working Group 
(IMWG) response criteria along with 95% CI will be calculated per investigator 
assessment for subjects with RRMM.  The lower bound of the binomial 2-sided 95% 
confidence interval for ORR not lower than 35% is considered clinically meaningful.   
Overall Design 
This is a phase 1b, multicenter, non-randomized, open-label expansion study.  
AMG 420 will be evaluated in adult subjects with RRMM.   
The study will consist of up to a 21-day screening, a treatment period, safety follow-up 
(SFU), and long-term follow-up (LTFU) period.  In the treatment period, treatment will be 
continued until progressive disease (PD) or relapse as defined by IMWG response 
criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other 
reason for permanent treatment discontinuation.  All subjects will be assessed for 
anti-myeloma activity according to the IMWG response criteria.  An SFU visit will be 
conducted 30 (+3) days after last administration of AMG 420, and an LTFU period that 
will begin after the SFU visit is completed.  The total duration of the LTFU will be up to 


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5 years from the first dose of AMG 420, or until subject death, whichever is first 
(See Study Schema). 
Phase 1b (Monotherapy Dose Confirmation) 
In phase 1b, approximately 10 subjects will be treated at the 400 g/day dose 
(comprising cohort 1).  Approximately 10 subjects will be treated at the 600 g/day dose 
level (cohort 2). 
The dose level review team (DLRT) will convene and review all available safety, 
laboratory, and pharmacokinetic (PK) data at the following scheduled time points: 
 
After at least 10 subjects in phase 1b cohort 1 (400 g/day dose level) have had the 
opportunity to complete the 4-week infusion period of the first treatment cycle:  On 
the basis of this review, the DLRT will make a recommendation regarding the 
initiation of phase 1b cohort 2 (600 g/day dose level).   
 
After at least 3 subjects with extramedullary (EM) relapsed disease in phase 1b 
cohort 1 (400 g/day dose level) have had the opportunity to complete the 4-week 
infusion period of the first treatment cycle:  On the basis of this review, the DLRT will 
make a recommendation regarding the appropriateness of continued enrollment of 
subjects with EM relapsed disease in phase 1b cohort 2 (600 g/day dose level).  
Please note that enrollment of subjects with EM relapsed disease in phase 1b 
cohort 2 will not be allowed until this safety review of the first 3 subjects with EM 
disease is completed by the DLRT.   
 
After the first 3 subjects have been dosed with AMG 420 at 600 g/day for the full 
4-week infusion cycle in phase 1b cohort 2.   
The safety data will be reviewed on an ongoing basis and enrollment may be terminated 
at any time.  To further reduce the risk of overdose to ongoing and future subjects, 
protocol-defined enrollment holding rules will be used.  These rules are based on a 
modified Toxicity Probability Interval (mTPI) (Ji et al, 2010), where the target Toxicity 
Probability Interval (TPI) is a dose-limiting toxicity (DLT) probability from 20% to 33% 
and the overdose TPI is > 33% DLT probability.  Enrollment to the ongoing dose 
level/schedule will be paused per the following rules during enrollment into phase 1b 
cohort 1 and 2:  
Number of DLTs 
 2 
 3 
 4 
Number of Treated Subjects 
 4 
 6 
 8 
If the rules for pausing enrollment are met, no further enrollment to the respective dose 
level/schedule will be allowed until after a careful review of all safety data by the DLRT.  
Additionally, enrollment will not resume until the protocol has been amended to include 
additional safeguards for subject safety (eg, modifications to dose level and schedule). 


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Subjects with EM disease will be able to enroll into cohort 2 after the safety evaluation is 
complete for 3 subjects with EM disease treated at 400 µg/day (cohort 1).  An 
investigator will review efficacy data and assess outcomes in accordance with IMWG 
criteria.  Investigator assessments will be used for primary efficacy analysis.   
Number of Subjects 
Approximately 20 subjects will be enrolled in this study. 
Summary of Subject Eligibility Criteria 
Male or female subjects ≥ 18 years of age at the time of informed consent who have 
multiple myeloma relapsed after and/or refractory to ≥ 3 lines of established and 
available therapies with known clinical benefit, including a PI, an immunomodulatory 
drug, and a CD38-directed monoclonal antibody.  Subjects must have measurable 
disease at screening as defined in the inclusion criteria and an Eastern Cooperative 
Oncology Group (ECOG) performance status of ≤ 2.  For a full list of eligibility criteria, 
refer to Section 6.1 and Section 6.2.   
Treatments 
AMG 420 will be administered as a continuous intravenous (cIV) infusion.  A treatment 
cycle consists of a 4-week infusion period followed by a 2-week infusion-free interval 
prior to the following treatment cycle (phase 1b, monotherapy).   
Phase 1b dosing for Cohort 1: 
Subjects in cohort 1 will receive a dose of 400 μg/day starting on day 1 of each 
treatment cycle.   
Phase 1b dosing for Cohort 2: 
Subjects in cohort 2 will receive a dose of 200 μg/day for the first 3 days of treatment 
cycle 1.  On day 4 of cycle 1 and for the remainder of cycle 1, the dose for cohort 2 will 
then be escalated (dose step) to 600 μg/day.  From cycle 2 onwards, the dose will 
remain at 600 μg/day and no dose step will be required.   
Subjects with EM disease will be able to enroll into cohort 2 after the safety evaluation is 
complete for 3 subjects with EM disease treated at 400 μg/day (cohort 1). 
In no case may initial treatment be continued beyond the end of the LTFU period of the 
last subject in the study. 
Inpatient Dosing/Hospitalization:   
Minimum hospitalization times for subjects will be as follows: 


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CONFIDENTIAL 
 
 
 
Cycle 1:  48 hours or 6 days after start of infusion if step dosing is utilized.  
 
Cycle 2:  24 hours monitoring after start of infusion; longer monitoring can be 
decided upon at investigator’s discretion. 
 
Cycles 3 and 4:  4 hours monitoring after start of infusion.  
 
Cycle 5 and subsequent cycles:  hospitalization not required unless subject 
experiences an adverse event requiring hospitalization as described in 
Section 7.1.1.4.1 of the study protocol or if clinically indicated.  The length of 
hospitalization required in these cases is to be determined by the investigator. 
 
Re-start of treatment after an interruption due to adverse event:  48 hours.  
 
Re-start of treatment after an interruption of > 4 hours due to technical/logistical 
issue:  24 hours. 
 
Any cycle with dose re-escalation:  48 hours after dose re-escalation.  
For cycles 1 and 2 in-hospital administration, study sites must have immediate access to 
a medical intensive care unit staffed by critical care providers.   
Outpatient Dosing:   
If deemed stable by the investigator, a subject may continue AMG 420 cIV infusion as an 
outpatient.   
For infusion bag changes in the outpatient setting, the subject will either return to the 
study site or be visited by a well-trained home health care service (HHCS) provider at 
the required frequency.  If home visits for IV bag changes are required, the HHCS 
provider will change the infusion bag, measure vital signs, monitor, document and report 
adverse events/serious adverse events per Section 9.2.3, and document any issues with 
the cIV infusion or infusion pump.  The subject and HHCS provider will be trained and 
will receive written instructions for storage of the IV bags, if applicable.  The HHCS 
provider will complete the study delegation log and will be authorized by the investigator 
before any study-related tasks are started.   
Procedures 
After providing informed consent, eligible subjects will undergo the following 
assessments during this study:  physical examination, neurological examination, ECOG 
performance status, height, weight, vital signs, pulse oximetry, ECG triplicate 
measurement, laboratory assessments (including serum pregnancy test, if applicable, 
coagulation, hematology, chemistry, urinalysis, hepatitis serology, immunoglobulins, 
latent tuberculosis test, and 
 test), biomarker and PK 
assessments (including plasmacytoma biopsy for extramedullary disease), and multiple 
myeloma response assessments including bone marrow (BM) aspirate/biopsy as well as 
imaging assessments and multiple myeloma serum and urine panels.  Reporting of 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 15 of 169 
CONFIDENTIAL 
 
 
adverse events, serious adverse events, and cases of pregnancy and lactation will be 
performed as described in Section 9.2.3. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Section 2.2. 
Statistical Considerations 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of 
AMG 420.  An overall assessment of safety with monotherapy treatment will be 
conducted on the Monotherapy Safety Analysis Set defined as all subjects that are 
enrolled in the study and receive at least 1 dose of AMG 420.  The analysis of DLT will 
be restricted to DLT-evaluable subjects (see Section 7.4.1).  The analysis of duration of 
response (DOR) will be restricted to subjects with a partial response or better.  The PK 
Analysis Set will contain all subjects who have received at least 1 dose of the 
investigational product and have at least 1 PK sample collected.  These subjects will be 
evaluated for PK analysis unless the number of data points required for analysis is not 
enough, or significant protocol deviations have affected the data, or if key dosing or 
sampling information is missing.   
The primary endpoints in phase 1b are safety endpoints.  Unless otherwise specified, 
statistical analyses on safety endpoints will be done using subjects from the Safety 
Analysis Set, which includes subjects that are enrolled and received at least 1 dose of 
AMG 420.  Interim analyses of safety data will also be conducted on an ongoing basis 
with the possibility of early termination of enrollment. 
Minimal residual disease negative rate, progression-free survival (PFS) and overall 
survival (OS) analyses will be done for all subjects included in the Full Analysis Set.  
Duration of response (DOR) and time to response analyses will be done for subjects 
who are in Full Analysis Set and have a best overall response (BOR) of PR or better.  
Kaplan-Meier (KM) proportions at select time points, KM quartiles (when estimable) and 
KM curves will be provided for duration of response, PFS and OS.  Descriptive statistics 
including mean, median, SD, and range will be provided for time to response.  Listings 
will be produced for all subjects indicating the MRD negativity, OS, PFS, time to 
response, and DOR. 
The primary analysis will occur when the target enrollment is complete and each subject 
has had the chance to be treated for at least 6 months.  


Product:  AMG 420 
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Date: 17 September 2021 
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CONFIDENTIAL 
 
 
A final analysis is planned after all subjects have ended the study.   
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name: Amgen Inc 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 17 of 169 
CONFIDENTIAL 
 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema for Monotherapy Dosing 
 
2
Amgen Proprietary—For Internal Use Only
400 µg/day 
AMG 420  cIV
(n = 10)a
600 µg/day 
AMG 420  cIV
(n = 10)a
Phase 1b – Dose Confirmation 
Screening (up to 21 days)
cIV = continuous intravenous; EOS = end of study; IMWG = International Myeloma Working Group; MRD = minimal residual disease; DLT = dose limiting toxicity 
a Subjects will continue to receive treatment until progressive disease (PD) or relapse as defined by IMWG response criteria, unacceptable safety events, next anti-multiple myeloma treatment, or 
other reason for permanent treatment discontinuation.
b At least 30 (+3) days of safety follow-up for each subject.
c Subjects attaining MRD-negative responses at 6 and 12 months will be able to increase treatment-free interval.
Day 1
Enrollment 
After safety 
review of 
first 10 
subjectsb
Progressive Disease
MRD Testing in Complete 
Responders
Continue on treatmentc
Safety Follow-up
Long-term Follow-up
30 (+ 3) days 
after last 
dose of IP
Month 6 and 12
EOS
 


Product:  AMG 420 
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Date: 17 September 2021 
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CONFIDENTIAL 
 
 
2.2 
Schedule of Activities 
Table 2-1.  Phase 1b Screening and Treatment Cycle 1 (With No Dose Step) 
  
SCR 
Treatment Period 
Cycle 
  
1 
Infusion-free 
Intervala 
Cycle Day 
-21 to -1 
1 
2 
3 
4 
5 
6 
8 
15 22 29 
36 
Hours 
  
Pre-
dose 
Relative to start of infusion  
 
 
 
 
  
  
 
  
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
 
  
  
  
  
  
GENERAL AND SAFETY ASSESSMENTS 
  
Informed consent 
X 
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
   
  
In-/Exclusion criteria 
X 
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
   
  
Demographics/Medical history 
X 
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
   
  
Hospitalizationb 
 
<------------------------------   48 hours     ----------------------------------------> 
 
 
 
 
 
 
 
 
Concomitant medications 
<----------------------------------------     continually from informed consent until SFU     ------------------------------------------------> 
SAE review 
<----------------------------------------     continually from informed consent until SFU    ------------------------------------------------->
AE review 
 
 
--------------------------------------     continually from first dose of AMG 420 until SFU     ------------------------------------->
Physical examination 
X 
X 
  
  
  
  
  
  
  
  
  
X 
X 
 
 
 
X 
X 
X 
X 
X 
Peripheral Neuropathy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
X 
  
Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, pulse oximetryc 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
ECG triplicate measurementc 
X 
X 
  
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
 
Page 1 of 4 
Footnotes defined after last page of table. 
Table 2-1.  Phase 1b Screening and Treatment Cycle 1 (With No Dose Step) 
  
SCR 
Treatment Period 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 19 of 169 
CONFIDENTIAL 
 
 
Cycle 
  
1 
Infusion-free Intervala  
Cycle Day 
-21 to -1 
1 
2 
3 
4 
5 
6 
8 
15 
22 
29 
36 
Hours 
  
Pre-
dose 
Relative to start of infusion   
 
 
 
 
  
  
 
  
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
 
  
  
  
   
  
LABORATORY ASSESSMENTS 
  
Pregnancy testd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulatione 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Hematology, chemistrye  
X 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Creatinine Clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ferritinf 
 
X 
       continue monitoring in case of CRS only      
Hepatitis serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Latent TB test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
Ig:  IgA, IgM, IgG 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK ASSESSMENTS 
AMG 420 PK collectiong 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
X 
X 
 
Xg 
 
Page 2 of 4 
Footnotes defined after last page of table. 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 20 of 169 
CONFIDENTIAL 
 
 
Table 2-1.  Phase 1b Screening and Treatment Cycle 1 (With No Dose Step) 
  
SCR 
Treatment Period 
Cycle 
  
1 
Infusion-free Intervala  
Cycle Day 
-21 to -1 
1 
2 
3 
4 
5 
6 
8 
15 
22 
29 
36 
Hours 
  
Pre-
dose 
Relative to start of infusion    
 
 
 
 
  
  
 
  
0 
1 
2 
4 
6 
8 
12 16 20 24 48 
 
 
 
  
  
  
  
  
DISEASE ASSESSMENTS 
SPEP/SIFEh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
UPEP/UIFEh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
sβ-2 microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
sFLC (ĸ/ʎ) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
BM aspirate/biopsyi  
X 
At initial suspected CR and at 6 (after 4 cycles) months and repeat at 12 months for subjects who continue to appear to be 
in CR and recommended in case of PD/relapse 
% MM involvementi 
X 
At initial suspected CR and at 6 (after 4 cycles) months and repeat at 12 months for subjects who continue to appear to be 
in CR and recommended in case of PD/relapse 
BM FISH/karyotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extramedullary 
plasmacytoma assessmentsj 
X 
        repeat only to confirm a PR or better only if measurable plasmacytoma present at baseline, every 12 weeks 
(± 2 weeks), as clinically indicated   
Skeletal surveyj 
X 
                                                   repeat only as clinically indicated                                                    
Page 3 of 4 
Footnotes defined after last page of table. 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 21 of 169 
CONFIDENTIAL 
 
 
Table 2-1.  Phase 1b Screening and Treatment Cycle 1 (With No Dose Step) 
  
SCR 
Treatment Period 
Cycle 
  
1 
Infusion-free 
Intervala  
Cycle Day 
-21 to 
-1 
1 
2 
3 
4 
5 
6 
8 
15 
22 
29 
36 
Hours 
  
Pre-
dose 
Relative to start of infusion    
 
 
 
 
  
  
 
  
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
48 
 
 
 
  
  
  
  
  
BIOMARKER ASSESSMENTS 
  
INVESTIGATIONAL PRODUCT DOSING 
AMG 420 cIV infusion 
 
 
--------------------------------------------------------------------------------------------------------------------------------> 
 
Premedicationo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 4 of 4 
Footnotes defined on next page 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 22 of 169 
CONFIDENTIAL 
 
 
AE = adverse event;
 cIV = continuous intravenous; CR = complete response; CRS = cytokine release syndrome; CT = computed tomography; 
 ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; FISH =  fluorescent in situ 
hybridization; Ig = immunoglobulins; MDSCs = myeloid derived suppressor cells; MM = multiple myeloma; MRD = minimal residual disease; MRI = magnetic resonance 
imaging;
;
 PD = progressive disease; PET = positron emission tomography;
 
PK = pha
se; SAE = serious adverse event;
 SCR = screening; sFLC (ĸ/ʎ) = serum free 
light chain (kappa/lambda); SFU = safety follow-up; SIFE = serum immunofixation; SPEP = serum protein electrophoresis; TB = tuberculosis; UIFE = urine 
immunofixation; UPEP = urine protein electrophoresis  
a Infusion-free interval = days 30 to 42, day 43 = day 1 of subsequent cycle. 
b See Section 7.1.1.4.1 for details on hospitalization requirements. 
c ECGs and vital signs should be performed approximately 15 min prior to any invasive procedures including IV bag change, if applicable, and approximately 15 min 
prior to EOI.  ECGs are only required in cycle 1 and 2. 
d Refer to Section 9.2.4.1 for details of required pregnancy testing. 
e As indicated in Section 12.2, hematology and chemistry panels include differential cell counts and comprehensive metabolic profile, as well as serum uric acid and 
phosphorous levels, and liver function tests.  Coagulation panel includes prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and D-dimer. 
f If ferritin value after CRS is abnormal, continue monitoring until values are back to baseline/event is resolved. 
g Time schedule for PK sampling cycle 1 day 29:  approximately 15 min prior to EOI and 4, 8, 24, and 48 hours after EOI. 
h Serum and urine immunofixation (IFE) for M-protein measurements.  Urine IFE to be only followed up if positive for M protein at baseline. 
Baseline imaging is required at screening (if done within 30 days prior to screening for standard of care, no need to repeat) to evaluate for extramedullary (EM) relapse 
using whole body MRI or PET/CT and should be repeated during treatment only to confirm a PR or better only if measurable plasmacytoma are present at baseline 
every 12 weeks (± 2 weeks) and as clinically indicated.  Skeletal survey does not need to be performed at screening if CT or PET CT performed and does not need to 
be repeated after screening unless clinically indicated.   
k MRD and 
 
l Collection of samples on day 29 should be done prior to EOI. 
See Section 7.1.4 for details on premedication requirements. 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 23 of 169 
CONFIDENTIAL 
 
 
Table 2-2.  Phase 1b Treatment Cycle 2, 3, and Following to End of Study 
  
Treatment Period 
Follow-up Period  
Cycle 
2 
Infusion-
free 
Intervala 
3 and all subsequent cycles 
Infusion-
free 
Intervala 
EOT 
SFU 
LTFUb,v 
Cycle Day 
1 
2 
8 
15 22 29 
36 
1 
8 
15 
22 
29 
36 
  
 30 (+3
) days  
Up to 5 yrs after first dose of 
IP, or subject death, whichever 
occurs first 
Hours 
Pre-
dose 
Relative to start of infusion  
Pre-
dos
e 
Relative to start of infusion  
  
6 
24   
  
  
  
  
4 
  
  
  
  
  
  
  
  
GENERAL AND SAFETY ASSESSMENTS 
Hospitalizationc  
  ---------------> 
  
  
  
  
  
-------> 
  
  
  
  
  
 
  
  
Concomitant medications 
<---------------------------------------     continually from informed consent until SFU     -------------------> 
  
Subsequent anti-MM 
treatment 
  
  
  
  
  
  
  
  
  
  
  
    
  
  
  
  
  
 X 
X 
SAE review 
<---------------------------------------     continually from informed consent until SFU     --------------------> 
Xd 
AE review 
-------------------------------------     continually from first dose of AMG 420 until SFU     ----------------> 
  
Physical examination 
X 
 
X 
X 
X 
X 
X 
X  
X 
  
 
 
 
 
 
X 
X 
 
Peripheral neuropathy 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
X 
  
X 
  
  
  
  
X 
  
X 
X 
 
Weight 
X 
 
 
 
 
 
 
  
X 
  
  
  
  
  
  
X 
X 
 
Vital signs, pulse oximetrye 
Xf 
Xf 
X 
X 
X 
X 
X 
X 
Xg 
 Xg 
X 
X 
X 
X 
 
X 
X 
 
ECG triplicate measuremente 
X 
 
X 
 
 
 
X 
  
  
  
  
  
  
  
  
X 
X 
  
Page 1 of 4 
Footnotes defined after last page of table. 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 24 of 169 
CONFIDENTIAL 
 
 
Table 2-2.  Phase 1b Treatment Cycle 2, 3, and Following to End of Study 
  
Treatment Period 
Follow-up Period  
Cycle 
2 
Infusion-
free 
Intervala 
3 and all subsequent cycles 
Infusion-
free 
Intervala 
EOT 
SFU 
LTFUb,v 
Cycle Day 
1 
2 
8 
15 
22 
29 
36 
1 
8 
15 
22 
29 
36 
  
 30 (+3
) days  
Up to 5 yrs after first dose 
of IP, or subject death, 
whichever occurs first 
Hours 
Pre-
dose 
Relative to start of infusion  
Pre-
dose 
Relative to start of infusion  
  
6 
24 
  
  
  
  
  
4 
  
  
  
  
  
  
  
  
LABORATORY ASSESSMENTS 
Coagulationh 
X 
  
X  
X 
X 
X 
X 
  
X 
  
X 
X 
X 
 
  
X 
X 
 
Hematology, 
chemistryh 
X 
 
X 
X 
X 
X 
X 
  
X 
  
X 
X 
X 
 
  
X 
X 
 
Ferritini 
----------------------------------------------------    continue monitoring in case of CRS only  ----------------------------------> 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
Ig:  IgA, IgM, IgG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK ASSESSMENTS 
AMG 420 PK 
collection 
 X 
  
X 
X 
X 
 
Xk 
  
 X 
  
   
 
 
Xk 
  
 
 
  
Page 2 of 4 
Footnotes defined after last page of table 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 25 of 169 
CONFIDENTIAL 
 
 
Table 2-2.  Phase 1b Treatment Cycle 2, 3, and Following to End of Study 
  
Treatment Period 
Follow-up Period  
Cycle 
2 
Infusion
-free 
Intervala 
3 and all subsequent cycles 
Infusion-
free 
Intervala 
EOT 
SFU 
LTFUb,v 
Cycle Day 
1 
2 
8 
15 
22 
29 
36 
1 
8 
15 
22 
29 
36 
  
 30 (+
3) 
days  
Up to 5 yrs after first 
dose of IP, or subject 
death, whichever 
occurs first 
Hours 
Pre-
dose 
Relative to start of infusion  
Pre-
dose 
Relative to start of infusion  
  
6 
24 
  
  
  
  
  
4   
  
  
  
  
  
  
  
DISEASE ASSESSMENTS 
SPEP/SIFEl 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
UPEP/UIFEl 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
sβ-2 microglobulin 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
sFLC (ĸ/ʎ) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
BM 
aspirate/biopsym  
At initial suspected CR and at 6 (after 4 cycles) months and repeat at 12 months for subjects who continue to appear to be in CR and 
recommended in case of PD/relapse 
% MM involvementm 
At initial suspected CR and at 6 (after 4 cycles) months and repeat at 12 months for subjects who continue to appear to be in CR and 
recommended in case of PD/relapse
Skeletal survey/ 
plasmacytoma 
assessmentsn 
        repeat only to confirm a PR or better only if measurable plasmacytoma present at baseline, every 12 weeks (± 2 weeks), as 
clinically indicated   
BIOMARKER ASSESSMENTS  
Page 3 of 4 
Footnotes defined after last page of table.   


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 26 of 169 
CONFIDENTIAL 
 
 
Table 2-2.  Phase 1b Treatment Cycle 2, 3, and Following to End of Study 
  
Treatment Period 
Follow-up Period  
Cycle 
2 
Infusion-
free 
Intervala 
3 and all subsequent cycles 
Infusion-
free 
Intervala 
EOT 
SFU 
LTFUb,v 
Cycle Day 
1 
2 
8 
15 
22 
29 
36 
1 
8 
15 
22 
29 
36 
  
 30 (
+3) 
days  
Up to 5 yrs after 
first dose of IP, or 
subject death, 
whichever occurs 
first 
Hours 
Pre-
dose 
Relative to start of infusion  
Pre-
dose 
Relative to start of infusion  
  
6 
24 
  
  
  
  
  
4 
  
  
  
  
  
  
  
  
BIOMARKER ASSESSMENTS (continued)  
INVESTIGATIONAL PRODUCT DOSING 
AMG 420 cIV 
infusion 
---------------------------------------------------> 
 
---------------------------------------------> 
 
 
 
 
Premedicationt  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Page 4 of 4 
Footnotes defined on next page 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 27 of 169 
CONFIDENTIAL 
 
 
AE = adverse event; 
; cIV = continuous intravenous; CR = complete response; CRS = cytokine release syndrome; CT = computed tomography; 
; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; EOT =  end of treatment; EOS = end 
of study; Ig = immunoglobulins; IP = investigational product; LTFU = long-term follow-up; MDSCs = myeloid derived suppressor cells; MM = multiple myeloma; 
MRD = minimal residual disease; MRI = magnetic resonance imaging;
 PB = peripheral blood; PD =  progressive disease; 
PET = positron emission tomography; 
; PK = pharmacokinetics; PR = partial response; SAE = serious adverse event; 
 
; sFLC (ĸ/ʎ) = serum free light chain (kappa/lambda); SFU = safety follow-up; SIFE = serum immunofixation; SPEP =  serum protein electrophoresis; 
UIFE = urine immunofixation; UPEP = urine protein electrophoresis 
a Infusion-free interval = days 30 to 42, day 43 = day 1 of subsequent cycle.  In case of extended treatment-free interval (treatment holiday), an on-site visit should be 
performed within one week prior to re-start of study treatment, assessments will be performed as on day 36 of cycle 1 (see Schedule of Assessment Table 2-1). 
b LTFU via on-site visit every 6 weeks (± 7 days) until progression of disease.  Afterwards, LTFU frequency will be 3 months for collecting information on survival and 
subsequent anti-MM treatment only, without the requirement for on-site visits. 
  
c See Section 7.1.1.4.1 for details on hospitalization requirements.  
d See Sections 9.2.3.1 and 12.4 for SAE reporting requirements during LTFU. 
 
e ECGs and vital signs should be performed approximately 15 min prior to any invasive procedures including IV bag change, if applicable, and approximately 15 min 
prior to EOI.  ECGs are only   required in cycle 1 and 2. 
f Cycle 2 day 1:  vital signs measurement also required 1, 2, and 4 hours after infusion start. 
g Cycle 3 and 4 day 1:  vital signs measurement also required 1 and 2 hours after infusion start. 
h As indicated in Section 12.2, hematology and chemistry panels include differential cell counts and comprehensive metabolic profile, as well as serum uric acid and 
phosphorous levels, and liver function tests.  Coagulation panel includes prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and D-dimer. 
i If ferritin value after CRS is abnormal, continue monitoring until values are back to baseline/event is resolved.  
 
k PK sampling should be done approximately 15 min prior to EOI. 
l Serum and urine immunofixation (IFE) for M-protein measurements.  Urine IFE to be only followed up if positive for M-protein at baseline. 
n Plasmacytoma assessments are to be repeated during treatment only to confirm a PR or better only if measurable plasmacytoma are present at baseline, to confirm PD, 
at initiation of other anti-MM treatment, or if clinically indicated.  The same technique (may include MRI, PET-CT, or other standard-of-care method) must be employed 
for each measurement.  Skeletal survey is not required for confirmation of PR or better. 
o MRD and
 
  
t See Section 7.1.4 for details on premedication requirements. 
During the Long-term follow-up phase serious adverse events suspected to be related to investigational product that the investigator becomes aware of 
will be reported to Amgen. 


Product:  AMG 420 
Protocol Number: 20160370 
Date:  17 September 2021 
Page 28 of 169 
CONFIDENTIAL 
 
 
3. 
Introduction 
3.1 
Study Rationale 
3.1.1 
Target Rationale 
B-cell maturation antigen (BCMA, TNFRSF17, CD269) is a tumor necrosis factor (TNF) 
receptor superfamily member and a type III integral membrane protein 
(Madry et al, 1998).  BCMA expression on normal tissues is highly restricted to the B-cell 
lineage where it is predominately expressed in the secondary follicle/germinal center of 
tonsils/lymph nodes (Chiu et al, 2007), on plasmablasts (Avery et al, 2003), and on 
differentiated plasma cells (O’Connor et al, 2004).  Analysis of BCMA mRNA and protein 
expression in human tissues indicated that, except for plasma cells, BCMA is not 
detectably expressed in normal human tissues (Carpenter et al, 2013).  The biological 
function of BCMA, promoting the survival of plasma cells, is mediated via binding to its 
ligands:  a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) 
(Yu et al, 2000).  In addition to BCMA, APRIL binds to transmembrane activator and 
calcium modulator (TACI) and BAFF binds to B-cell activating factor receptor (BAFF-R) 
(Thompson et al, 2001; Gross et al, 2000).  Both APRIL and BAFF are expressed 
predominately by myeloid-derived cells including macrophages, dendritic cells, and 
neutrophils that form part of the bone marrow (BM) stroma and also reside in lymphoid 
organs.  Disruption of the BCMA/BAFF-APRIL interaction in mice deficient for BCMA 
results in decreased survival of long-lived plasma cells (Avery et al, 2003).  
B-cell maturation antigen is expressed at relatively higher levels on malignant plasma 
cells (multiple myeloma) than the level observed on normal plasma cells 
(Zhao et al, 2008).  Multiple independent analyses of mRNA in primary human multiple 
myeloma samples indicate that all multiple myeloma patients’ samples have high levels 
of BCMA (Tai et al, 2006; Moreaux et al, 2004).  The high prevalence of BCMA 
expression in multiple myeloma has been confirmed at the protein level by 
immunohistochemistry or flow cytometry, which demonstrated cell-surface BCMA 
expression in neoplastic plasma cells from all patients with multiple myeloma tested 
(Carpenter et al, 2013; Novak et al, 2004).  For this phase 1 trial, relapsed and/or 
refractory multiple myeloma (RRMM) has been chosen as the indication to pursue with 
AMG 420 because of the near 100% incidence of BCMA expression in this patient 
population.  


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3.1.2 
Target Population Rationale 
The 5-year survival rate for multiple myeloma has improved from approximately 25% for 
newly diagnosed patients in 1975 to approximately 50% in 2013 (SEER, 2014).  This is 
mainly attributed to new drugs such as proteasome inhibitors (PIs) and 
immunomodulators (IMiDs).  Most recently, daratumumab has been approved for RRMM 
and is likely to further improve long-term outcomes.  Patients refractory to PIs and IMiDs 
have a poor prognosis with a median OS of 9 months with further treatment and 
3 months without (Kumar et al, 2012).  Outcome is particularly poor in molecularly 
defined populations such as the high-risk subgroup del17p13 positive multiple myeloma 
(Avet-Loiseau et al, 2007).  Daratumumab in combination with lenalidomide and 
dexamethasone, or bortezomib and dexamethasone, has substantially improved PFS 
and overall response rate (ORR) for previously treated patients with multiple myeloma, 
regardless of prior treatment exposure or cytogenetic risk (Dimopoulos et al, 2016; 
Palumbo et al, 2016).  However, there is still a significant need for new therapies for 
multiple myeloma patients, particularly as the vast majority of disease responses are 
transient in nature with existing therapies and there remains no established cure for this 
malignancy (Carpenter et al, 2013; Novak et al, 2004). 
3.2 
Background 
3.2.1 
Disease 
Multiple myeloma is a neoplastic plasma-cell disorder characterized by clonal 
proliferation of malignant plasma cells in the BM microenvironment, monoclonal protein 
in the blood or urine and associated organ dysfunction (Palumbo and Anderson, 2011).  
Multiple myeloma accounts for almost 2% of all cancers and 20% of hematologic 
malignancies.  The disease is slightly more common in males and African Americans 
(Siegel et al, 2015).  Multiple myeloma remains an incurable cancer, although recent 
improved understanding of pathogenesis of myeloma has led to the development of new 
treatments and improved survival (Smith and Yong, 2013).  
Myeloma arises from an asymptomatic premalignant proliferation of monoclonal plasma 
cells that are derived from post–germinal-center B-cells.  Multistep genetic and 
micro-environmental changes lead to the transformation of these cells into a malignant 
neoplasm.  Myeloma is thought to evolve most commonly from a monoclonal 
gammopathy of undetermined clinical significance (usually known as MGUS) that 
progresses to smoldering myeloma and, finally, to symptomatic myeloma.  The 
diagnosis of multiple myeloma requires the presence of 1 or more myeloma defining 


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events (MDE) in addition to evidence of either 10% or more clonal plasma cells on BM 
examination or a biopsy-proven plasmacytoma.  Myeloma defining events consist of 
established CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features 
as well as 3 specific biomarkers:  clonal BM plasma cells ≥ 60%, serum free light chain 
(sFLC) ratio ≥ 100 (provided involved sFLC level is ≥ 100 mg/L), and more than 1 focal 
lesion on magnetic resonance imaging (MRI) (Rajkumar et al, 2014).  Several genetic 
abnormalities that occur in tumor plasma cells play major roles in the pathogenesis of 
myeloma and determine disease prognoses (Palumbo and Anderson, 2011). 
The uncontrolled growth of myeloma cells has many consequences, including skeletal 
destruction, BM failure, increased plasma volume and viscosity, suppression of normal 
immunoglobulin (Ig) production, and renal insufficiency (Durie, 2011).  
Symptomatic (active) disease should be treated immediately, whereas asymptomatic 
(smoldering) myeloma requires only clinical observation, since early treatment with 
conventional chemotherapy has shown no clear benefit yet.  Investigational trials are 
currently evaluating the ability of IMiDs to delay the progression from asymptomatic to 
symptomatic myeloma.  For active myeloma, current data support the initiation of 
induction therapy regimens including thalidomide, lenalidomide, and/or bortezomib 
followed by autologous hematopoietic stem cell transplantation (HSCT) after major 
disease response for many patients who can tolerate auto-HSCT conditioning regimens.  
Considerations of physiologic age, which may differ from chronologic age, and the 
presence of coexisting conditions drive decisions of treatment choice and drug dose 
(Palumbo and Anderson, 2011).  For example, less intensive approaches are desirable 
for patients with significant comorbidities, including cardiopulmonary or hepatic 
impairment, limiting treatment-related mortality, and mitigating risk of treatment 
interruption.  
Treatment of RRMM presents a special therapeutic challenge, due to the heterogeneity 
of disease at relapse and the absence of clear biological based recommendations 
regarding the choice of salvage therapies at various time points of disease progression.  
With increasing recognition of the inherent clonal heterogeneity and genomic instability 
of the plasma cells influencing both inherent and acquired therapeutic resistance, the 
identification of the optimal choice and sequence of therapies has become critical.  
Several new agents and targets are currently under development and show considerable 
promise.  Besides carfilzomib and pomalidomide that were granted approval by United 
States (US) Food and Drug Administration (FDA) in 2012 and 2013, respectively, for 


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RRMM, the next generation PIs (ixazomib, marizomib, and oprozomib), other 
molecularly targeted therapies directed at specific cell signaling pathways (including 
histone deacetylase inhibitors, PI3K/AKT/mTOR inhibitors, Hsp90 inhibitors, cell cycle 
inhibitors, kinesin spindle protein inhibitors) are currently in development.  The first 
monoclonal antibodies targeting SLAMF7 (elotuzumab) and CD38 (daratumumab) have 
recently been granted approval.  Emplicity™ (elotuzumab) is indicated in combination 
with lenalidomide and dexamethasone for the treatment of patients with multiple 
myeloma who have received 1 to 3 prior therapies.  The 1- and 2-year rates of PFS for 
elotuzumab in combination with lenalidomide and dexamethasone treatment were 
68% and 41%, respectively, compared with 57% and 27%, respectively, for lenalidomide 
and dexamethasone treatment in the corresponding phase 3 trial (Lonial et al, 2015).  
Darzalex® (daratumumab) approval was based on the pivotal phase 3 POLLUX and 
CASTOR clinical studies.  Daratumumab in combination with lenalidomide and 
dexamethasone, or bortezomib and dexamethasone, substantially improved PFS and 
ORRs for previously treated patients with multiple myeloma, regardless of prior 
treatment exposure or cytogenetic risk.  Daratumumab with lenalidomide and 
dexamethasone lowered the risk of disease progression or death by 64%, compared 
with lenalidomide and dexamethasone alone, in patients with multiple myeloma who had 
received 1 to 3 prior lines of therapy.  Daratumumab with bortezomib and 
dexamethasone reduced the risk of disease progression or death by 61% in similar 
patients, compared with bortezomib and dexamethasone alone (Dimopoulos et al, 2016; 
Palumbo et al, 2016).  Even newer approaches such as chimeric antigen receptor (CAR) 
T-cells, antibody-drug conjugates, and bispecific antibodies targeting BCMA have also 
demonstrated first promising anti-myeloma activity (Berdeja et al, 2016; 
Cohen et al, 2016; Panowski et al, 2016).  Despite advances in the management of 
multiple myeloma as described, relapse is inevitable in almost all patients.  Recurrence 
of myeloma is typically more aggressive with each relapse, leading to the development 
of treatment refractory disease, which is associated with a shorter survival 
(Dimopoulos et al, 2015).  Thus, additional treatment options are warranted. 
3.2.2 
Amgen Investigational Product Background:  AMG 420 
AMG 420 (formerly known as Boehringer Ingelheim [BI] investigational product 
BI 836909) is a member of a novel class of bispecific antibody constructs called 
“bispecific T-cell engagers” or BiTE® antibody constructs (Frankel and Baeuerle, 2013).  
They have been designed to direct T cells towards target cells.  The proximity induced 


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by the BiTE® antibody construct triggers target cell specific cytotoxicity which closely 
resembles standard cytotoxic T lymphocyte activation.  
AMG 420, targeting the surface antigen BCMA, is a novel BiTE® antibody construct 
which is being developed with the intent to treat patients with multiple myeloma.  T cells 
are bound by its anti-CD3 moiety, whereas multiple myeloma cells are bound by the 
anti-BCMA moiety.  This unique feature of AMG 420 allows it to transiently connect 
malignant cells with T cells, thereby inducing T-cell mediated killing of the bound 
malignant cell.  In preclinical models, AMG 420-mediated T-cell activation involves the 
transient release of inflammatory cytokines and proliferation of T cells.  The subsequent 
serial lysis of multiple malignant cells by a single AMG 420-activated T cell closely 
resembles a natural cytotoxic T-cell reaction. 
A phase 1 first-in-human (FIH) dose-escalation study with AMG 420, conducted by BI to 
estimate the maximum tolerated dose (MTD), is currently ongoing (BI study 
number 1351.1, NCT02514239) with 400 g/day defined as a safe and effective dose, 
with DLTs identified in 2 of 3 subjects treated at the next dose that was tested, 
800 g/day. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
AMG 420 is provided in the AMG 420 Investigator’s Brochure. 
3.2.2.1 
Nonclinical Pharmacology 
In vitro Pharmacology 
AMG 420 is a highly potent molecule selectively mediating redirected lysis of 
BCMA+ cells, while viability of target-negative cells remains unaltered.  The cytotoxic 
effect of AMG 420 is time- and dose-dependent, with mean concentrations inducing 
half-maximal target cell lysis (EC50) ranging from 5 pg/mL to 2011 pg/mL with human 
effector cells.  
In the presence of target cells, AMG 420 induced a polyclonal activation of T cells, which 
resulted in an up-regulation of the T-cell activation markers CD25 and CD69, induction 
of granzyme B and perforin synthesis, T cell proliferation and release of cytokines like 
interferon-(IFN-), TNF, interleukin (IL)-2 and IL-10. 
B-cell maturation antigen can be shed from the cell surface and was found in serum 
samples of multiple myeloma patients as well as in healthy subjects 
(Sanchez et al, 2012).  Median serum concentrations were higher in multiple myeloma 
patients (17.79 ng/mL) than in healthy blood donors (2.57 ng/mL) and highest levels 


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were observed in patients with progressive disease (PD) (19.76 ng/mL; 
Sanchez et al, 2012).  A more recent publication demonstrated that soluble BCMA 
(sBCMA) levels correlated with the proportion of plasma cells in BM biopsies, clinical 
status and can be tracked with changes in M-protein levels.  In this study, healthy donors 
had a median sBCMA blood concentration of 36.8 ng/mL, similar to median levels 
observed in patients with complete response (CR) (38.9 ng/mL).  Patients with 
smoldering multiple myeloma had higher concentrations (median 88.9 ng/mL); whereas 
patients with active untreated multiple myeloma had highest levels (median 
505.9 ng/mL).  With a median of 9.0 versus 3.6 months, PFS was longer for patients with 
sBCMA levels below the median (326.4 ng/mL) when compared with those with levels 
above the median (Ghermezi et al, 2017). 
The impact of sBCMA on AMG 420-induced cytotoxicity and T-cell activation was 
evaluated in co-cultures of BCMA-positive tumor cells, human peripheral blood 
mononuclear cell (PBMC), and recombinant human sBCMA, which is a 50-amino acid 
polypeptide (5.3 kDa) region of the BCMA protein (Sigma-Aldrich) at concentrations up 
to 400 ng/mL.  Although maximal target cell lysis was not affected by sBCMA, 
EC50 values increased with increasing sBCMA concentrations.  
Ex vivo, an AMG 420-mediated depletion of BCMA+ cells by autologous T cells was 
observed in a BM aspirate from a multiple myeloma patient. 
In vivo Pharmacology 
The anti-tumor activity of AMG 420 was evaluated in multiple myeloma xenograft 
models. 
In an orthotopic multiple myeloma model non-obese diabetic/severe combined 
immunodeficiency (NOD/SCID) mice were intravenously (IV) injected with L-363 tumor 
cells.  AMG 420 significantly prolonged survival of animals at dose levels of 0.005, 0.05, 
and 0.5 mg/kg/day when IV administered for 26 consecutive days.   
In a second xenograft model NOD/SCID mice were subcutaneously (SC) injected with 
NCI-H929 multiple myeloma tumor cells.  AMG 420 inhibited SC tumor growth when 
administered for 19 consecutive days at IV dose levels of 0.5 or 0.05 mg/kg/day or SC 
administration at 4 or 0.4 mg/kg/day. 


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3.2.2.2 
Pharmacokinetics 
Non-clinical Pharmacokinetics 
The toxicokinetics of AMG 420 was investigated in a 7-day dose range-finding cIV 
infusion or SC injection toxicity and toxicokinetic study in the cynomolgus monkey.  The 
dose levels were 0, 5, 15, 45, and 135 µg/kg/day by cIV infusion and 135 and 
405 µg/kg/day by once-daily SC injection.  Blood samples for toxicokinetics were 
collected on drug day 0 and 7 for the cIV infusion doses and drug days 0 and 6 for the 
SC doses.  Serum samples were analyzed for AMG 420 concentrations using an 
electrochemiluminescence method with a lower limit of quantification of 0.5 ng/mL.  
AMG 420 exposure (maximum concentration [Cmax] and area under the 
concentration-time curve from time 0 to the last measurable concentration [AUClast]) 
increased approximately proportionally to the increase in dose level.  There was no 
apparent sex difference in exposure.  
The toxicokinetics of AMG 420 was also investigated in a 4-week cIV infusion and SC 
toxicity study in the cynomolgus monkey.  The dose levels were 0, 15, 45, and 
135 µg/kg/day using cIV infusion and 405 µg/kg/day using once-daily SC injection.  
Blood samples for toxicokinetics were collected on study days 2, 7, 14, 21, and 27 for 
both the cIV and SC dose groups.  AMG 420 exposure increased approximately 
proportionally to the increase in dose level in the cIV dose groups.  There was no 
consistent accumulation of AMG 420 exposure upon cIV dosing for 28 days, whereas a 
slight accumulation of AMG 420 exposure upon repeated SC dosing was observable.  
There was no apparent sex difference in exposure in both the cIV and SC dose groups. 
Clinical Pharmacokinetics 
AMG 420 concentration data were collected from 34 subjects with RRMM in the ongoing 
AMG 420 FIH study, Study 1351.1.  AMG 420 was dosed as a continuous IV (cIV) 
infusion for 4 weeks, in escalating dose levels ranging from 0.2 µg/day to 800 µg/day. 
Following cIV infusion of AMG 420, free steady-state concentrations (Css) were reached 
in approximately 2 days and remained stable over the infusion period.  Mean free 
AMG 420 Css values increased with increasing dose. 
Please refer to the Investigator’s Brochure for further details of preliminary PK analyses 
for AMG 420.   


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3.2.2.3 
Toxicology 
The nonclinical safety assessment of AMG 420 was conducted in cynomolgus monkey 
by cIV infusion or SC administration and consisted of 7- and 28-day repeat-dose 
toxicology studies.  Results hereafter refer to cIV dosing in the Good Laboratory Practice 
(GLP) 28-day repeat-dose toxicology study; the toxicological profile of the two routes of 
administration was similar at the highest doses tested (135 µg/kg cIV and 405 µg/kg 
SC).  In the 28-day GLP study, a dose of 135 µg/kg/day resulted in moribundity/mortality; 
two animals were euthanized during the study due to either complications with the 
catheterization site or hypothermia and decreased activity.  In the premature decedents, 
the pharmacological action of AMG 420 induced a systemic lymphoid depletion 
intensified by hematological disorders (hemolytic anemia) which enabled the onset of 
opportunistic secondary infections in some animals that were responsible for their death 
or moribund condition.  Doses of 15 and 45 µg/kg were well tolerated. 
At doses ≥ 45 μg/kg/day, emesis, increased body temperature (up to 1.7°C) and 
increases in serum IL-2, IL-6 and IFN-γ were seen in most animals on the day of 
treatment initiation (4 to 8 hours after the start of AMG 420 administration) and resolved 
within 24 to 48 hours.  
Serum chemistry evaluations indicated AMG 420-related changes at 24 hours after the 
initiation of administration and/or on day 28 mostly at 135 µg/kg.  These changes 
consisted of decreased calcium (at ≥ 15 µg/kg), decreased total protein levels (due to 
decreased albumin and/or globulin levels, at 135 µg/kg), and increased creatinine 
(135 µg/kg).  In addition, a dose-responsive increase in C-reactive protein levels was 
observed at 24 hours after the start of administration for all dose levels.  All changes 
were generally reversible after a 4-week recovery period. 
Large modifications in white blood cell parameters were observed at all dose levels 
when compared with pretest and control animal values.  Most animals treated with 
AMG 420 showed an initial increase (< 4.4-fold) in absolute neutrophil counts (ANC) at 
4 hours after the start of infusion/dosing and decreases (up to 90%) in absolute and/or 
relative lymphocyte, monocyte, eosinophil, basophil, and large unstained cell counts at 
4 to 24 hours.  This lymphopenia showed a trend toward reversibility but not full reversal 
at the end of the treatment period or the recovery period. 
Decreases in T and B lymphocytes (≥ 15 µg/kg) and natural killer (NK) cells (≥ 45 µg/kg) 
were observed at 4 and 24 hours after initiation of treatment with a corresponding 
decrease in activated (CD25+ and/or CD69+) T lymphocytes at the 4-hour time point at 


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all dose levels.  A further decrease in activated T lymphocytes, B lymphocytes, and NK 
cells was observed on day 28 at most previously-affected doses.  At the end of the 
recovery period, all lymphocyte subtypes were similar to control values with the 
exception of low B lymphocytes in one 135 µg/kg male. 
AMG 420-related light microscopic findings (eg, lymphoid depletion, increased 
cellularity) were present in the tonsils, lymph nodes, spleen, and BM (smears) at all dose 
levels.  Histologic effects on sternal BM (increased cellularity) were present at doses 
 135 μg/kg/day.  The AMG 420-related lymphoid microscopic changes at 135 g/kg 
were accompanied by hematological (hemolytic anemia) and inflammatory changes 
(mainly in the liver) similar to those observed in premature decedents and were, 
therefore, considered adverse.  Inflammatory and hematological changes persisted in 
2 animals at the end of the recovery period.  At 15 or 45 g/kg, the lymphoid depletion 
was considered not adverse due to absence of secondary infections and/or 
hematological changes; there was evidence of at least partial reversal of lymphoid 
depletion at the end of the recovery period. 
Dose-dependent decreases in BM plasma cells (an expected consequence of the 
pharmacologic activity of AMG 420) were detected in the BM smears at all doses.  At the 
end of the recovery phase, plasma cell percentages were comparable with those of 
control animals or were increased relative to the day 28 values, indicating partial to 
complete recovery. 
AMG 420 did not demonstrate any effects on neurological, renal, or cardiovascular 
functions including electrocardiograms (ECGs) in the 28-day toxicology study.  
In conclusion, AMG 420-associated changes in the 28-day toxicology study were 
generally consistent with the expected BiTE® mode of action and targeting of BCMA.  
The changes were largely reversible and/or considered nonadverse at the doses 
≤ 45 µg/kg.  The highest non-severely toxic dose of AMG 420 following daily cIV infusion 
for 28 days was considered to be 45 µg/kg. 
Please refer to the Investigator’s Brochure for further details of the toxicology studies 
performed with AMG 420. 


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3.2.2.4 
Clinical Experience With Other BiTE® Antibody Constructs and 
AMG 420 
BiTE® antibody constructs exert a unique but also uniform mechanism of action 
independent from their respective target.  Consequently, experiences with other BiTE® 
antibody constructs are regarded as being relevant for AMG 420. 
Most clinical experience exists with a BiTE® antibody construct called blinatumomab 
(BLINCYTO®, AMG 103; specificity for CD3 and CD19), which has shown that 
administration of BiTE® antibody constructs by cIV infusion is feasible and efficacious in 
subjects with late-stage hematological malignancies (Yuraszeck et al, 2017; 
Benjamin and Stein, 2016; Nagorsen et al, 2012).  Blinatumomab has demonstrated 
clinical activity in acute lymphoblastic leukemia (ALL).  Clinical responses have been 
seen in both adults and children (Amgen clinical studies 103-206 [NCT01209286], 
103-205 [NCT01471782], 103-211 [NCT01466179], and 00103311/TOWER 
[NCT02013167]) confirming the activity of BiTE® antibody constructs in B-precursor ALL 
(Kantarjian et al, 2017; Von Stackelberg et al, 2016; Topp et al, 2015; Topp et al, 2014).  
Based on these data, blinatumomab is approved in multiple regions for the treatment of 
Philadelphia chromosome-negative relapsed and/or refractory B-cell precursor ALL. 
The most common adverse reactions (≥ 20%) were pyrexia, headache, peripheral 
edema, febrile neutropenia, nausea, hypokalemia, tremor, rash, and constipation.  
According to the US prescribing information, additional adverse reactions included 
cytokine release syndrome (CRS), neurological toxicities, infections, tumor lysis 
syndrome (TLS), neutropenia and febrile neutropenia, effects on ability to drive and use 
machines, elevated liver enzymes, leukoencephalopathy, and preparation/administration 
errors.  
Several other BiTE® antibody constructs have entered clinical trials.  Adverse events 
common to these constructs and blinatumomab include fever and fatigue.  However, the 
spectrum of neurologic and psychiatric adverse events observed in patients treated with 
blinatumomab (eg, confusion, disorientation) has not been reported with these 
constructs to date. 
A phase 1, FIH, open-label, dose escalation study (1351.1) is ongoing to characterize 
the safety, tolerability, pharmacokinetics, and pharmacodynamics of cIV doses of 
AMG 420 in subjects with RRMM.  AMG 420 is administered as a cIV infusion for 
4 consecutive weeks via an indwelling central IV line.  After a 2-week treatment-free 


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period, the subjects receive up to a total of five 4-week on/2-week off courses.  If 
subjects experience continued benefit, up to 5 more courses may be given.   
Data from 35 subjects (up to 800 g/day) were available at the time of data snapshot 
(22 May 2018).  Subjects were treated at doses ranging from 0.2 g/day to 
800 g/day.  In general, AMG 420 was well tolerated.  All 35 subjects (100%) had 
adverse events; 32 of 35 subjects (91.4%) had adverse events grade ≥ 3.  The most 
frequent adverse events were lymphocyte count decreased (21 subjects, 60.0%); 
anemia (12 subjects, 34.3%); white blood cell count decreased (12 subjects, 34.3%); 
pyrexia (11 subjects, 31.4%); and CRS (10 subjects, 28.6%).  Infections and infestations 
occurred in 23 subjects (65.7%), most notably device related infections in 7 subjects 
(20.0%).  Thirty-three of 35 subjects (94.3%) had an adverse event considered 
drug-related by the investigator.  The most frequent drug-related adverse events (> 20%) 
were lymphocyte count decreased (21 subjects, 60.0%) and CRS (10 subjects, 
28.6%).  Drug-related grade 3 and grade 4 adverse events occurred in 10 subjects 
(28.6%) and 17 subjects (48.6%), respectively.  The most frequent drug-related 
grade 3 and grade 4 adverse events were lymphocyte count decreased, with 6 subjects 
(17.1%) reporting grade 3 events and 14 subjects (40.0%) reporting grade 4 events.  No 
drug-related grade 5 events were reported in this study.  Serious adverse events were 
reported in 17 subjects (48.6%).  The most frequent serious adverse events were 
device-related infections, pneumonia, and cytokine release syndrome (CRS) in 
3 subjects (8.6%) each.  Most subjects reporting serious adverse events had 
grade 3 adverse events (12 subjects, 34.3%).  Drug-related serious adverse events were 
CRS in 3 subjects (8.6%), and peripheral motor neuropathy, generalized edema, and 
pyrexia in 1 subject (2.9%) each.  Two dose-limiting toxicities (DLTs) were reported in 
the 800 g/day cohort; 1 grade 3 CRS and 1 grade 3 peripheral motor neuropathy. 
In this FIH trial, 10 of 12 CRS-specific adverse events occurring in 10 subjects were 
limited to cycle 1 administration of AMG 420 and had an onset within 24 hours of 
administration.  All events of CRS occurring at doses under 800 g/day were grade 1 by 
Common Terminology Criteria for Adverse Events (CTCAE) criteria.  Two of the 
12 CRS-specific adverse events occurred in 2 subjects during cycle 2, were grade 1 in 
severity, and had an onset within 24 hours of treatment administration.  
As of the 22 May 2018 data snapshot, preliminary efficacy data have shown an objective 
response in 8 subjects (23%).  Six subjects achieved a best response of CR as 
assessed by the investigator using International Myeloma Working Group (IMWG) 


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response criteria, including 1 each at 6.5, 100, and 200 µg/day, and 3 at 400 µg/day.  
Four of the 6 CRs (1 at 200 g/day and 3 at 400 g/day) were also MRD-negative.  As of 
the data cutoff date, 4 out of the 6 subjects remain in CR (all 4 were MRD-negative).  
Two additional subjects demonstrated a response to AMG 420; 1 subject at 50 g/day 
achieved a partial response (PR) and 1 subject at 800 g/day achieved a very good 
partial response (VGPR).   
For additional information refer to the current version of the Investigator’s Brochure. 
A phase 1, FIH, open-label, dose-escalation study (Study 20170122) evaluating the 
safety, tolerability, PK, and pharmacodynamics of AMG 701 subjects with RRMM is 
currently ongoing.  AMG 701 is a molecule that is related to AMG 420 in that an scFc 
fragment has been introduced into the canonical BiTE® antibody structure to prolong its 
half-life.  AMG 701, which also shares the same BCMA target as AMG 420, is 
administered as a short intravenous infusion once weekly.  As of 25 November 2019, 
1 subject in dose escalation has achieved stringent CR, with AMG 701 treatment at the 
800 μg weekly dose.  Seven subjects achieved partial responses (PR) or very good PRs 
(VGPR) out of a total of 19 evaluable enrolled in the 3000, 4500, and 6500 μg target 
dose cohorts.  Out of 4 subjects enrolled in the 6500 μg target dose, 2 subjects have 
attained VGPRs, 1 subject attained minimal response (MR), and one subject 
experienced rapid disease progression after receiving the 800 μg run-in dose and never 
received the target dose.  As of 25 November 2019, 7 of 8 clinical responses are 
continuing, with the longest response lasting over 1 year, and dose 
exploration/escalation ongoing. 
3.3 
Benefit/Risk Assessment 
At this time, there is limited clinical experience with AMG 420 in humans.  Based on 
nonclinical toxicity studies of AMG 420, and preliminary clinical safety and efficacy 
experience with AMG 420, the overall benefit/risk profile favors further clinical 
development of AMG 420 for patients with RRMM.  Clinical signs and symptoms, along 
with other safety laboratory parameters, will be monitored during the study and at the 
appropriate time points to ensure subjects’ safety.  
The following benefit risk assessment supports the conduct of this clinical trial.  
Reference should be made to the Investigator’s Brochure for further data on AMG 420. 


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3.3.1 
Therapeutic Context 
Multiple myeloma treatment has evolved rapidly in recent years.  Progress has been 
made with the introduction of several breakthrough drugs, including IMiDs and PIs, as 
well as anti-CD38 targeting monoclonal antibodies, which have led to a significant 
increase in response rate as well as survival rate (Dimopoulos et al, 2016; 
Palumbo et al, 2016; Kumar et al, 2012).  While treatment for multiple myeloma will often 
induce remission, multiple myeloma is characterized by a recurring pattern of remission 
and relapse.  With each subsequent line of treatment, the duration and depth of 
response decreases (Cook et al, 2018), and patients eventually develop treatment 
resistance (Papadas et al, 2017).  It is not uncommon for patients to be treated with 3 or 
more lines of therapy.  
The goal of treatment for RRMM is to achieve the longest progression-free survival 
(PFS) and subsequently overall survival (OS).  The depth of response is associated with 
OS and a critical factor to achieving that goal (Chanan-Khan and Giralt, 2010; 
Richardson et al, 2007).  Additional goals include controlling disease to prevent or delay 
associated complications (such as bone fractures, renal insufficiency, and infections), 
maintaining an acceptable health related quality of life, and providing relief of pain and 
other disease-related symptoms.  Investigational agents that utilize both novel targets 
and mechanisms of action, especially those that have shown clinical activity in 
first-in-human studies, have the potential to achieve these goals, particularly in patients 
with a high unmet need after their disease has progressed following treatment with 
available standard-of-care therapies. 
3.3.2 
Key Benefits 
As AMG 420 is still in early development and clinical experience is still limited, key 
benefits are still being investigated and will be described when the data become 
available. 
3.3.3 
Key Risks  
The target cell populations of AMG 420 are plasma cells, mature and activated B-cells 
shown to express BCMA; hence the potential on-target toxicity is depletion of these 
hematologic cell types and immunoglobulin level, which could result in an increased risk 
of infection.  
At this time, there is limited clinical experience with AMG 420 in humans.  Based on 
biological possibility, nonclinical toxicity studies of AMG 420, and clinical safety 
experience with AMG 420 and other BiTE® antibody constructs in hematology, such as 


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blinatumomab, the safety risks for AMG 420 include cytokine release syndrome (CRS), 
infections, and neurologic events (see Table 3-1). 
Table 3-1.  Key Safety Risks for AMG 420 
Safety Risk 
Description 
Important Identified Risks 
Cytokine Release 
Syndrome (CRS) 
Cytokine release syndrome (CRS), including serious events, has 
been reported for patients receiving AMG 420 in the clinical trial 
setting. 
Signs and symptoms many include the following: 
 
Constitutional – fever, rigors, fatigue, malaise 
 
Neurologic – headache, mental status changes, dysphasia, 
tremors, dysmetria, gait abnormalities, seizure 
 
Respiratory – dyspnea, tachypnea, hypoxemia 
 
Cardiovascular – tachycardia, hypotension 
 
Gastrointestinal – nausea, vomiting, transaminitis, 
hyperbilirubinemia 
 
Hematology – bleeding, hypofibrinogenemia, elevated D-dimer 
 
Skin – rash 
Important Potential Risks 
Infections 
Infections, including device-/catheter-related infections, have been 
reported in the clinical trial setting with administration of AMG 420. 
Neurologic Events 
Neurologic events, including headache and peripheral neuropathy, 
have been reported in the clinical trial setting with administration of 
AMG 420. 
Clinical signs and symptoms of CRS, infections, and neurologic events, along with other 
safety labs, will be monitored during the study and at the appropriate time points to 
ensure subjects’ safety.  Refer to Section 7.4.2.1.2 for specific recommendations 
regarding the mitigation and management of CRS, infections, and neurologic events. 
Please refer to the AMG 420 Investigator’s Brochure for further description of the key 
safety risks. 
3.3.3.1 
Risks 
Refer to the AMG 420 Investigator’s Brochure for further description of safety risks.   


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4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Phase 1b 
Primary 
 
Establish the safety and tolerability of 
AMG 420 at dose levels of 400 g/day 
and 600 g/day in subjects with 
relapsed and/or refractory multiple 
myeloma (RRMM)   
 
Dose-limiting toxicities (DLTs), 
treatment-emergent adverse events, 
treatment-related adverse events, and 
changes in vital signs, 
electrocardiograms (ECGs), and 
clinical laboratory tests 
Key Secondary 
 
Estimate overall response rate (ORR) 
and duration of response (DOR) of 
AMG 420 in subjects with RRMM 
 
ORR 
 
DOR 
 
Evaluate the rate of minimal residual 
disease (MRD)-negativity at the time 
of CR 
 
MRD negativity at the time of CR 
Secondary 
 
Establish the safety and tolerability of 
AMG 420 in subjects with 
extramedullary relapsed multiple 
myeloma 
 
DLTs, treatment-emergent adverse 
events, treatment-related adverse 
events, and changes in vital signs, 
ECGs, and clinical laboratory tests 
 
Characterize the pharmacokinetics 
(PK) of AMG 420 when administered 
as 4-week continuous intravenous 
(cIV) infusion 
 
AMG 420 PK parameters including, 
but not limited to, half-life (t1/2), 
clearance, and apparent Css 


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Objectives 
Endpoints 
Secondary 
 
Evaluate other measures of 
anti-myeloma activity of AMG 420 in 
subjects with RRMM: 
 
Time to response  
 
Progression-free survival (PFS) 
 
Overall survival (OS) 
 
Best overall response (BOR) 
 
Efficacy parameters according to 
International Myeloma Working Group 
(IMWG) response criteria, per 
investigator assessment: 
 
Time to response  
 
PFS  
 
OS 
 
BOR 


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Objectives 
Endpoints 
Exploratory  
 


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4.2 
Hypotheses 
A safe and tolerable dose of AMG 420 will have evidence of anti-tumor activity in 
patients with relapsed and/or refractory multiple myeloma as measured by the rate of 
overall response. 
The ORR according to IMWG response criteria along with 95% CI will be calculated per 
investigator assessment for subjects with RRMM.  The lower bound of the binomial 
2-sided 95% confidence interval for ORR not lower than 35% is considered clinically 
meaningful.   
5. 
Study Design 
5.1 
Overall Design 
This is a phase 1b, multicenter, non-randomized, open-label expansion study.  
AMG 420 will be evaluated in adult subjects with RRMM.  
The study will consist of up to a 21-day screening, a treatment period, safety follow-up 
(SFU), and long-term follow-up (LTFU) period.  In the treatment period, treatment will be 
continued until PD or relapse as defined by IMWG response criteria (see Section 12.8), 
unacceptable safety events, next anti-multiple myeloma treatment, or other reason for 
permanent treatment discontinuation.  All subjects will be assessed for anti-myeloma 
activity according to the IMWG response criteria.  An SFU visit will be conducted 
30 (+3) days after last administration of AMG 420, and an LTFU period will begin after 
the SFU visit is completed.  The total duration of the LTFU will be up to 5 years from the 
first dose of AMG 420, or until subject death, whichever is first.   
5.1.1 
Phase 1b (Monotherapy Dose Confirmation) 
In phase 1b, approximately 10 subjects will be treated at the 400 g/day dose 
(comprising cohort 1).  Approximately 10 subjects will be treated at the 600 g/day dose 
level (cohort 2).   
The dose level review team (DLRT) will convene and review all available safety, 
laboratory, and PK data at the following scheduled time points: 
 
After at least 10 subjects in phase 1b cohort 1 (400 g/day dose level) have had the 
opportunity to complete the 4-week infusion period of the first treatment cycle:  On 
the basis of this review, the DLRT will make a recommendation regarding the 
initiation of phase 1b cohort 2 (600 g/day dose level).   
 
After at least 3 subjects with EM relapsed disease in phase 1b cohort 1 (400 g/day 
dose level) have had the opportunity to complete the 4-week infusion period of the 
first treatment cycle:  On the basis of this review, the DLRT will make a 
recommendation regarding the appropriateness of continued enrollment of subjects 


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with EM relapsed disease in phase 1b cohort 2 (600 g/day dose level).  Please note 
that enrollment of subjects with EM relapsed disease in phase 1b cohort 2 will not be 
allowed until this safety review of the first 3 subjects with EM disease is completed 
by the DLRT.   
 
After the first 3 subjects have been dosed with AMG 420 at 600 g/day for the full 
4-week infusion cycle in phase 1b cohort 2. 
In phase 1b, the safety data will be reviewed on an ongoing basis and enrollment may 
be terminated at any time.  To further reduce the risk of overdose to ongoing and future 
subjects, protocol-defined enrollment holding rules will be used.  These rules are based 
on a modified Toxicity Probability Interval (mTPI) (Ji et al, 2010) where the target TPI is 
a DLT probability from 20% to 33% and the overdose TPI is > 33% DLT probability.  
Enrollment to the ongoing dose level/schedule will be paused per the rules in Table 5-1 
during enrollment into phase 1b cohorts 1 and 2. 
Table 5-1.  Rules for Holding Enrollment in Phase 1b 
Number of Dose-limiting Toxicities 
 2 
 3 
 4 
Number of Treated Subjects 
 4 
 6 
 8 
If the rules for pausing enrollment are met, no further enrollment to the respective dose 
level/schedule will be allowed until after a careful review of all safety data by the DLRT.  
Additionally, enrollment will not resume until the protocol has been amended to include 
additional safeguards for subject safety (eg, modifications to dose level and schedule). 
Subjects with EM disease will be able to enroll into cohort 2 after the safety evaluation is 
complete for 3 subjects with EM disease treated at 400 µg/day.   
For definition of the DLT evaluation period and DLT-evaluable subject refer to 
Section 7.4.1.  For details on the mTPI model see Section 10.3. 
An investigator will review efficacy data and assess outcomes in accordance with IMWG 
criteria.  Investigator assessments will be used for primary efficacy analysis.   
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
Approximately 20 subjects will be enrolled in this study.   
Subjects in this clinical investigation shall be referred to as “subjects.”  For the sample 
size justification, see Section 10.1. 


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5.2.1 
Replacement of Subjects 
Subjects that are not DLT-evaluable may be replaced.  A subject is non-DLT-evaluable if 
subject discontinues treatment for any reason other than a DLT prior to completing the 
DLT evaluation period (see Section 7.4.1 for DLT details). 
5.2.2 
Number of Sites 
Approximately 15 investigative sites in the European Economic Area, Australia, Japan, 
and the US will be included in the study.  Sites that do not enroll subjects within 
4 months of site initiation may be closed.  Additional countries or sites may be added if 
deemed necessary. 
5.3 
End of Study 
5.3.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), whether the study concluded as planned in the protocol or was 
terminated early. 
The primary completion date is the date when data for the primary endpoint of phase 1b 
are last collected at month 6 after the last subject is enrolled.  
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study (EOS) date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, LTFU), as applicable. 
5.3.2 
Study Duration for Subjects 
It is anticipated that an individual subject will participate in the study for up to 
approximately 5 years.  
This includes a screening period lasting up to 21 days, a treatment period lasting for a 
median of approximately 8 months, and a follow-up period lasting up to 5 years from the 
first dose of AMG 420.  
The actual duration for individual subjects will vary depending upon tolerability of 
AMG 420, evidence of clinical progression, and willingness to participate in the study. 


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5.4 
Justification for Investigational Product Dose (AMG 420) 
The primary purposes in phase 1b are to 1) confirm the safety and tolerability of the 
400 g/day dose level in subjects with or without extramedullary (EM) disease and 
2) establish the safety and tolerability of the 600 g/day dose level.   
The rationale for dosing in this study is based on the observations and experiences with 
AMG 420 in the separate FIH study conducted by BI (1351.1), which suggests that a cIV 
administration is safe and has the potential to induce durable remissions in patients with 
RRMM.  This BI 1351.1 study has identified the 400 g/day dose level as a preliminary 
safe and effective dose, as this dose was well tolerated in n = 3 subjects, whereas 2 of 
3 subjects treated at the 800 g/day dose experienced DLTs.  The 600 g/day dose 
level was not evaluated in the FIH study.  Subjects may benefit from higher exposures 
than are achieved at the 400 g/day dose level; thus, safety and tolerability of the 
600 g/day dose level may be evaluated in this phase 1b study.  The DLRT will convene 
and review all available safety, laboratory, and PK data from all subjects treated in 
phase 1b cohort 1 at the 400 g/day dose before recommending evaluation of the 
600 µg/day dose (phase 1b cohort 2).  If the DLRT recommends the 600 g/day dose to 
be safe and well-tolerated after reviewing the phase 1b cohort 2 data, the sponsor may 
propose changing the recommended phase 2 dose be 600 µg/day on the basis of interim 
data analyses.   
5.5 
Patient Input on Study Design 
Subject input was not obtained for this study. 
6. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  
Eligibility criteria will be evaluated during screening.   
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 12.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
6.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 


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101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures 
102 
Age  18 years at the time of the signing of informed consent 
103 
Multiple myeloma meeting the following criteria: 
 
Pathologically-documented diagnosis of multiple myeloma that is relapsed or 
is refractory (see Section 12.9) as defined by the following:  
 
Relapsed after  3 lines of prior therapy that must include a PI, an IMiD, 
and a CD38-directed antibody in any order during the course of treatment 
OR refractory to PI, IMiD, and CD38-directed antibody. 
 
Measurable disease, defined by 1 or more of the following at time of 
screening: 
 
serum M-protein  0.5 g/dL measured by serum protein electrophoresis 
(SPEP) 
 
urinary M-protein excretion  200 mg/24 hours 
 
Involved sFLC measurement  10 mg/dL, provided that the sFLC ratio is 
abnormal as per IMWG response criteria 
104 
Eastern Cooperative Oncology Group (ECOG) performance status of  2  
105 
Life expectancy of at least 3 months as per investigator`s judgment at time of 
screening 
106 
Hematological function without transfusion support (within 7 days from screening 
assessment) as follows: 
 
ANC  1.0 x 109/L (without growth factor support) 
 
platelet count  50 x 109/L (without transfusions), but  25 x 109/L if the 
marrow is replaced by  50 myeloma (unless receiving anticoagulation 
therapy then platelet count must be  50 x 109/L) 
 
hemoglobin  7.0 g/dL (transfusions permitted no later than 48 hours before 
screening) 
107 
Renal function as follows: 
 
calculated or measured creatinine clearance  30 mL/min using the 
Cockcroft-Gault equation or via 24-hour urine collection with plasma and 
urine creatinine concentrations, respectively 
108 
Hepatic function as follows: 
 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
 3 x upper limit of normal (ULN) 
 
total bilirubin (TBIL)  1.5 x ULN (unless considered due to Gilbert’s 
syndrome) 
6.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
201 
Known central nervous system involvement by multiple myeloma 


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202 
Evidence of primary or secondary plasma cell leukemia at the time of screening  
203 
Waldenstrom’s macroglobulinemia 
204 
Unresolved toxicities from prior anticancer therapy, defined as not having 
resolved to CTCAE version 5.0 grade 1 or to levels dictated in the eligibility criteria with 
the exception of grade 2 peripheral neuropathy, alopecia, or toxicities from prior 
anticancer therapy that are considered irreversible (defined as having been present and 
stable for > 4 weeks) which may be allowed if they are not otherwise described in the 
exclusion criteria and there is agreement to allow by both the investigator and Amgen 
medical monitor 
Other Medical Conditions 
205 
History of other malignancy within the past 3 years, with the following exceptions: 
 
malignancy treated with curative intent and with no known active disease 
present for ≥ 1 year before enrollment and felt to be at low risk for recurrence 
by the treating physician 
 
adequately-treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
 
adequately-treated cervical carcinoma in situ without evidence of disease 
 
breast ductal carcinoma in situ with full surgical resection (ie, negative 
margins) and without evidence of disease 
 
prostate cancer with a Gleason score equal to 6 with undetectable prostate 
specific antigen (PSA) over 12 months 
 
treated medullary or papillary thyroid cancer 
 
adequately-treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ 
 
similar neoplastic conditions with an expectation of > 95% five-year 
disease-free survival 
 
see exclusion criterion 202 for exclusion of subjects with evidence of primary 
or secondary plasma cell leukemia at the time of screening 
206 
Known history of amyloidosis 
207 
Current or known history of autoimmune diseases requiring systemic treatment in 
past 5 years except vitiligo, resolved childhood asthma/atopy, or subjects with history of 
hypothyroidism after completing treatment for autoimmune thyroid disease, stable on 
hormone replacement therapy. 
208 
Clinically not-controlled chronic or ongoing infectious disease requiring treatment 
at the time of study day 1 or within the 14 days before study day 1 
209 
Symptomatic peripheral sensory or motor neuropathy of grade  3 
210 
History or presence of clinically relevant central nervous system (CNS) pathology 
as uncontrolled epilepsy or seizure disorder, paresis, aphasia, stroke, severe brain 
injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, and 
psychosis 
211 
Active hepatitis B and C based on the following results: 
 
Positive for hepatitis B surface antigen (HepBsAg) (indicative of chronic 
hepatitis B or recent acute hepatitis B) 


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 
Negative HepBsAg and positive for hepatitis B core antibody:  Negative 
hepatitis B virus DNA by polymerase chain reaction (PCR) result is 
necessary.  Detectable hepatitis B virus DNA suggests occult hepatitis B. 
 
Positive Hepatitis C virus antibody (HepCAb):  Negative hepatitis C virus 
RNA by PCR result is necessary.  Detectable hepatitis C virus RNA suggests 
chronic hepatitis C 
212 
Known or suspected HIV infection or subjects who are HIV seropositive 
213 
Baseline ECG QTc > 470 msec (applying Fridericia correction), defined as the 
average of individual baseline ECGs 
Prior/Concomitant Therapy 
214 
Previously received an allogeneic stem cell transplant and the occurrence of 1 or 
more of the following: 
 
received the transplant within 6 months prior to study day 1 
 
received immunosuppressive therapy within the last 3 months prior to study 
day 1 
 
any active acute graft versus host disease (GvHD), grade 2 to 4, according to 
the Glucksberg criteria or active chronic GvHD requiring systemic treatment 
 
any systemic therapy against GvHD within 2 weeks prior to start of 
investigational product treatment 
215 
Autologous stem cell transplantation  90 days prior to study day 1 
216 
Treatment with systemic immune modulators including, but not limited to, 
nontopical systemic corticosteroids (unless the dose is ≤ 10 mg/day prednisone or 
equivalent), cyclosporine, and tacrolimus within 2 weeks before study day 1 
217 
Last anticancer treatment (chemotherapy, IMiD, PI, molecular targeted therapy) 
< 2 weeks prior to study day 1 
218 
Last treatment with a therapeutic antibody less than 4 weeks prior to study day 1 
219 
Radiation therapy to multiple anatomic sites within 28 days prior to study day 1.  
Focal radiotherapy within 14 days prior to study day 1. 
220 
Major surgery defined as surgery requiring general anesthesia with endotracheal 
intubation within 28 days prior to study day 1, unless discussed with and eligibility 
approved by Amgen medical monitor 
221 
Prior treatment with any drug that specifically targets BCMA on tumor cells 
(eg, other bi-specific antibody constructs, antibody drug conjugates, or CAR T-cells, 
except for subjects who were previously treated with AMG 420 in this study. 
222 
Treatment with medications known to cause QTc interval prolongation within the 
washout periods described in Section 12.10 unless approved by the Amgen medical 
monitor 
Prior/Concurrent Clinical Study Experience 
223 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or drug 
study(ies).  Other investigational procedures while participating in this study are 
excluded. 


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Other Exclusions 
224 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 6 weeks after the last dose of 
investigational product.   
225 
Female subjects of childbearing potential unwilling to use 1 highly effective 
method of contraception during treatment and for an additional 6 weeks after the last 
dose of investigational product.  Refer to Section 12.5 for additional contraceptive 
information. 
226 
Female subjects with a positive pregnancy test assessed at screening or within 
7 days prior to enrollment (unless a confirmatory  serum pregnancy test is negative after 
a positive urine result).   
227 
Male subjects with a female partner of childbearing potential who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or use contraception 
during treatment and for an additional 14 weeks after the last dose of investigational 
product.  Refer to Section 12.5 for additional contraceptive information. 
228 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom during treatment and for an additional 14 weeks after the last dose of 
investigational product. 
229 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 14 weeks after the last dose of investigational product. 
230 
Subject has known sensitivity to immunoglobulins or any of the products or 
components to be administered during dosing. 
231 
Subjects likely to not be available to complete all protocol-required study visits or 
procedures, including BM aspirates/biopsies, and/or to comply with all required study 
procedures to the best of the subject and investigator’s knowledge.   
232 
History or evidence of any other clinically-significant disorder, condition, or 
disease (eg, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia requiring therapy at time of screening) with the exception of those outlined 
above that, in the opinion of the investigator or Amgen medical monitor, if consulted, 
would pose a risk to subject safety or interfere with the study evaluation, procedures, or 
completion. 
6.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 12.3). 
Subjects may be eligible to enroll once all screening tests and procedures are completed 
and results indicate that all eligibility criteria are met.  A site representative will complete 
and send the enrollment eligibility worksheet to Amgen along with the lab results and 
any requested supporting documentation for review of eligibility criteria.  The completed 
Eligibility Worksheet should be emailed to the Amgen representative at least 3 days prior 


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to the planned day of first dose.  The Amgen representative will acknowledge receipt of 
the paperwork and send confirmation of the subject’s eligibility.   
The subject must personally sign and date the IRB/IEC and Amgen approved informed 
consent before commencement of study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment electronic case report form (eCRF). 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject signs the informed consent) receives a unique subject identification 
number before any study-related activities/procedures are performed.  The subject 
identification number will be assigned by Interactive Response Technology (IRT).  This 
number will be used to identify the subject throughout the clinical study and must be 
used on all study documentation related to that subject. 
The unique subject identification number will consist of 11 digits.  The first 3 digits will 
represent the last 3 digits of the protocol number (ie, 370).  The next 5 digits will 
represent the country code and site number (eg, 26001) and will be identical for all 
subjects at the site.  The next 3 digits will be assigned in sequential order as subjects 
are screened (eg, 001, 002, or 003).  For example, the first subject to enter screening at 
site 26001 will receive the number 37026001001, and the second subject at the same 
site will receive the number 37026001002.  
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.   
Enrollment in the study will begin with  cohort 1.  An Amgen representative will notify the 
site in writing when cohort 2 is open to screen and enroll subjects.  Sites will also be 
informed as to which cohort their subjects will be allocated to by the Sponsor. 
6.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, medical history, prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened a maximum of 2 times.  Refer to Section 9.1.1. 


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7. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Section 7.1 below. 
7.1 
Treatment Procedures 
7.1.1 
Investigational Product:  AMG 420 
7.1.1.1 
AMG 420 Dosage Formulation 
AMG 420 is manufactured by Boehringer Ingelheim Pharma GmbH & Co. KG, packaged 
by Amgen Inc., and distributed using Amgen clinical study drug distribution procedures.  
AMG 420 is supplied as a sterile, preservative-free lyophilized powder for IV 
administration after reconstitution with sterile Water for Injection (WFI).  The final 
container is a single-use, 4 mL glass vial and contains a target extractable amount of 
75 g AMG 420.  
The intravenous solution stabilizer (IVSS) is supplied as a sterile solution in a 10 cc 
glass vial containing 10 mL deliverable product.  The IVSS does not contain an active 
pharmaceutical ingredient.  The IVSS is intended for pretreatment of the IV bags prior to 
dilution of AMG 420 drug product.   
Refer to the IPIM for further details. 
7.1.1.2 
AMG 420 Dosage, Administration, and Schedule 
AMG 420 will be administered as a cIV infusion.  A treatment cycle consists of a 4-week 
infusion period followed by a 2-week infusion-free interval prior to the following treatment 
cycle (phase 1b, monotherapy).  Refer to Section 7.4.2.1.2.2 for treatment delays due to 
AEs. 
Cohort 1 
Subjects in cohort 1 will receive a dose of 400 μg/day starting on day 1 of each 
treatment cycle.  If a dose step is determined to be needed after DLRT review of all 


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available safety data, the initial dose will be 200 μg/day for the first 3 days of treatment 
cycle 1.  On day 4 of cycle 1 and for the remainder of cycle 1, the dose for cohort 1 will 
then be escalated (dose step) to 400 μg/day.  From cycle 2 onwards, the dose will 
remain at 400 g/day, no dose step will be required. 
Cohort 2 
Subjects in cohort 2 will receive a dose of 200 μg/day for the first 3 days of treatment 
cycle 1.  On day 4 of cycle 1 and for the remainder of cycle 1, the dose for cohort 2 will 
then be escalated (dose step) to 600 μg/day.  From cycle 2 onwards, the dose will 
remain at 600 μg/day and no dose step will be required.  See Section 12.11 for 
procedures.   
Subjects with EM disease will be able to enroll into cohort 2 after the safety evaluation is 
complete for 3 subjects with EM disease treated at 400 μg/day (cohort 1). 
7.1.1.3 
MRD-based Extended Treatment-free Interval  
The treatment-free interval may be increased as follows: 
 
Up to 4 weeks in subjects who attain MRD-negative disease status at 6 months from 
enrollment (based on all appropriate assessments to fulfill IMWG criteria), 
 
Up to 8 weeks in subjects who remain in MRD-negative disease status at 12 months 
from enrollment.  Treatment will continue until progression or at the discretion of the 
investigator, can be discontinued at 24 months if subjects remains in complete 
remission. 
The treatment free interval may be decreased to the initial treatment free interval 
of 2 weeks at the discretion of the investigator upon informing the sponsor.  
Reinstatement of the treatment free interval at the cadence prior to the decrease is 
not permitted.  
7.1.1.4 
Dosing Instructions 
The Amgen investigational product (AMG 420) will be dispensed at the research facility 
by a qualified staff member. 
At the beginning of a treatment cycle a physician or nurse trained in emergency medical 
care must be available when the infusion of investigational product (AMG 420) is started 
for immediate intervention in case of complications. 
AMG 420 will be delivered using infusion pumps approved for use by the appropriate 
regulatory authority for the country in which the subject is undergoing treatment.  
AMG 420 solution for infusion will be prepared in bags for IV infusion and delivered 
through infusion lines.    


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The drug will be administered as a cIV infusion at a constant flow rate.  
The drug should not be administered as a bolus and flushing residual drug at the time of 
bag change is prohibited.  The final solution for infusion should be administered through 
a sterile 0.2 μm in-line filter.  
Infusion bags should be changed in accordance with country regulations and local 
pharmacy standards for infusion of compounded sterile products up to 48 hours in the 
US and up to 96 hours in Australia and Europe.  
The start time of infusion should be chosen carefully to avoid any interference or 
inconvenience with time points of safety assessments, PK/pharmacodynamic 
measurements, and infusion bag changes.  
Any infusion interruption that is longer than 1 hour should be recorded on the eCRF 
(including start date/time and stop date/time) with the exception of adverse events.  Any 
infusion interruption due to an adverse event, independent of the duration of the 
interruption, should be recorded on the eCRF.   
Details for handling infusion interruptions are outlined in Section 7.4.2. 
7.1.1.4.1 
AMG 420 Inpatient Dosing/Hospitalization 
Minimum hospitalization times for subjects will be as follows: 
 
Cycle 1:  48 hours or 6 days after start of infusion if step dosing is utilized. 
 
Cycle 2:  24 hours monitoring after start of infusion; longer monitoring can be 
decided upon at investigator’s discretion. 
 
Cycles 3 and 4:  4 hours monitoring after start of infusion.  
 
Cycle 5 and subsequent cycles:  hospitalization not required unless subject 
experiences an adverse event requiring hospitalization as indicated in Section 2.2 of 
the study protocol or if clinically indicated.  The length of hospitalization required in 
these cases is to be determined by the investigator.   
 
Re-start of treatment after an interruption due to adverse event:  48 hours.  
 
Re-start of treatment after an interruption of  4 hours due to technical/logistical 
issue:  24 hours. 
 
Any cycle with dose re-escalation:  48 hours after dose re-escalation.  
For cycles 1 and 2 in-hospital administration, study sites must have immediate access to 
a medical intensive care unit staffed by critical care providers.  Prior to hospital 
discharge, vital signs will be measured in order to detect possible signs and symptoms 
of infusion reactions or CRS.  If required for logistical reasons (eg, long travel times), 


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subjects may be hospitalized the day before start of dosing (day -1) of any cycle, as well 
as at the end of infusion (EOI) for cycle 1 for required PK samples.   
7.1.1.4.2 
AMG 420 Outpatient Dosing 
If deemed stable by the investigator, a subject may continue AMG 420 cIV infusion as an 
outpatient.   
For infusion bag changes in the outpatient setting, the subject will either return to the 
study site or be visited by a well-trained home health care service (HHCS) provider at 
the required frequency.  If home visits for IV bag changes are required, the HHCS 
provider will change the infusion bag, measure vital signs, monitor, document and report 
adverse events/serious adverse events per Section 9.2.3, and document any issues with 
the cIV infusion or infusion pump.  The subject and HHCS provider will be trained and 
will receive written instructions for storage of the IV bags, if applicable.  The HHCS 
provider will complete the study delegation log and will be authorized by the investigator 
before any study-related tasks are started.   
Refer to the home health care manual for detailed information on the storage, handling, 
and administration of AMG 420, mandatory procedures, and data collection 
requirements. 
Following each visit or telephone contact by the HHCS provider, the information 
collected will be documented on the HHCS’s visit worksheet and forwarded to the 
investigator.  Any unexpected or unusual events, as well as deviations will be 
communicated promptly to the investigator.  If any adverse event/serious adverse event 
occurs in the outpatient setting, the HHCS provider should directly contact the site for 
further management.  The HHCS professionals provide 24-hour emergency on-call 
service for any pump related issues.  In the event of an infusion interruption of the AMG 
420 cIV infusion management of the interruption and re-start of the infusion should be 
performed as outlined in Section 7.4.2. 
7.1.1.5 
Drug Accountability 
The planned dose, start date, start time, stop date, stop time, dose administered, reason 
for dose change, and package lot number of AMG 420 are to be recorded on each 
subject's eCRF(s) and the site’s study files.   
7.1.2 
Non-investigational Products 
This study will not use non-investigational products. 


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7.1.3 
Medical Devices 
No investigational medical device(s) will be used in this study. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Amgen investigational product (AMG 420) must be administered using infusion pumps 
approved for use by the appropriate regulatory authorities for the country in which the 
subject is undergoing treatment in both the inpatient and outpatient setting.  
Investigational product solution for infusion will be prepared in bags for IV infusion and 
delivered through infusion lines with a 0.2 m in-line filter that are both compatible with 
the investigational product.  Non-investigational medical devices (eg, syringes, sterile 
needles), that are commercially available are not usually provided or reimbursed by 
Amgen (except, for example, if required by local regulation).  The investigator will be 
responsible for obtaining supplies of these devices. 
7.1.4 
Other Protocol-required Therapies 
All other protocol-required therapies including, glucocorticoids and tocilizumab, that are 
commercially available are not provided or reimbursed by Amgen (except if required by 
local regulation).  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies. 
7.1.4.1 
Glucocorticoid Premedication 
Premedication with IV glucocorticoids, as described below, is required.  Administration of 
glucocorticoids is recommended to occur 30 to 60 minutes before the start of 
AMG 420 treatment cycles and must not occur earlier than 2 hours, to prevent/reduce 
severity of infusion-related reactions and CRS.  
 
prior to cycles 1 and 2, as well as prior to dose step in cycle 1:  equivalent to 50 mg 
prednisone, 40 mg methylprednisone, or 8 mg dexamethasone 
 
prior to cycle 3:  equivalent to 25 mg prednisone, 20 mg methylprednisone, or 4 mg 
dexamethasone 
If AMG 420 is tolerated well, the investigator may decide to further reduce or do without 
premedication in later treatment cycles. 
Premedication will also be required 30 to 60 minutes before re-start of the infusion in 
case of an infusion interruption for > 1 week.  The premedication dose will be the same 
that was administered prior to start of the cycle unless adjustments are needed based on 
investigator judgement.     


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7.1.4.2 
CRS Treatment 
For administration of dexamethasone or tocilizumab after occurrence of CRS, follow 
guidance in Table 7-3.  In advance of AMG 420 administration and possible CRS that 
may warrant the administration of tocilizumab for CRS, evaluate subjects for tuberculosis 
risk factors and identify those at risk for reactivation via notation in the medical record.  
For subjects with a past medical history of latent or active tuberculosis or positive test for 
latent tuberculosis at screening, tocilizumab should be administered according to 
warning and precautions guidelines for tuberculosis provided in the tocilizumab regional 
prescribing information.  All sites will ensure that CRS rescue medications are available 
on-site, including corticosteroids and (for sites in regions where tocilizumab is approved 
and available, eg, the US and Germany) 2 doses of tocilizumab per study subject. 
7.1.5 
Other Treatment Procedures 
No other treatment procedures are applicable in this study. 
7.1.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, or device after it is released for distribution to market or clinic by 
either (1) Amgen or (2) distributors and partners for whom Amgen manufactures the 
material.  This includes all components distributed with the drug such as 
packaging drug containers, delivery systems, labelling, and inserts. 
This includes any investigational product (AMG 420) provisioned and/or 
repackaged/modified by Amgen. 
Any product complaint(s) associated with an investigational product (AMG 420) supplied 
by Amgen are to be reported according to the instructions provided in the IPIM. 
7.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments and/or procedures are excluded during the treatment period of 
the study (until SFU):  
 
any antitumor therapy other than AMG 420, such as: 
 
cytotoxic and/or cytostatic drugs 
 
radiation therapy (with the exception of radiotherapy for palliative care such as 
bone pain; this is only permitted after discussion with Amgen medical monitor) 
 
immunotherapy  


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 
any other immunosuppressive therapies (except for the management of acute, 
treatment-related toxicities such as transient - ie, for up to 2 weeks - use of 
corticosteroids and tocilizumab) 
- high-dose corticosteroid therapy (dexamethasone > 24 mg/day or equivalent) is 
only allowed for up to 7 days 
 
any other investigational agent 
 
treatment with medications known to cause QTc interval prolongation unless 
approved by the Amgen medical team (see Section 12.10) 
 
any major surgery, except for surgery for palliative repair of pathologic fractures, as 
long as determined not to be due to disease progression  
 
none of the medications mentioned in Section 7.8.2 are excluded during the study  
7.1.8 
Vaccines 
The use of vaccines except live and live-attenuated vaccines will be allowed 
during therapy per regional and institutional standard of care.  Throughout the 
trial, SARS-COV-2 vaccination should be avoided within 3 days after the 
administration of AMG 420.  In the event where a patient requires steroids for 
treatment of AEs, vaccination should be avoided while on steroids. 
7.2 
Method of Treatment Assignment 
An Amgen representative will notify the site(s) in writing when a cohort or study part, 
respectively, are open to screen and enroll subjects.   
Subjects who meet eligibility criteria will be assigned to treatment with AMG 420.   
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment eCRF. 
7.3 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
7.4 
Dose Modification 
7.4.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules  
The DLT evaluation period (ie, DLT-evaluable period) will be the 4 weeks on AMG 
420 treatment within the first treatment cycle, starting on day 1 (start of infusion).  The 
DLT evaluation period may also be extended to assess events starting within the window 
in case the DLT definition is time dependent. 
Treatment in AMG 420 cycle 1 will be considered complete and the subject will be DLT 
evaluable if the subject has completed the DLT evaluation period or experienced a DLT 
any time during the DLT evaluation period.  A subject will be non-DLT evaluable if 
he/she drops out before completion of the DLT-evaluable period for reasons other than a 


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DLT.  All available safety data for subjects who are non-DLT-evaluable will still be 
evaluated and considered in DLRT decisions (see also Section 10.4.1.1.1.1).     
See Section 5.2.1 for description of replacement of subjects. 
A DLT will be defined as any of the events described below occurring in a subject during 
the DLT evaluation period unless clearly attributable to causes other than treatment with 
AMG 420.  The CTCAE version 5.0 (see Section 12.4) will be used to assess 
toxicities/adverse events with the exception of CRS and TLS (see Section 7.4.2.1.2.5 
and Section 12.12 for grading criteria of CRS and TLS, respectively).  
 
Death not clearly due to the underlying disease or extraneous causes. 
Non-hematologic DLTs:  
 
Non-hematological adverse event grade 3 or higher, EXCEPT: 
 
infection responding to antibiotic/anti-infective treatment within 48 hours 
 
grade 3 fatigue or asthenia 
 
grade 3 headache resolving to ≤ grade 2 within 72 hours 
 
grade 3 insomnia resolving to ≤ grade 2 within 7 days 
 
grade 3 fever resolving to ≤ grade 2 within 72 hours 
 
grade 3 nausea, vomiting, or diarrhea responding if successfully managed with 
optimal medical support and resolved within 72 hours 
 
laboratory parameters of grade ≥ 3, not considered clinically relevant, and 
improved to grade ≤ 2 within 72 hours 
 
Any subject meeting the criteria for Hy’s Law case (ie, severe drug-induced liver 
injury [DILI]) will be considered a DLT.  A Hy’s Law case is defined as:  AST or ALT 
values of ≥ 3 x ULN AND with serum TBIL level of > 2 x ULN or international 
normalized ratio (INR) > 1.5 without signs of cholestasis and with no other clear 
alternative reason to explain the observed liver-related laboratory abnormalities 
(see Section 7.4.3 for hepatotoxicity management and Section 12.7 for further 
explanation of Hy’s law case and management of hepatic function). 
Hematologic DLTs: 
 
febrile neutropenia grade 4 
 
febrile neutropenia grade 3 unless responding to antibiotic/anti-infective treatment 
within 48 hours 
 
grade 4 neutropenia lasting more than 5 days, grade 4 thrombocytopenia lasting 
more than 7 days, grade 3 thrombocytopenia with hemorrhage or required platelet 
transfusion, or grade 4 anemia in the absence of detectable multiple myeloma as it 
may reflect a marrow toxic effect of AMG 420 
The dosing schedule is described in the Schedule of Activities (Section 2.2). 


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7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.2.1 
Amgen Investigational Product:  AMG 420 
The reason for dose change of AMG 420 is to be recorded on each subject’s eCRF(s). 
7.4.2.1.1 
Infusion Interruptions and Re-Start in Case of Technical/Logistical 
Issues 
The administration of AMG 420 should not be interrupted, if possible.  In case of infusion 
interruption due to any technical or logistical reason (eg, a technical problem with the 
infusion pump, diagnostic measurements, or the investigational product is incorrectly 
prepared or administered), the interruption should be as short as possible, and the 
infusion continued at the earliest time possible.  
If the interruption is longer than 4 hours, re-start of the infusion should be performed in 
the hospital, under the supervision of the investigator.  If the interruption occurs during 
cycles 1 or 2, the subject should be observed for 24 hours after re-start for possible side 
effects.  If the interruption occurs in cycle 3 or beyond, the subject should be observed 
for 4 hours.  Premedication as described in Section 7.1.4 must be administered prior to 
resumption of AMG 420 infusion, if applicable.  
The assessments that should be performed prior to re-start of infusion as for 
cycle 1 days 1 and 2 are specified in the Schedule of Activities (see Section 2.2).   
Every interruption longer than 1 hour should be documented on the eCRF.   
7.4.2.1.2 
Infusion Interruptions/Re-Start/Dosage Adjustments due to Adverse 
Events 
7.4.2.1.2.1 
General Guidelines 
Subjects should be assessed for adverse events at each visit.  The severity of the 
adverse event will be graded using the CTCAE version 5.0 (Section 12.4), with the 
exception of CRS, which must be graded using the criteria referenced in the publication 
by Lee et al, 2014 (see Table 7-3) and TLS, which must be graded according to the 
Cairo Bishop criteria referenced in the publication by Coiffier et al, 
2008 (see Section 12.12).   
Infusion modification and dose reduction due to an adverse event will be performed 
according to the instructions described below and outlined in Table 7-1 and Table 7-3. 
Infusion interruptions for other reasons need to be discussed with the Amgen medical 
monitor. 


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If infusion interruptions of  14 days occur within a cycle the cycle will be resumed.  The 
counting of the cycle days will not be stopped with an infusion interruption (eg, if the 
infusion is stopped on cycle day 5 and resumed 5 days later, the day of re-start is cycle 
day 10). 
Following an infusion interruption with  7 days remaining for infusion after resumption of 
the cycle, the last treatment days can be skipped and treatment will be continued with 
the next cycle after a 2-week infusion free interval.  
However, treatment should not be given for  14 days per cycle.  An infusion interruption 
of more than 2 weeks or several interruptions exceeding a total of 14 days of treatment 
per cycle due to serious adverse events/adverse events require permanent treatment 
discontinuation. 
Please note:  the guidance in Section 7.4.2.1.2 does not apply to the treatment holiday 
described in Section 7.1.1.2. 
7.4.2.1.2.2 
Infusion Interruptions Due to Adverse Events  
Events occurring during the 4-week infusion period of a treatment cycle and requiring 
treatment interruption will be managed by infusion interruption.   
Any treatment interruption due to an adverse event, independent of the duration of the 
interruption, should be documented on the eCRF including start and stop date/time of 
the infusion.   
Delay of Subsequent Infusion due to Adverse Events 
Events occurring after the end of the infusion and requiring a delay of treatment will be 
managed by delay of the subsequent infusion.  The site should record any delay of an 
infusion on the eCRF and provide the start and stop date/time of the infusion. 
Events requiring a delay of the subsequent infusion are listed in Table 7-1.  Infusion 
interruptions or delays greater than 7 days for other reasons need to be discussed with 
the Amgen Medical Monitor.  Delays of treatment cycles beyond 14 days are not 
permitted. 
Events requiring an infusion interruption including guidance for management, re-start, 
and permanent discontinuation are listed in Table 7-1 and Table 7-3.   


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7.4.2.1.2.3 
Re-Start of Infusion 
Re-starting treatment after interruption due to an adverse event should be performed in 
the hospital under medical supervision.  Premedication as described in Section 7.1.4 
must be administered prior to re-start, if applicable.  
The assessments that should be performed as for cycle 1 days 1, 2, and 3 are specified 
in the Schedule of Activities (see Section 2.2):   
The subject should be hospitalized for at least 48 hours after re-start of the infusion 
(see also Section 7.1.1.4.1). 
7.4.2.1.2.4 
Dosage Adjustments/Re-Start at a Lower Dose Level/ 
Dose-Escalation 
For adverse events for which re-start of treatment is allowed according to the guidelines 
outlined in Table 7-1 and Table 7-3, treatment may be resumed under medical 
supervision at the same dose or a lower dose.  
Premedication as described in Section 7.1.4 must be administered prior to re-start, if 
applicable.  
Re-start at a lower dose level: 
If clinically indicated per the guidance provided in Table 7-1 and Table 7-3, treatment will 
be resumed at a lower dose level (ie, 200 g/day for subjects originally receiving 
400 g/day or 400 g/day for those originally receiving 600 g/day) and continued until 
the pre-scheduled end of the cycle. 
The assessments that should be performed as for cycle 1 days 1, 2, and 3 are specified 
in the Schedule of Activities (see Section 2.2).    
The subject should be hospitalized for at least 48 hours after re-start of the infusion 
(see also Section 7.1.1.4.1).  
Only one dose de-escalation step per subject is allowed in the study.  In case an 
additional dose de-escalation is required for a subject, permanently discontinue 
treatment. 
Dose-escalation: 
Dose-escalation is allowed with start of the next treatment cycle if treatment is well 
tolerated and escalation is appropriate according to the investigator’s judgement.  In 
addition to the assessments required as per Schedule of Activities (see Section 2.2), a 


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neurological examination should be performed before dosing in case the infusion 
interruption was due to a neurologic event. 
The subject should be hospitalized for at least 48 hours after dose-escalation (see also 
Section 7.1.1.4.1).


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Table 7-1.  Infusion Interruptions/Permanent Discontinuations and Management of Adverse Events Including Dose Reductions 
 
Interruption 
Specific Management 
Re-Start Guidance 
Permanent 
Discontinuation 
Infusion-related Reaction 
Grade 1 
n/a 
 Consider supportive 
medication according to local 
standard of care.  
 Increase monitoring of vital 
signs as medically indicated. 
Continue infusion 
n/a 
Grade 2 
Immediate 
interruption until 
event has improved 
to grade  1 
 
Resume infusion at half the previous 
rate when symptoms have resolved for 
at least 30 minutes, observe patient 
and re-escalate to basal rate after 
60 minutes if successfully managed 
and improvement to grade  1 in 
 14 days.  
 
Hospitalization:  48 hours for start of 
next infusion 
 
Dose modification:  resume at the same 
dose OR consider reducing to next 
lower dose if clinically indicated 
(ie, 200 g/day for subjects originally 
receiving 400 g/day or 400 g/day for 
those originally receiving 600 g/day)  
 
Additional measures:  additional 
assessments and premedication as 
indicated in 
Sections 7.4.2.1.2.3 /7.4.2.1.2.4 
If interruption is 
 14 days 
Page 1 of 4 


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Table 7-1.  Infusion Interruptions/Permanent Discontinuations and Management of Adverse Events Including Dose Reductions 
Interruption 
Specific Management 
Re-Start Guidance 
Permanent 
Discontinuation 
Infusion-related Reaction (continued) 
Grade 3 
Immediate 
interruption until 
event has improved 
to grade  1 
 Consider supportive 
medication including steroids 
as clinically indicated. 
 Increase monitoring of vital 
signs as medically indicated.  
 
As for grade 2 infusion-related reaction, 
with the exception that dose 
modification is mandatory:  reduce to 
next lower dose (200 g/day for 
subjects originally receiving 400 g/day 
or 400 g/day for those originally 
receiving 600 g/day) 
If interruption is 
 14 days 
 
If occurs on 
 2 occasions 
Grade 4 
Immediate 
interruption  
As for grade 3 infusion-related 
reaction 
Do not restart 
Permanent 
discontinuation 
Cytokine Release Syndrome 
For Grading, Stopping and Rechallenge Rules please refer to Table 7-3 
Page 2 of 4 


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Table 7-1.  Infusion Interruptions/Permanent Discontinuations and Management of Adverse Events Including Dose Reductions 
Interruption 
Specific Management 
Re-Start Guidance 
Permanent 
Discontinuation 
Tumor Lysis Syndrome (TLS) – Grading according to Cairo-Bishop Criteria 
Grade2 - 3 
Immediate 
interruption until 
event has improved 
to grade  1 
TLS prevention and 
management as per local 
standard of care and institutional 
guidelines. 
 
Re-start possible if successfully 
managed and improvement to 
grade  1 in  14 days 
 
Hospitalization:  Minimum 48 hours for 
start of next infusion 
 
Dose modification:  reduce to next 
lower dose (ie, 200 g/day for subjects 
originally receiving 400 g/day or 
400 g/day for those originally receiving 
600 g/day) or if dose escalation is 
desired consult with Amgen medical 
monitor. 
Additional measures:  additional 
assessments and TLS premedication prior 
to infusion restart and next cycle infusion 
as per institutional standards 
Sections 7.4.2.1.2.3/7.4.2.1.2.4 
If symptoms/signs do 
not resolve in 
 14 days, consult 
with Amgen medical 
monitor if restarting 
treatment is desired. 
In case of 
appearance of same 
event at grade 3 or 
higher. 
 
Grade 4 
Immediate 
interruption  
As for grade 3 TLS 
 
Do not restart 
Permanent 
discontinuation 
Page 3 of 4


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Table 7-1.  Infusion Interruptions/Permanent Discontinuations and Management of Adverse Events Including Dose Reductions 
Interruption 
Specific Management 
Re-Start Guidance 
Permanent 
Discontinuation 
Neurotoxicity 
 Grade 3 
OR 
if increased from 
grade 0 to grade 2 
Immediate 
interruption 
Neurological examination should 
be performed before resuming 
dosing in case the infusion 
interruption was due to a 
neurologic event. 
 Re-start possible if successfully managed 
and improvement to  grade 1 or baseline 
in  14 days (up to 28 days if approved by 
medical monitor) 
 Hospitalization:  48 hours 
 Dose modification:  resume at lower dose 
(200 g/day) 
 
Additional measures:  additional 
assessments and premedication as 
indicated in 
Sections 7.4.2.1.2.3/7.4.2.1.2.4 
 If interruption is 
 28 days 
 Grade 3 event 
leading to treatment 
interruption and has 
not resolved to 
 grade 1 within 
14 days despite 
infusion interruption 
 Grade 3 event that 
recurs after dose 
reduction 
 Grade 4 event 
Hepatotoxicity 
For Stopping and Rechallenge Rules please refer to Section 7.4.3 
Page 4 of 4 


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Table 7-2.  Additional Guidance on Infusion Interruptions/Permanent Discontinuations and Management of Adverse Events 
Including Dose Reductions 
 
Interruption 
Specific Management 
Re-Start Guidance 
Permanent 
Discontinuation 
Any other AMG 420 related events not meeting dose-limiting toxicity (DLT) criteria 
 Grade 3  
Interruption 
required if Grade 
4 event, or if 
Grade 3 event is 
deemed intolerable 
by the subject or 
investigator and not 
responding to 
appropriate medical 
management until 
event has improved 
to 
grade  2 (grade  
1 in the case of 
neurological event) 
Neurological examination should 
be performed before resuming 
dosing in case the infusion 
interruption was due to a 
neurologic event. 
 
Re-start possible if successfully 
managed and improvement to 
grade  2 in  14 days. 
 
Hospitalization:  48 hours 
 
Dose modification:  resume at the same 
dose or reduce to next lower dose if 
clinically indicated (ie, 200 g/day for 
subjects originally receiving 400 g/day 
or 400 g/day for those originally 
receiving 600 g/day)  
 
Additional measures:  additional 
assessments and premedication as 
indicated in 
Sections 7.4.2.1.2.3/7.4.2.1.2.4 
If interruption is 
 14 days 
In case of 
reappearance of 
same event at 
Grade 4 
Page 1 of 4 
Abbreviations and footnotes defined on last page of table. 


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Table 7-2.  Additional Guidance on Infusion Interruptions/Permanent Discontinuations and Management of Adverse Events 
Including Dose Reductions 
 
Interruption 
Specific Management 
Re-Start Guidance 
Permanent 
Discontinuation 
Any Non-AMG 420 related events 
Grade 4  
 
Interruption 
required if Grade 
4 event, or if 
Grade 3 event is 
deemed intolerable 
by the subject or 
investigator and not 
responding to 
appropriate medical 
management until 
event has improved 
to Grade  2 
n/a 
 
Re-start possible if successfully 
managed and improvement to 
grade  2 in  14 days. 
 
Hospitalization:  48 hours 
 
Dose modification:  resume at the same 
dose or reduce to next lower dose if 
clinically indicated (ie, 200 g/day for 
subjects originally receiving 400 g/day 
or 400 g/day for those originally 
receiving 600 g/day) 
 
Additional measures:  additional 
assessments and premedication as 
indicated in 
Sections 7.4.2.1.2.3/7.4.2.1.2.4 
If interruption is 
 14 days  
 
In case of 
reappearance of 
same event at 
Grade 4 
Page 2 of 4 
Abbreviations and footnotes defined on last page of table. 


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Table 7-2.  Additional Guidance on Infusion Interruptions/Permanent Discontinuations and Management of Adverse Events 
Including Dose Reductions 
 
Interruption 
Specific Management 
Re-Start Guidance 
Permanent 
Discontinuation 
SARS-CoV-2 infection and COVID19 disease 
asymptomatic 
Interruption 
required until at 
least 10 days since 
positive SARS-COV-
2 test UNLESS 
patient previously 
fully vaccinated 
against SARS-COV-
2.  If patient 
previously 
vaccinated and tests 
positive, then 
discuss with 
Medical Monitor. 
Follow local guidelines 
and standard of care for 
COVID-19 treatment and 
isolation 
Contact Amgen Medical 
Monitor within 1 business 
day to ensure appropriate 
documentation & 
management of study 
activities. 
 
Re-start possible upon agreement between 
Investigator and Amgen Medical Monitor 
provided:  
o 
There are no new findings on physical 
exam related to SARS-COV-2, AND 
o 
Subject tests negative for SARS-COV-
2 by RT-PCR  
OR 
o 
If subject continues to test positive for 
SARS-COV-2 more than 10 days after 
initial positive test, or If subject initially 
tests positive in the setting of prior 
COVID vaccination, resume IP only 
after discussion with patient and 
reassessment of individual risk/benefit   
 
Consider chest imaging, ECG, ECHO, and 
cardiology assessment 1  
 
Consider hospitalization for re-start of IP based 
on length of treatment interruption, risk of CRS 
at restart, and amount of time since patient was 
last treated 2 
 
Dose modification:  resume at the same dose or 
reduce to next lower dose if clinically indicated 
 
Premedication and assessments: follow 
guidance in SOA tables 
Immediately stop the 
infusion (if applicable) 
and permanently 
discontinue IP therapy 
IF: 
Subject required 
treatment interruption 
greater than 28 days 
and upon discussion 
with Amgen Medical 
Monitor the decision is 
made to permanently 
discontinue treatment 
OR 
Initial benefit/risk 
assessment for 
individual patient is not 
maintained any longer 
Page 3 of 4 
Abbreviations and footnotes defined on last page of table. 


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Table 7-2.  Additional Guidance on Infusion Interruptions/Permanent Discontinuations and Management of Adverse Events 
Including Dose Reductions 
 
Interruption 
Specific Management 
Re-Start Guidance 
Permanent 
Discontinuation 
SARS-CoV2 infection and COVID19 disease 
symptomatic 
Interruption 
required until at 
least 10 days since 
complete resolution 
of acute symptoms 
Follow local guidelines 
and standard of care for 
COVID-19 treatment and 
isolation 
Contact Amgen Medical 
Monitor within 1 business 
day to ensure appropriate 
documentation & 
management of study 
activities. 
 
Re-start possible upon agreement between 
Investigator and Amgen Medical Monitor 
provided: 
o 
There are no new findings on physical 
exam and chest imaging, related to 
SARS-COV-2 
o 
Subject tests negative for SARS-COV-
2 by RT-PCR  
OR 
o 
If subject continues to test positive for 
SARS-COV-2 more than 10 days after 
initial positive test, resume IP only after 
discussion with patient and 
reassessment of individual risk/benefit 
 
Consider chest imaging, ECG, ECHO, and 
cardiology assessment 1  
 
Consider hospitalization for re-start of IP based 
on length of treatment interruption, risk of CRS 
at restart, and amount of time since patient was 
last treated 2  
 
Dose modification:  resume at the same dose or 
reduce to next lower dose if clinically indicated 
 
Premedication and assessments: follow 
guidance in SOA tables 
Immediately stop the 
infusion (if applicable) 
and permanently 
discontinue IP therapy 
IF 
Subject required 
treatment interruption 
greater than 28 days 
due to severe or life-
threatening COVID-19 
OR 
Initial benefit/risk 
assessment for 
individual patient is not 
maintained any longer 
Page 4 of 4  


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CRS  cytokine release syndrome; CTCAE  Common Terminology Criteria for Adverse Events; COVID-19  coronavirus disease 2019; ECG  
electrocardiogram; ECHO  echocardiogram; IP  investigational product; RT-PCR  real time polymerase chain reaction; SARS-COV-2  severe acute 
respiratory syndrome coronavirus 2; SOA  Schedule of Activities.


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7.4.2.1.2.5 
Specific Guidance for Cytokine Release Syndrome  
Cytokine release syndrome is clinically defined and may have various manifestations.  
There are no established diagnostic criteria.  Signs and symptoms of CRS may include:   
 
constitutional:  fever, rigors, fatigue, malaise 
 
neurologic:  headache, mental status changes, dysphasia, tremors, dysmetria, gait 
abnormalities, seizure 
 
respiratory:  dyspnea, tachypnea, hypoxemia 
 
cardiovascular:  tachycardia, hypotension 
 
gastrointestinal:  nausea, vomiting, transaminitis, hyperbilirubinemia 
 
hematology:  bleeding, hypofibrinogenemia, elevated D-dimer 
 
skin:  rash 
Subjects may be at an increased risk for CRS during the first few days following the 
initial infusion of AMG 420.  Cytokine release syndrome may be life-threatening or fatal.  
Infusion reactions may be clinically indistinguishable from manifestations of CRS.  
Throughout the treatment with AMG 420, monitor subjects for clinical signs (eg, fever, 
tachycardia, dyspnea, tremors) and laboratory changes (eg, transaminase increase) 
which may be related to CRS. 
Grading and management of CRS should be performed according to the guidelines 
provided in Table 7-3 (based on the adopted grading system referenced in 
Lee et al, 2014).  
Please also refer to the general guidance for re-start of infusion after interruption due to 
adverse event in Section 7.4.2.1.2 
For grade 3 and 4 CRS, please also see Section 7.4.1 for DLT considerations.


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Table 7-3.  Grading and Management of Cytokine Release Syndrome  
CRS 
Grade 
Description of 
Severitya 
Interruption 
Minimum Expected Intervention 
Re-Start Guidance 
Permanent 
Discontinuation 
1 
Symptoms are not 
life-threatening 
and require 
symptomatic 
treatment only, 
eg, fever, nausea, 
fatigue, headache, 
myalgias, malaise 
n/a 
Administer symptomatic treatment 
(eg, paracetamol/acetaminophen for fever). 
Monitor for CRS symptoms including vital signs 
and pulse oximetry at least Q2 hours for 
12 hours or until resolution, whichever is 
earlier. 
n/a 
n/a 
2 
Symptoms require 
and respond to 
moderate 
intervention 
 Oxygen 
requirement 
 40 (for room 
air, oxygen 
saturation 90 
or less), OR  
 Hypotension 
responsive to 
fluids or low 
dose of 
1 vasopressor, 
OR 
 Grade 2 organ 
toxicity or 
grade 3 transami
nitis per CTCAE 
criteria 
Immediately 
interrupt 
AMG 420 unti
l event has 
improved to 
CRS grade 
 1, but for 
no less than 
72 hours. 
Administer:  
 Symptomatic treatment 
(eg, paracetamol/acetaminophen for fever) 
 Supplemental oxygen when oxygen 
saturation is  90 on room air 
 Intravenous fluids or low dose vasopressor 
for hypotension when systolic blood pressure 
is  85 mmHg.  Persistent tachycardia 
(eg,  120 bpm) may also indicate the need 
for intervention for hypotension. 
Monitor for CRS symptoms including vital signs 
and pulse oximetry at least Q2 hours for 
12 hours or until resolution to CRS grade  1, 
whichever is earlier. 
Investigators may also use tocilizumabc as an 
additional therapy in this setting at a dose of 
4-8 mg/kg as a single dose, particularly if CRS 
does not improve to grade  1 within 4 hours 
after dose interruption.  
For subjects with extensive co-morbidities or 
poor performance status, manage per 
grade 3 CRS guidance below. 
 Re-start possible, if 
successfully managed and 
improvement to CRS 
grade  1 within 7 days,  
 Consult with Amgen 
medical monitor first. 
 Hospitalization:  48 hours 
 In the event of 
2 consecutive cases of 
CRS of grade 2, consider 
reducing dose to 
200 g/day for subjects 
originally receiving 
400 g/day or 400 g/day 
for those originally 
receiving 600 g/day 
 Additional measures:  
additional assessments 
and premedication as 
indicated in 
Sections 7.4.2.1.2.3/ 
7.4.2.1.2.4 
 If there is no 
improvement to 
CRS  
grade 1 within 
7 days 
 If interruption is 
 14 days 
 In case of repeat 
grade 2 event 
despite dose 
reduction 
 
Page 1 of 2 


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Footnotes defined on last page of table. 
Table 7-3.  Grading and Management of Cytokine Release Syndrome 
CRS 
Grade 
Description of 
Severitya 
Interruption 
Minimum Expected Intervention 
Re-Start Guidance 
Permanent 
Discontinuation 
3  
Symptoms require 
and respond to 
aggressive 
intervention 
 Oxygen 
requirement 
 40, OR 
 Hypotension 
requiring high 
doseb or multiple 
vasopressors, OR 
 Grade 3 organ 
toxicity or 
grade 4 transamin
itis per CTCAE 
criteria 
Immediately 
interrupt/ 
delay 
AMG 420 unti
l event has 
improved to 
CRS grade 
 1. 
 
Admit to intensive care unit for close clinical 
and vital sign monitoring per institutional 
guidelines. 
Administer dexamethasone (or equivalent) 
IV at a dose maximum of 3 doses of 8 mg 
(24 mg/day).  The dose should then be 
reduced step-wise. 
AND/OR 
Investigators should also consider use of 
tocilizumabc as an additional therapy in this 
setting at a dose of 4-8 mg/kg as a single 
dose.  
As for CRS grade 2 
 If there is no 
improvement to 
CRS 
 grade 2 within 
5 days and CRS 
 grade 1 within 
7 days. 
 In case of 
2 separate 
grade 3 CRS 
events. 
 If interruption is 
 14 days 
4 
Life-threatening 
symptoms 
 Requirement for 
ventilator support 
OR 
 Grade 4 organ 
toxicity (excluding 
transaminitis) per 
CTCAE criteria 
n/a 
Admit to intensive care unit for close clinical 
and vital sign monitoring per institutional 
guidelines. 
Administer dexamethasone (or equivalent) 
IV at a dose maximum of 3 doses of 8 mg 
(24 mg/day).  Further corticosteroid use 
should be discussed with the Amgen medical 
monitor. 
Additionally, tocilizumabc should be 
administered at a dose of 4-8 mg/kg as a 
n/a 
Immediately stop 
the infusion 
(if applicable) and 
permanently 
discontinue 
AMG 420 therapy. 


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single dose and may be repeated once within 
24 to 48 hours based on clinical assessment. 
Page 2 of 2 
Footnotes defined on next page 
CRS  cytokine release syndrome; CTCAE  Common Terminology Criteria for Adverse Events; IV  intravenous 
a Revised grading system for cytokine release syndrome (Lee et al, 2014) 
b High dose vasopressors (all doses are required for  3 hours):  norepinephrine monotherapy  20 g/min, dopamine monotherapy  10 g/kg/min, phenylephrine 
monotherapy  200 g/min, epinephrine monotherapy  10 g/min; if on vasopressin, vasopressin  norepinephrine equivalent of  10 g/min; if on combination 
vasopressors (not vasopressin), norepinephrine equivalent of  20 g/min. 
c All sites will ensure that CRS rescue medications are available on-site, including corticosteroids and (for sites in regions where tocilizumab is approved and available, 
eg, the US and Germany) 2 doses of tocilizumab per study subject.


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7.4.2.1.3 
Permanent Discontinuation of AMG 420 
AMG 420 treatment will be permanently discontinued in the event of: 
 
infusion-related reaction grade 4 (the infusion has to be stopped immediately)  
 
grade 4 CRS  
 
grade 2 or 3 CRS meeting any of the criteria listed below: 
 
grade 2 or 3 CRS that does not improve to  grade 1 within 7 days 
 
grade 3 CRS that does not improve to  grade 2 within 5 days 
 
if a subject experiences 2 separate grade 3 CRS events 
 
if a subject experiences repeat grade 2 CRS event after dose reduction 
 
grade 3 CRS at the initial run-in dose of the first treatment cycle if a dose step is 
being used 
 
grade 3 or higher TLS 
 
neurologic events considered related to AMG 420 by the investigator and meeting 
one or more of the following criteria: 
 
grade 3 neurologic event leading to treatment interruption and has not resolved 
to  grade 1 within 14 days despite infusion interruption 
 
grade 3 neurologic event that recurs after dose reduction 
 
grade 4 neurologic event 
 
DLT or other unmanageable toxicity unless a subject has a clear clinical benefit from 
treatment, the toxicity has resolved to  grade 1 or baseline and after consultation 
with the sponsor 
 
in case of re-appearance of the same grade 4 adverse event 
 
treatment interruption of more than 2 weeks or several interruptions exceeding a total 
of 14 days of treatment per cycle due to serious adverse events/adverse events 
 
possible DILI requiring permanent withholding as per Section 7.4.3 
 
non-manageable GvHD 
 
subjects who require more than 1 dose reduction 
 
disease progression as defined by revised IMWG response criteria 
 
relapse of disease subsequent to response (stringent CR, CR, very good PR, or PR) 
on protocol treatment. 
 
occurrence or progression of a medical condition which in the opinion of the 
investigator should preclude further participation of the subject in the study 
 
administration of relevant non-permitted concomitant medications 
 
requirement for alternative therapy 
 
subject’s request 


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 
subject or investigator not compliant with the study protocol 
 
Women who become pregnant or breastfeed while on treatment (see Section 12.5 
for pregnancy and lactation cases reporting requirements) 
For grading of events, refer to Section 9.2.3.1. 
All reasons for treatment discontinuation should be clearly and comprehensively 
documented in the eCRF.  If a subject has not continued to present for study visits, the 
investigator should determine the reason and circumstances as completely and 
accurately as possible.   
In any case of premature treatment discontinuation, the investigator should make every 
effort to perform all examinations scheduled for the end of treatment (EOT).  
7.4.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 12.7 for details regarding DILI injury guidelines, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009.  
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product, non-investigational product, or other 
protocol-required therapies during the study are provided in the IPIM. 
7.6 
Treatment Compliance 
Compliance to treatment and the corresponding assessments should be followed 
according to the Schedule of Activities (Section 2.2) and the Treatment Procedures 
(Section 7.1).  Refer to the IPIM for additional information.   
7.7 
Treatment of Overdose 
The effects of overdose of this product are not known.  The daily AMG 420 dose may be 
up to 10% lower or higher than specified in the protocol in order to account for possible 
pump inaccuracies.  A dose of up to 10% higher than the intended dose may not require 
specific intervention.   
In case of overdose of > 10% of planned dose, the infusion should be immediately 
stopped.  Consultation with the Amgen medical monitor is required for prompt reporting 
of clinically apparent or laboratory adverse events possibly related to overdosage.  
Consultation with the Amgen medical monitor is also required even if there are no 
adverse events, in order to discuss further management of the subject.  If the overdose 


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results in clinically apparent or symptomatic adverse events, the subject should be 
followed carefully until all signs of toxicity are resolved or returned to baseline and the 
adverse event(s) should be recorded/reported per Section 9.2.3. 
Resumption of AMG 420 infusion is possible after consultation with the Amgen medical 
monitor and should adhere to the guidelines in Section 7.4.2. 
A dose of >10% higher than the intended AMG 420 dose will be considered clinically 
important and classified as a serious adverse event under the criterion of “other 
medically important serious event” per Section 12.4. 
7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
Prior therapies that were being taken/used from initial diagnosis of multiple myeloma 
through the start of screening will be collected. 
For prior therapies being taken for multiple myeloma, the therapy line, name of 
therapeutic agent, regimen, type of therapy, start date, and stop date will be collected, 
as well as best responses. 
For radiotherapy the name, site, start date, and stop date will be collected.  
For prior autologous or allogeneic HSCT, hematopoietic stem cell mobilization source, 
conditioning regimen, number of cells infused (CD34+/kg) on day 0, date of neutrophil 
engraftment (first day that ANC > 0.5 x 109/L for 3 consecutive days), date of platelet 
engraftment (first day that platelets > 20 x 109/ L), and complications need to be 
collected.   
7.8.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 7.1.7. 
Concomitant therapies are to be collected from start of screening through the end of 
safety follow-up period.   
All concomitant medications, including all prescription, over-the-counter, herbal 
supplements, and IV medications and fluids will be recorded on the eCRF. 
During the LTFU period until EOS, any anti-multiple myeloma treatment is to be 
recorded. 


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For all concomitant medication collect therapy name, indication, dose, unit, frequency, 
route, start date, and stop date. 
7.8.2.1 
Supportive Care 
Subjects should receive supportive care according to local guidelines for blood product 
support, antibiotics, antivirals, analgesics, etc  
Please refer to Section 7.4.2.1.2.2 and Section 7.4.2.1.2.5 for management of CRS and 
infusion related reaction. 
Oxygen administration as supportive measure is permitted during study treatment.   
To prevent TLS, all subjects should receive at the discretion of the investigator 
appropriate hydration and supportive measures (eg, rasburicase) according to local 
standard of care and institutional guidelines.  Please refer to Section 7.8.2.7 for 
management guidelines of TLS. 
7.8.2.2 
Treatment of Myeloma Bone Disease, Hypercalcemia, Pain, and 
Renal Failure 
Treatment of myeloma bone disease, hypercalcemia, pain, and renal failure should be 
done according to institutional standards.  This may include concurrent treatment with 
bisphosphonates or denosumab.  Radiotherapy for palliative care such as bone pain is 
only permitted after discussion with Amgen medical monitor. 
7.8.2.3 
Bone Disease Therapy 
Bisphosphonate or other therapy to mitigate myeloma bone disease and associated 
complications is permitted and should follow investigators’ standard of care.  Such 
therapy is ideally administered during weeks between AMG 420 infusions.   
7.8.2.4 
Intravenous Immunoglobulin Treatment 
Intravenous immunoglobulin (IVIG) may be administered to patients per investigators’ 
standard of care, providing this treatment commences following cycle 2 infusion of 
AMG 420 and is provided during weeks between AMG 420 infusions.  
7.8.2.5 
Growth Factors 
The use of growth factors such as erythropoiesis-stimulating proteins as well as 
granulocyte colony stimulating factor (G-CSF) will be allowed during therapy per regional 
and investigator standard of care.  However, growth factors are not allowed at inclusion 
(within 7 days of applicable screening assessment) and should be avoided, if subject`s 
condition allows, in the first treatment cycle for better assessment of safety parameters.  


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7.8.2.6 
Infections 
Prophylactic antibiotics, antifungal, and antivirals are allowed and should be given 
according to institutional standards.  Pneumocystis prophylaxis should also be given 
according to institutional standards.  For subjects who are considered to have an 
increased risk for herpes infections, prophylaxis is mandatory unless medically 
contraindicated.  Subjects who may experience neutropenia for 7 days or longer are at a 
high risk for infectious complications.  As appropriate, these subjects should be 
administered prophylactic antibacterial, antifungal, and antiviral medications.  These 
subjects should be monitored for early signs of breakthrough infections after the initiation 
of antibacterial therapy to prompt additional evaluation and possible therapy 
modification. 
Subjects presenting with evidence of active infection after the start of AMG 
420 treatment should be closely monitored while being treated with AMG 420.  Subjects 
with identified, active systemic infections requiring IV antibiotics, antivirals, or antifungals 
should not be dosed with AMG 420 until infection has resolved, and if being treated with 
an anti-infectious therapy, the course of such therapy should have been completed. 
Patients who develop fever greater than 38.0°C lasting more than 1 hour or fever greater 
than 38.3°C of any duration during AMG 420 treatment should be promptly evaluated for 
infection as well as cytokine release syndrome (CRS).  Workup should include 
evaluation for bacterial, fungal, and viral etiologies using radiographic imaging and 
appropriate microbiological/serologic assays, and empiric therapy should be considered 
using investigator’s institutional standard of care approach.  Guidelines for dose 
interruption and AMG 420 discontinuation as detailed in Tables 7-1 and 7-2 should be 
followed.  Investigators should consider the potential immunosuppressive effects of CRS 
rescue medications (eg, tocilizumab, corticosteroids) in their empiric management of 
fever.  If patients develop febrile neutropenia (defined as ANC < 1000 106/L with a single 
temperature of > 38.3°C [101°F] or a sustained temperature of ≥ 38°C [100.4°F] for more 
than one hour), use of standardized guidelines for management and initial treatment of 
neutropenic fever (eg, Infectious Diseases Society of America Clinical Practice 
Guidelines, Management of Febrile Neutropaenia:  ESMO Clinical Practice Guidelines) 
is encouraged. 


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7.8.2.7 
Tumor Lysis Syndrome 
Tumor Lysis Syndrome is a severe, life-threatening disorder that typically occurs in 
highly proliferative malignancies.  Tumor Lysis Syndrome is frequently observed in 
patients with hematologic malignancies such as ALL and Burkitt’s lymphoma.  Tumor 
Lysis Syndrome is rarely reported in patients with multiple myeloma although patients 
with a high tumor burden may be at greater risk for TLS (Chang et al, 2011; 
Cairo et al, 2010).  However, given effective new treatments are now available TLS 
incidence has been reported to be ≤ 5% in patients with multiple myeloma who received 
different treatments (Howard et al, 2016).  Tumor Lysis Syndrome is characterized by a 
group of metabolic disorders caused by the massive and abrupt release of cellular 
metabolites into the blood including lactase dehydrogenase (LDH), uric acid, 
phosphorus, potassium, and calcium after lysis of the malignant cells 
(Coiffier et al, 2008).  The metabolic complications predispose patients with cancer to 
various clinical complications included renal failure, seizures, cardiac arrhythmias, and 
even sudden death.  To allow for early diagnosis all subjects must be monitored closely 
for laboratory and clinical evidence of a possible TLS as outlined in Section 12.12 of the 
protocol. 
To prevent TLS, ensure all subjects are well hydrated and provided supportive care 
measures before administration of AMG 420 as detailed in Section 7.8.2.1.  Monitor for 
evidence of TLS during treatment and manage promptly including interruption of 
AMG 420 infusion as outlined in Table 7-1.  Subjects who experience TLS should be 
managed according to the local standard of care and institutional guidelines.  Supportive 
therapy, including rasburicase, may be used as clinically indicated at the investigator's 
discretion. 
8. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 8.1, 8.2.1, and 8.2.2. 


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8.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities 
(see Section 2.2) including different options of follow-up (eg, in person, by phone/mail, 
through family/friends, in correspondence/communication with other treating physicians, 
from the review of medical records) and collection of data (including endpoints, adverse 
events, and serious adverse events) and must document this decision in the subject’s 
medical records.  Subjects who have discontinued investigational product and/or other 
protocol-required therapies or procedures should not be automatically removed from the 
study.  Whenever safe and feasible, it is imperative that subjects remain on-study to 
ensure safety surveillance and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with  
Section 12.3. 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance  
 
Adverse event 
 
Subject request 
 
Disease progression, based on IMWG criteria, in which confirmation of progression 
requires 2 consecutive laboratory evaluations, except in cases in which progression 
is based on EM or bone lesions.  Laboratory assessments should be separated in 
time by at least 1 calendar day  
 
Requirement for alternative therapy 
 
Pregnancy 


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8.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly 
(see Section 12.6 for further details).  Refer to the Schedule of Activities (Section 2.2) for 
data to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
8.2.1 
Reasons for Removal From Washout, Run-in or Invasive Procedures 
Not applicable to this study. 
8.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
8.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 


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 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator can search publicly available 
records where permitted to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible. 


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9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities.  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the informed consent form, the site will register the subject in the IRT and screen 
the subject in order to assess eligibility for participation.  The screening window is up to 
21 days.  All screening procedures must be performed within 21 days prior to start of 
investigational product administration, unless otherwise noted.  The ICF may be signed 
earlier than 21 days prior to start of investigational product in case of washout times that 
have to be observed to meet eligibility criteria.   
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 6.4) as applicable. 
Laboratory assessments used to determine subject eligibility may be repeated once for 
confirmation during each 21-day screening period before the subject is considered a 
screen failure.  If laboratory assessments are repeated during the screening period, the 
result of the last sample taken prior to start of treatment with AMG 420 will be taken into 
account for determination of subject eligibility.  
Assessments that were performed as standard of care prior to signature of informed 
consent, but within 21 days prior to start of treatment with AMG 420 can be used as 
screening assessments and do not need to be repeated to confirm subject eligibility.  


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Note:  The screening 
 sample should be collected on the first day of screening 
and immediately be sent to the central laboratory.  The results should be available prior 
to start of investigational product treatment. 
Re-Screening: 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening 2 times at the discretion of the investigator, after consultation with Amgen.   
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 21-day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 21 days 
after the original signing of the informed consent form, all screening procedures, 
including informed consent, must be repeated. 
The following assessments do not have to be repeated during re-screening, if they were 
performed as standard of care or during the initial screening attempt within the time 
frames specified below: 
 
Hepatitis serology test does not need to be repeated if they were performed within 
6 weeks prior to start of treatment with AMG 420. 
 
Imaging and BM assessments do not need to be repeated if they were performed 
within 4 weeks prior to start of treatment with AMG 420. 
 
Any other assessments do not need to be repeated if they were performed within 
21 days prior to start of treatment with AMG 420. 
 
Plasmacytoma biopsy (if applicable) does not have to be repeated 
9.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Section 2.2).  The date of the first dose of 
investigational product is defined as day 1.  All subsequent doses and study visits will be 
scheduled based on the day 1 date.  Administration of AMG 420 is to be administered as 
applicable during each visit that it is required. 
Starting with day 4 post infusion, assessments should be performed on the indicated 
study day, but not at a certain hour of the day.  The D6 sample may also be taken on D7 
if logistically required (eg, sample cannot be processed at the weekend).  Bone marrow 
assessments post-treatment start may be performed within a window of  3 days.  Visits 
during treatment-free interval, if applicable, may occur within a window of  1 day.   


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Furthermore, start of a treatment cycle can be delayed for administrative/logistical 
reasons for up to 7 days to allow for appropriate scheduling.  Start of treatment cycles 
later than 7 days from planned next cycle day 1 must only occur after discussion 
with and final approval by sponsor.  Delays of treatment cycles beyond 14 days are 
not permitted. 
The DLRT may implement a  1-day window for infusions following the day 1 infusion. 
In any case of premature treatment discontinuation prior to day 29 (EOI) the 
assessments for day 29 do not have to be performed, but the investigator should make 
every effort to perform all examinations scheduled for the EOT (see Section 2.2). 
The expected treatment period is to treat until PD per IMWG (or other protocol-specific 
reasons as per Section 8.1). 
9.1.3 
End of Treatment 
The EOT visit will occur after last dose of AMG 420.  This also applies to subjects who 
prematurely discontinue investigational product treatment.  The EOT visit should occur 
as soon as possible after the last dose of investigational product was administered.  The 
procedures that will be completed during the EOT visit are designated in the Schedule of 
Activities (Section 2.2).  For subjects who receive second-course treatment, 2 EOT visits 
will be documented. 
9.1.4 
Safety Follow-up 
The SFU visit should occur 30 (+3) days after the last dose of AMG 420/other 
protocol-required therapies.  Every effort should be made to conduct this visit for all 
subjects enrolled into the study, including subjects who withdraw from treatment early.  
The procedures that will be completed during the SFU visit are designated in the 
Schedule of Activities (Section 2.2). 
9.1.5 
Long-term Follow-up 
Following the SFU visit, there will be a LTFU period for clinical evaluation of disease 
status and survival.  All subjects will be followed every 3 months (± 2 weeks) for survival 
and anti-multiple myeloma treatment (on-site visits are not required, if needed also 
interrogation of public databases is acceptable).  For subjects who discontinue treatment 
for reasons other than PD or death, additional on-site visits are required every 6 weeks 
(± 7 days) for assessments of disease status and documentation of anti-multiple 


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myeloma treatment until PD.  Subjects will be followed for a maximum of 5 years from 
the first dose of AMG 420, or until subject death, whichever occurs first.     
Subjects will allow Amgen continued access to medical records so that information 
related to subjects’ health condition, including disease status, response to treatment, 
and survival, may be obtained. 
The procedures that will be performed during the LTFU are designated in the Schedule 
of Assessments (Section 2.2) as long as on-site visits apply. 
9.1.6 
End of Study 
End of study is defined as the date of the final study visit (eg, LTFU visit) when 
assessments and/or procedures are performed.    
9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
9.2.1 
General Assessments  
9.2.1.1 
Informed Consent 
A signed ICF must be obtained from each subject prior to any study-mandated 
procedures.  All subjects who are enrolled and receive investigational product treatment 
should be reconsented with any updated versions of IRB/IEC approved informed 
consents during study participation as applicable and per institutional guidelines 
9.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact of the protocol-required 
therapy on biomarker variability and PK.   
9.2.1.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started 5 years prior to screening through the time of signing of informed consent.  
Medical history will include information on the subject’s concurrent medical conditions.  
Relevant medical history, antecedent hematologic or oncologic disease, other 
diseases/symptoms such as fatigue, polyneuropathy, and infection (resolved and 
ongoing) will be collected.  The current toxicity grade will be collected for each condition 
that has not resolved.  


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Multiple myeloma history must date back to the initial diagnosis and any response 
duration must be recorded.  
All findings will be recorded on the Medical History eCRF.   
9.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate eCRF (eg, medical history, event). 
A complete physical examination as per standard of care will be performed by the 
investigator or designee at screening and at the time points specified in the Schedule of 
Activities (Section 2.2).  The physical examination will include general appearance, 
including examination of the skin, spleen, and respiratory, cardiovascular, 
musculoskeletal, and neurological systems.  The individual performing the physical 
examination will characterize their findings as either normal or abnormal.  Abnormal 
physical examination findings found during screening should be reported on the Medical 
History eCRF.  Abnormal physical examination findings found after the subject has 
received investigational product will be reported on the Event eCRF.   
9.2.1.5 
Physical Measurements 
Height in centimeters should be measured without shoes.  Weight in kilograms should 
be measured without shoes. 
9.2.1.6 
Performance Status  
The performance status will be assessed at the time points indicated in the Schedule of 
Activities (Section 2.2) using the ECOG performance status scale (see Section 12.14). 
9.2.2 
Efficacy Assessments 
9.2.2.1 
Blood and Bone Marrow 
Blood and BM samples are to be collected for biomarker assessments and development, 
and safety and response assessments at time points specified in the Schedule of 
Activities (Section 2.2).   
Samples will be investigated by local and central laboratories as specified in 
Section 12.2 . 
Refer to the laboratory manual for detailed collection and handling procedures.   


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9.2.2.2 
SPEP, UPEP, and Tumor Assessment 
Serum protein electrophoresis (SPEP) and 24-hour UPEP are required for all subjects 
as indicated in the Schedule of Activities (Section 2.2).  Immunofixation is required at 
screening and should be repeated as shown in Schedule of Activities (Section 2.2).  
Urine immunofixation (UIFE) is not required to be repeated if negative at baseline.  
Assessments will be performed centrally.  
Tumor assessment will be done by analysis of percent myeloma involvement, 
fluorescence in situ hybridization (FISH) as well as karyotyping in BM.  BM 
FISH/karyotyping will be performed locally.  Analysis of percent myeloma involvement 
will be assessed centrally.  Data for BM karyotyping and FISH may be obtained from a 
BM sample obtained as part of standard of care within 120 days prior to treatment start 
with investigational product.   
Further BM samples will be required as described in the Schedule of Activities 
(Section 2.2).  
9.2.2.3 
Serum Free Light Chain 
Serum free light chain assay and ratio will be performed at each time point as specified 
in the Schedule of Activities (Section 2.2).  In case of free light chain (FLC) multiple 
myeloma (M-protein negative cases), FLC will be analyzed in serum and urine at the 
same time points as for SPEP/UPEP described above.  Levels of involved/uninvolved 
FLC, ratio of monoclonal λFLC/κFLC, and ratio of monoclonal κFLC/λFLC will be 
determined. 
9.2.2.4 
Quantitative Immunoglobulin 
Quantitative immunoglobulin (Ig) will be performed at screening and at time points 
indicated in the Schedule of Activities (Section 2.2).  In addition, quantitative 
immunoglobulin will be repeated if clinically indicated, ie, frequent infection despite 
multiple myeloma disease control or deemed clinically indicated by the investigator.  
9.2.2.5 
Beta-2 Microglobulin 
Beta-2 microglobulin in serum will be assessed at screening as part of risk stratification 
and during the study as indicated in the Schedule of Activities (Section 2.2). 
9.2.2.6 
Skeletal Survey/Plasmacytoma Assessments 
Skeletal survey and plasmacytoma assessments (if applicable) will be performed at time 
points specified in the Schedule of Activities (Section 2.2).  Results from prior 


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assessment for multiple myeloma if one of these techniques were used are acceptable 
for screening if performed within 30 days before cycle 1 day 1.  The same technique 
must be employed for each measurement.  Imaging studies will be read locally.  
Bi-dimensional lesion measurements (SPD; sum of the products of the maximal 
perpendicular diameters of measured lesions) for skeletal lesions (lytic or 
plasmacytoma) and for extrameduallary lesions must be performed and recorded in the 
designated eCRF. 
All subjects are required to have screening imaging to evaluate for EM relapse using 
whole-body MRI or PET/CT.   
A skeletal survey is required if no other imaging appropriate for assessment of bone 
lesions is performed. 
For subjects who have whole-body MRI for plasmacytoma assessment, a separate 
skeletal assessment to detect lytic bone lesions is required (skeletal x-ray, low dose 
whole body computed tomography (CT), or FDG PET/CT).  For subjects, who have 
positron emission tomography (PET)/computed tomography (CT) imaging for 
plasmacytoma assessment, a separate skeletal survey to detect lytic bone lesions is not 
required.  
Extramedullary plasmacytoma assessments should be repeated every 12 weeks 
(± 2 weeks) during treatment to confirm a PR or better only if measurable plasmacytoma 
are present at baseline, or if clinically indicated.  Skeletal lesion assessments should be 
repeated only as clinically indicated.  The same technique (may include CT scan, MRI, 
PET, PET-CT, or other standard-of-care method) must be employed for each 
measurement.  SPD must be performed and recorded in the designated eCRF. 
Skeletal survey is not required for confirmation of PR or better. 
9.2.2.7 
Minimal Residual Disease 
Minimal residual disease in BM is a mandatory biomarker measurement in this study.  
Minimal residual disease will be measured centrally by a 
.  Bone 
marrow aspirates will be collected at specific time points for subjects suspected to be 
complete responders, according to the Schedule of Activities (Section 2.2).  The BM 
aspirates will be processed and stored according to a protocol that is provided to the 
central lab.   


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9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Section 2.2). 
9.2.3.1 
Adverse Events 
9.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
9.2.3.1.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE and is 
described in Section 12.4, with the following exceptions:  CRS will be graded according 
to the criteria referenced in the publication by Lee et al (2014) described in 
Section 7.4.2.1.2.5 and TLS will be graded based on Cairo-Bishop criteria 
(Coiffier et al, 2008) described in Section 12.12. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product or other protocol-required therapies, whichever occurs first through the safety 
follow-up visit (30 [+3] days after last dosing interval of investigational product) are 
reported using the Event eCRF. 
9.2.3.1.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through safety follow-up visit or 30 days after last day of dosing interval of 
investigational product(s)/protocol-required therapies, whichever occurs later are 
reported using the Events eCRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours following the investigator’s knowledge of the event, as 
indicated in Section 12.4.  The investigator will submit any updated serious adverse 
event data to the sponsor within 24 hours of it being available. 
The criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events.  It is left to the investigator’s judgment to report these grade 
4 abnormalities as serious adverse events. 


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9.2.3.1.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
If the investigator becomes aware of serious adverse events suspected to be 
related to IP after the protocol-required reporting period is complete, then these 
serious adverse events will be reported to Amgen within 24 hours following the 
investigator’s awareness of the event on the Events CRF. In addition, the 
investigator will need to collect/report fatal serious adverse events (regardless of 
causality) to Amgen within 24 hours following the investigator’s awareness of the 
events on the Events CRF. 
After End of Study, there is no requirement to actively monitor study subjects for 
serious adverse events. However, if the investigator becomes aware of serious 
adverse events suspected to be related to investigational product, then these 
serious adverse events will be reported to Amgen within 24 hours following the 
investigator’s awareness of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  
If further safety related data is needed to fulfill any regulatory reporting 
requirements for a reportable event, then additional information may need to be 
collected from the subject’s records if the subjects ends the study. 
9.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
9.2.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Section 12.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 


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discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event eCRF. 
9.2.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
9.2.3.1.5 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and female partners of 
male subjects will be collected after the start of study treatment and until 6 weeks after 
the last dose of AMG 420 or in a male subject's female partner through 14 weeks after 
the last dose of AMG 420. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 
Section 12.5.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 


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Further details regarding pregnancy and lactation are provided in Section 12.5. 
9.2.3.1.6 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
9.2.3.2 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Subject must be in a supine position in a rested 
and calm state for at least 5 minutes before blood pressure assessments are conducted.  
If the subject is unable to be in the supine position, the subject should be in most 
recumbent position as possible.  The position selected for a subject should be the same 
that is used throughout the study and documented on the vital sign eCRF.  The 
temperature location selected for a subject should be the same that is used throughout 
the study and documented on the vital signs eCRF.  Record all measurements on the 
vital signs eCRF. 
9.2.3.3 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  ECGs should be 
performed in a standardized method, in triplicate, and run consecutively (ie, 
approximately 60 seconds apart), prior to blood draws or other invasive procedures.  
Each ECG must include the following measurements:  QRS, QT, QTc, RR, and PR 
intervals.  
 
 3 baseline ECGs collected  30 minutes apart, with each baseline ECG in triplicate 
run consecutively (ie, approximately 60 seconds apart) [ie, total  9 ECGs]  
 
Single ECGs at time points after dosing  
The Baseline ECG QTc (defined as the average of the individual baseline ECGs), should 
not be > 470 msec (applying Fridericia correction).  Baseline is defined as predose 
assessments from cycle 1 day 1.  The investigator or designated site physician will 
review all ECGs.  ECGs will be transferred electronically to an ECG central reader for 
analysis per Amgen instructions.  Once signed, the original ECG tracing will be retained 
with the subject's source documents.  At the request of the sponsor, a copy of the 
original ECG will be made available to Amgen.  Standard ECG machines should be used 
for all study-related ECG requirements.  


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9.2.3.4 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
9.2.3.5 
Other Safety 
9.2.3.5.1 
Pulse Oximetry 
Oxygen saturation will be measured using a standard pulse oximeter.  The subject must 
be in a rested and calm state for at least 5 minutes before pulse oximetry assessments 
are completed.   
9.2.3.5.2 
Peripheral Neuropathy 
The peripheral neuropathy assessment should be done at screening and time points 
specified in the Schedule of Activities (Section 2.2).  All assessments must be reported 
on the corresponding eCRF page (see Section 12.16) for peripheral neuropathy 
assessment tool.  Assessments will include historical information on neuropathy 
symptoms, including relationship to prior anti-MM therapies, severity and duration of 
symptoms.   
9.2.4 
Clinical Laboratory Assessments 
Refer to Section 12.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 2.2) for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event eCRF.  The 
investigator must determine whether an abnormal value in an individual study subject 
represents a clinically significant change from the subject’s baseline values.  In general, 
abnormal laboratory findings without clinical significance (based on the investigator's 
judgment) are not to be recorded as adverse events.  However, laboratory value 
changes that require treatment or adjustment in current therapy are considered adverse 
events.  Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event. 
All protocol-required laboratory assessments, as defined in Section 12.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Section 2.2).  


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9.2.4.1 
Pregnancy Testing 
A highly sensitive (urine or serum) pregnancy test should be completed at screening and 
within 7 days of initiation of investigational product for females of childbearing potential.  
In the case of a positive urine result. A serum pregnancy test should be performed for 
confirmation. 
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see Figure 12-2).  Refer to Section 12.5 for contraceptive requirements.  
Additional pregnancy testing (serum or urine) during treatment with protocol-required 
therapies will be performed as indicated in Section 2.2 and at the safety follow-up. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 


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9.2.5 
Pharmacokinetic Assessments 
All subjects enrolled will have pharmacokinetic samples assessed. 
Whole blood samples of approximately 2 mL will be collected for measurement of serum 
concentrations of AMG 420 as specified in the Schedule of Activities (Section 2.2).  
Instructions for the collection and handling of biological samples will be provided by the 
sponsor.  The actual date and time (24-hour clock time) of each sample will be recorded. 
9.2.6 
Pharmacodynamic Assessments 
Venous blood samples of approximately 20 mL per visit will be collected for 
measurement of AMG 420 response. 


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9.2.9 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
In oncology, there is a particular interest in the molecular changes underlying the 
oncogenic processes that may identify cancer subtypes, stage of disease, assess the 
amount of tumor growth, or predict disease progression, metastasis, and responses to 
investigational product(s) or protocol-required therapies. 
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to AMG 420 to investigate and further understand 
multiple myeloma. 
Exploratory assays – 
 
  
 
 
 
   


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10. 
Statistical Considerations 
10.1 
Sample Size Determination 
Approximately 20 subjects will be enrolled (approximately 10 treated at the 400 g/day 
dose level and approximately 10 treated at the 600 g/day dose level).   
The sample size is based on practical considerations and it is consistent with the 
number of subjects enrolled in a dose expansion cohort of a conventional, oncology 
phase 1 study.  With 10 subjects treated at a dose level/schedule, there is a 65% to 89% 
probability of observing an adverse event if the true event rate is 10% to 20%.   
10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of 
AMG 420.  An overall assessment of safety with monotherapy treatment will be 
conducted on the Monotherapy Safety Analysis Set defined as all subjects that are 
enrolled in the study and receive at least 1 dose of AMG 420.  The analysis of DLT will 
be restricted to DLT-evaluable subjects (see Section 7.4.1).  The analysis of DOR will be 
restricted to subjects with a partial response or better.  DLT evaluation analysis set 
includes subjects complete the DLT evaluable period or experienced a DLT any time 
during the DLT evaluable period.  The PK Analysis Set will contain all subjects who have 
received at least 1 dose of the investigational product and have at least 1 PK sample 
collected.  These subjects will be evaluated for PK analysis unless the number of data 
points required for analysis is not enough, or significant protocol deviations have 
affected the data, or if key dosing or sampling information is missing. 
10.2.2 
Covariates 
There are no planned covariates in this study. 
10.2.3 
Subgroups 
Subgroup analyses will be performed for the primary and secondary efficacy endpoints.  
The baseline variables for the subgroup analyses may include: 
 
baseline demographics and characteristics:  
 
age (< 65, 65-74, ≥ 75 years) 
 
sex (female, male) 
 
race (White, Asian, other) 
 
baseline disease characteristics:  


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 
revised International Staging System (ISS) stage (Stage I, Stages II or III) 
 
BM percent of plasma cells (< 50%, ≥ 50%) 
 
 
 
extramedullary disease (yes, no).  Until safety evaluation is complete for 
3 subjects with EM disease, imaging evaluation at screening will be used to 
document EM disease status as described in Section 9.2.2.6.  After DLRT 
confirms safety in setting of EM disease, EM disease status will utilize 
investigator assignment.  
 
number of prior lines of therapy (only 3, > 3) 
 
prior allogeneic HSCT (yes, no) 
 
refractory to  
 
IMiD (yes, no) 
 
PI (yes, no) 
 
IMiD + PI (yes, no) 
 
daratumumab or other CD 38-targeting antibody (yes, no) 
In addition, safety in the subgroup of subjects with EM disease will be reviewed. 
Subgroup analysis will not be performed if the sample size within a subgroup is too 
small.  Details will be documented in statistical analysis plan 
10.2.4 
Handling of Missing and Incomplete Data 
The descriptive statistics will identify the extent of missing data.  Missing or incomplete 
dates that are critical to efficacy and safety analysis, for example, death date and 
adverse event start dates, will be imputed.  Detailed imputation rules will be documented 
in statistical analysis plan. 
10.3 
Adaptive Design 
The rules for halting enrollment, or dose de-escalation, are based on an mTPI design.  
The mTPI was developed by Ji et al (2010).  The mTPI models the probability of toxicity 
for each dose level using a Bayesian model where each dose level has the same prior 
on the probability of toxicity, a Beta (1,1).  When subjects are treated at the current dose 
level, the posterior probability of toxicity is updated using the observed data from this 
level.  Enrollment recommendations are made based on this posterior probability of 
toxicity, using three toxicity probability intervals (TPI). 
 
Under-dosing TPI:  DLT rate from 0 to < 20% 
 
Target TPI:  DLT rate from 20% to 33%    


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 
Over-dosing TPI:  DLT rate > 33% 
For the current dose level and after adjusting for the width of each TPI interval, if the 
DLT rate is most likely in the under-dosing TPI or most likely in the target TPI then the 
recommendation is to continue enrollment at the current level.  If the DLT rate is most 
likely in the over-dosing TPI then the recommendation is to halt enrollment.   
10.4 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 5.3.1. 
10.4.1 
Planned Analyses 
10.4.1.1 
Interim Analysis and Early Stopping Guidelines 
10.4.1.1.1 
Interim Analyses 
10.4.1.1.1.1 
Safety data will be reviewed by the DLRT on an ongoing basis with 
the possibility of early termination of enrollment, as described in 
Section 5.1. Dose Level Review Team  
A DLRT will be responsible for monitoring safety and making recommendations 
regarding termination of enrollment and dose level/schedule changes.   
See Section 12.3 for further details of DLRT responsibilities.   
10.4.1.2 
Primary Analysis 
The primary analysis will occur when the target enrollment is complete and each subject 
has had the chance to be treated for at least 6 months.   
10.4.1.3 
Final Analysis 
A final analysis is planned after all subjects have ended the study. 
10.4.2 
Methods of Analyses 
10.4.2.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, 
pharmacodynamic and biomarker data by dose, dose schedule, and time as appropriate.  
Descriptive statistics on continuous data will include means, medians, standard 
deviations and ranges, while categorical data will be summarized using frequency 
counts and percentages.  Time to event endpoints will be summarized with 
Kaplain-Meier (KM) proportions at select time points, KM quartiles (when estimable), the 
number of subjects with events, the number of subjects censored, and censoring 


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reasons.  Duration of follow-up for time to event endpoints will be estimated using the 
reverse Kaplan Meier method (Schemper and Smith, 1996).  Point estimates for efficacy 
endpoints will be accompanied by 2-sided 95% confidence intervals including KM 
quartiles (Klein and Moeschberger, 1997), KM proportions 
(Kalbfleisch and Prentice, 1980), and binomial proportions (Clopper and Pearson, 1934).  
Graphical summaries of the data may also be presented.   
10.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable for phase 1b.   
Secondary 
Tabular summaries of efficacy endpoints will be reported separately by dose 
level and part.  
For subjects included in the Safety Analysis Set, the proportion of subjects 
with BOR of PR or better per IMWG and MRD negativity at the time of CR will 
be calculated and tabulated. DOR and time to response analyses will be done 
for subjects who are in Safety Analysis Set and have a best overall response 
of PR or better.  The percentage of subjects with extended TFI of 4 weeks at 
approximately 6 months and 4 weeks or 8 weeks at approximately 12 months, 
out of all treated subjects and out of those who are eligible based on 
response status (only patients with MRD-negative CR at these landmark 
times are eligible for the extended TFI calculation).  If appropriate, KM 
proportions at select time points, KM quartiles (when estimable) and KM 
curves will be provided for DOR, PFS, and OS.  Descriptive statistics 
including median and range will be provided for time to response.  Listings will 
be produced for all subjects indicating the MRD negativity, OS, PFS, time to 
response, and DOR. 
Exploratory 
Will be described in the statistical analysis plan finalized before database lock 
 
10.4.2.3 
Safety Analyses 
10.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary endpoints are safety endpoints.  Unless otherwise specified, 
statistical analyses on safety endpoints will be done using subjects from the 
Safety Analysis Set, which includes subjects that are enrolled and received at 
least 1 dose of AMG 420.  Descriptive statistics for safety endpoints will be 
tabulated overall and by dose level and part. 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated 
by system organ class and preferred term.  The number and percentage of 
subjects reporting adverse events will be evaluated overall and by AMG 
420 dose level and part will also be tabulated by relationship to AMG 420.  
Tables of adverse events, fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product or other 


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Endpoint 
Statistical Analysis Methods 
protocol-required therapies, and significant treatment-emergent adverse 
events will also be provided. 
Dose Limiting Toxicities  
The analysis of the probability of DLTs will include data from DLT-evaluable 
subjects (see Section 7.4.1 for definition of DLT-evaluable).  The primary 
analysis will only include DLTs that occur within the first cycle.  If DLTs occur 
outside the first cycle, a sensitivity analysis will be performed where DLTs 
occurring outside of the specified time interval are included.  The number and 
percentage of subjects reporting DLTs will be evaluated overall and by AMG 
420 dose level and part.  
Clinical Laboratory Tests 
Clinical chemistry, hematology, and urinalysis data will be listed and reviewed 
for each subject.  Values outside the normal laboratory reference ranges will 
be flagged as high or low on the listings.  Depending on the size and scope of 
changes in laboratory data, the analyses of safety laboratory endpoints will 
include summary statistics over time and/or changes from baseline over time.  
Maximum shifts in grades of selected safety laboratory values between 
baseline and the worst on-study value may be tabulated. 
Vital Signs 
Vital signs data will be listed and reviewed for each subject.  Depending on 
the size and scope of changes, the analyses of vital signs may include 
summary statistics over time and/or changes from baseline over time.   
Electrocardiograms 
Summaries over time and/or changes from baseline over time will be provided 
for all ECG parameters.  Subjects' maximum change from baseline in QTcF 
will be categorized and the number and percentage of subjects in each group 
will be summarized.  Subjects' maximum post baseline values will also be 
categorized and the number and percentage of subjects in each group will be 
summarized.  All on-study ECG data will be listed, and select parameters of 
interest may be plotted. 
 
10.4.2.3.2 
Adverse Events  
Statistical analysis on adverse events is described in Section 10.4.2.3.1. 
10.4.2.3.3 
Laboratory Test Results 
Statistical analysis on laboratory test results is described in Section 10.4.2.3.1. 
10.4.2.3.4 
Vital Signs 
Statistical analysis on vital signs is described in Section 10.4.2.3.1. 
10.4.2.3.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics at baseline. 


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10.4.2.3.6 
Electrocardiogram 
Statistical analysis on electrocardiogram data is described in Section 10.4.2.3.1. 
10.4.2.3.8 
Exposure to Investigational Product 
The average dose per administration (g), cumulative dose (g), number of cycles, 
duration of usage, number and percentage of subjects with dose modifications, reasons 
for modification will be summarized using descriptive statistics.  Subject-level data may 
be provided instead of the summary if the subject incidence is low or single dose is 
given. 
10.4.2.3.9 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term for each treatment group as coded by the World Health Organization 
Drug dictionary. 
10.4.2.4 
Other Analyses 
10.4.2.4.1 
PK Analyses 
The PK parameters of AMG 420 including, but not limited to, average Css, clearance, 
and half-life (t1/2) for serum AMG 420 will be estimated using non-compartmental 
methods and summarized by dose level using means, geometric means, standard 
deviations, coefficients of variation, medians, minimums, and maximums.  Individual 
concentration-time profiles will be summarized by dose level.  Plasma AMG 
420 concentrations at each time point along with PK parameter values may be listed for 
each subject.  Summary statistics will be computed for each sampling time and 
parameter as appropriate.  The relationship between AMG 420 exposure and 
efficacy/safety may be conducted.   


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11. 
References 
AMG 420 Investigator’s Brochure.  Thousand Oaks, CA:  Amgen Inc.  
Avery DT, Kalled SL, Ellyard JI, et al,  BAFF selectively enhances the survival of 
plasmablasts generated from human memory B cells.  J Clin Invest.  2003;112:286-297.  
Avet-Loiseau H, Attal M, Moreau P, et al,  Genetic abnormalities and survival in multiple 
myeloma:  the experience of the Intergroupe Francophone du Myélome.  Blood.  
2007;109(8):3489–3495.  
Benjamin JE, Stein AS.  The role of blinatumomab in patients with relapsed/refractory 
acute lymphoblastic leukemia.  Ther Adv Hematol.  2016;7(3):142-156. 
Berdeja JG, Lin Y, Raje N, et al,  Clinical remissions and limited toxicity in a 
first-in-human multicenter study of bb2121, a novel anti-BCMA CAR T cell therapy for 
relapsed/refractory multiple myeloma.  Eur J Cancer.  2016;68(Supplement 1):S5.  
Cairo MS, Coiffer B, Reiter A, et al,  Recommendations for the evaluation of risk and 
prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant 
disease:  an expert TLS panel consensus.  Br J Haematol.  2010;149(4):578-586. 
Carpenter RO, Evbuomwan MO, Pittaluga S, et al,  B-cell maturation antigen is a 
promising target for adoptive T-cell therapy of multiple myeloma.  Clin Cancer Res.  
2013;19(8):2048-2060. 
Chanan-Khan AA, Giralt S.  Importance of achieving a complete response in multiple 
myeloma, and the impact of novel agents.  J Clin Oncol.  2010;28:2612-2624.   
Chang H, Lee SY, Tang TC.  Tumor lysis syndrome in patients with light chain multiple 
myeloma:  report of two cases.  Chang Gung Med J.  2011;34(6 Suppl):70-75. 
Chiu A, Xu W, He B, et al,  Hodgkin lymphoma cells express TACI and BCMA receptors 
and generated survival and proliferation signals in response to BAFF and APRIL.  Blood.  
2007;109(2):729-739. 
Cohen AD, Garfall AL, Stadtmauer EA, et al,  B-Cell Maturation Antigen (BCMA)-
Specific Chimeric Antigen Receptor T Cells (CART-BCMA) for Multiple Myeloma (MM):  
Initial Safety and Efficacy from a Phase I Study.  Blood.  2016;128:1147. 
Cook G, Zweegman S, Mateos MV, Suzan F, Moreau P.  A question of class:  Treatment 
options for patients with relapsed and/or refractory multiple myeloma.  Crit Rev Oncol 
Hematol. 2018;121:74-89.   
Clopper CJ, Pearson ES.  The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika.  1934;26(4):404-413. 
Coiffier B, Altman A, Pui CH, Younes A, Cairo MS.  Guidelines for the management of 
pediatric and adult tumor lysis syndrome:  an evidence-based review.  J Clin Oncol.  
2008;26(16):2767-2778. 
Dimopoulos MA, Oriol A, Nahi H, et al,  Daratumumab, Lenalidomide, and 
Dexamethasone for Multiple Myeloma.  N Engl J Med.  2016;375(14):1319-1331. 
Dimopoulos MA, Richardson PG, Moreau P, Anderson KC.  Current treatment 
landscape for relapsed and/or refractory multiple myeloma.  Nat Rev Clin Oncol.  
2015;12:42–54. 
Drug Facts and Comparison 2006.  60th ed.  Philadelphia, PA:  Lippincott Williams & 
Wilkins; 2005. 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
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Durie BG.  Multiple Myeloma Cancer of the Bone Marrow.  Concise Review of the 
Disease and Treatment Options.  International Myeloma Foundation, 2011/2012. 
Frankel SR, Baeuerle PA.  Targeting T cells to tumor cells using bispecific antibodies.  
Curr Opin Chem Biol.  2013;17(3):385-392. 
Ghermezi M, Li M, Vardanyan S, et al,  Serum B-cell maturation antigen:  a novel 
biomarker to predict outcomes for multiple myeloma patients.  Haematologica.  
2017;102(4):785-795. 
Gross JA, Johnston J, Mudri S, et al,  TACI and BCMA are receptors for a TNF 
homologue implicated in B-Cell autoimmune disease.  Nature.  2000;404(6781):995-999. 
Goodman & Gilman’s The Pharmacological Basis of Therapeutics.  9th ed.  New York 
City, NY:  McGraw Hill Professional; 1996. 
Howard SC, Trifilio S, Gregory TK, Baxter N, McBride A.  Tumor lysis syndrome in the 
era of novel and targeted agents in patients with hematologic malignancies:  a 
systematic review.  Ann Hematol.  2016;95(4):563-573. 
Ji Y, Liu P, Li Y, Bekele BN.  A modified toxicity probability interval method for dose-
finding trials.  Clin Trials.  2010;7(6):653-663.  
Kalbfleisch JD, Prentice RL.  The Statistical Analysis of Failure Time Data, Hoboken, 
New Jersey:  John Wiley & Sons; 1980. 
Kantarjian H, Stein A, Goekbuget N, et al,  Blinatumomab versus Chemotherapy for 
Advanced Acute Lymphoblastic Leukemia.  N Engl J Med.  2017;376(9):836-847.   
Klein JP, Moeschberger ML.  Survival Analysis:  Techniques for Censored and 
Truncated Data, New York:  Springer-Verlag; 1997.   
Kumar S, Paiva B, Anderson KC, et al,  International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple 
myeloma.  Lancet Oncol.  2016;17(8):e328-346. 
Kumar SK, Lee JH, Lahuerta JJ, et al,  Risk of progression and survival in multiple 
myeloma relapsing after therapy with IMiDs and bortezomib:  a multicenter international 
myeloma working group study.  Leukemia.  2012;26(1):149-157.   
Novak AJ, Darce JR, Arendt BK, et al,  Expression of BCMA, TACI, and BAFF-R in 
multiple myeloma:  a mechanism for growth and survival.  Blood. 
2004 Jan 15;103(2):689-94.  
Richardson PG, Sonneveld P, Schuster MW, et al,  Extended follow-up of a phase 3 trial 
in relapsed multiple myeloma:  final time-to-event results of the APEX trial.  Blood. 
2007;110(10):3557–60.   
Schemper M, Smith TL.  A note on quantifying follow-up in studies of failure time.  
Control Clin Trials. 1996;17(4):343–46.   
Smith EM, Cohen JA, Pett MA, Beck SL.  The Reliability and Validity of a Modified Total 
Neuropathy Score-Reduced and Neuropathic Pain Severity Items When Used to 
Measure Chemotherapy-induced Peripheral Neuropathy in Patients Receiving Taxanes 
and Platinums.  Cancer Nurs.  2010;33(3):173-183. 
Lee DW, Gardner R, Porter DL, et al,  Current concepts in the diagnosis and 
management of cytokine release syndrome.  Blood.  2014;124(2):188-195.  Erratum in:  
Blood.  2015;126(8):1048.  Dosage error in article text. 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
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Lonial S, Dimopoulos M, Palumbo A, et al,  Elotuzumab Therapy for Relapsed or 
Refractory Multiple Myeloma.  N Engl J Med.  2015;373(7):621-631. 
Madry C, Labbi Y, Callebaut I, et al,  The characterization of murine BCMA gene defines 
it as a new member of the tumor necrosis factor receptor superfamily.  Int Immunol.  
1998;10(11):1693-1702. 
Moreaux J, Legouffe E, Jourdan E, et al,  BAFF and APRIL protect myeloma cells from 
apoptosis induced by interleukin 6 deprivation and dexamethasone.  Blood.  
2004;103(8):3148-3157. 
Nagorsen D, Kufer P, Baeurle PA, Bargou R.  Blinatumomab:  a historical perspective.  
Pharmacol Ther.  2012;136(3):334-342. 
O’Connor BP, Raman VS, Erickson LD, et al,  BCMA is essential for the survival of 
long-lived bone marrow plasma cells.  J Exp Med.  2004;199(1):91-98. 
Oken MM, Creech RH, Tormey DC, et al,  Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group.  Am J Clin Oncol.  1982;5:649-655. 
Palumbo A, Chanan-Khan A, Weisel K, et al,  Daratumumab, Bortezomib, and 
Dexamethasone for Multiple Myeloma.  N Engl J Med.  2016;375(8):754-766. 
Palumbo A, Anderson K.  Multiple myeloma.  N Engl J Med.  2011;364(11):1046-1060. 
Panowski SH, Kuo T, Chen A, et al,  Preclinical Evaluation of a Potent Anti-Bcma CD3 
Bispecific Molecule for the Treatment of Multiple Myeloma.  Blood.  2016;128:383. 
Papadas A, Asimakopoulos F.  Mechanisms of Resistance in Multiple Myeloma.  Handb 
Exp Pharmacol.  2017. 
Physician’s Desk Reference 2002:  PDR Library/Hospital Edition.  56th ed.  Montvale, 
NJ:  Medical Economics Company; 2002. 
Rajkumar SV, Dimopoulos MA, Palumbo A, et al,  International Myeloma Working Group 
updated criteria for the diagnosis of multiple myeloma.  Lancet Oncol.  
2014;15(12):e538-548.  
Rajkumar SV, Harousseau JL, Durie B, et al,  Consensus recommendations for the 
uniform reporting of clinical trials:  report of the International Myeloma Workshop 
Consensus Panel 1.  Blood.  2011;117(18):4691-4695. 
Sanchez E, Li M, Kitto A, et al,  Serum B-cell maturation antigen is elevated in multiple 
myeloma and correlates with disease status and survival.  Br J Haematol.  
2012;158(6):727-738. 
SEER Stat fact sheets:  myeloma.  U.S. Department of Health & Human Services, 
National Institutes of Health, National Cancer Institute, Surveillance Epidemiology and 
End Results (SEER) 2014. 
Siegel R, Miller KD, Jemal A.  Cancer Statistic 2015.  CA Cancer J Clin.  2015;65:5–29. 
Smith D, Yong K.  Multiple myeloma.  BMJ.  2013;346:f3863. 
Tai YT, Li XF, Breitkreutz I, et al,  Role of B-cell-activating factor in adhesion and growth 
of human multiple myeloma cells in the bone marrow microenvironment.  Cancer Res.  
2006;66(13):6675-6682. 
Thompson JS, Bixler SA, Qian F, et al,  BAFF-R, a newly identified TNF receptor that 
specifically interacts with BAFF.  Science.  2001;293(5537):2108-2111. 


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Topp MS, Goekbuget N, Stein AS, et al,  Safety and activity of blinatumomab for adult 
patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia:  a 
multicentre, single-arm, phase 2 study.  Lancet Oncol.  2015;16(1):57-66. 
Topp MS, Goekbuget N, Zugmaier G, et al,  Phase II trial of the anti-CD19 bispecific T 
cell-engager blinatumomab shows hematologic and molecular remissions in patients 
with relapsed or refractory B-precursor acute lymphoblastic leukemia.  J Clin Oncol.  
2014;32(36):4134-4140. 
United States Food and Drug Administration.  Guidance for Industry Drug-Induced Liver 
Injury:  Premarketing Clinical Evaluation.  
https://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf 
Von Stackelberg A, Locatelli F, Zugmaier G, et al,  Phase I/Phase II Study of 
Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic 
Leukemia.  J Clin Oncol.  2016;34(36):4381-4389.   
Yu G, Boone T, Delaney J, et al,  APRIL and TALL-1 and receptors BCMA and TACI:  
system for regulating humoral immunity.  Nat. Immunol.  2000;1(3):252-256. 
Yuraszeck T, Kasichayanula S, Benjamin JE.  Translation and Clinical Development of 
Bispecific T cell Engaging Antibodies for Cancer Treatment.  Clin Pharmacol Ther.  
2017;101(5):634-645. 
Zhao C, Inoue J, Imoto I, et al,  Pou2AF1, an amplification target at 11q23, promotes 
growth of multiple myeloma cells by directly regulating expression of B-cell maturation 
factor, TNFRSF17.  Oncogene.  2008;27:63-75. 


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12. 
Appendices 


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12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ADL 
activities of daily living 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
APRIL 
a proliferation-inducing ligand 
AST 
aspartate aminotransferase  
AUClast 
area under the concentration-time curve from time 0 to the last 
measurable concentration 
BAFF 
B-cell activating factor 
BAFF-R 
B-cell activating factor receptor 
BCMA 
B-cell maturation antigen 
BI 
Boehringer Ingelheim 
BiTE® 
bispecific T-cell engager 
BM 
bone marrow 
BOR 
best overall response 
CAR 
chimeric antigen receptor 
CBC 
complete blood count 
cIV 
continuous intravenous 
Cmax 
maximum concentration 
CR 
complete response 
CRP 
C-reactive protein 
CRS 
cytokine release syndrome 
Css 
steady-state concentration 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
DILI 
drug-induced liver injury 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
dose limiting toxicity 
DOR 
duration of response 


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Abbreviation or Term 
Definition/Explanation 
DRT 
data review team 
EC50 
half-maximal target cell lysis 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EM 
extramedullary 
EMA 
European Medicines Agency 
EOI 
end of infusion 
EOS 
end of study 
EOT 
end of treatment 
FCBP 
females of childbearing potential 
FDA 
Food and Drug Administration 
FDG PET 
fluorodeoxyglucose positron emission tomography 
FIH 
first-in-human 
FISH 
fluorescent in situ hybridization 
FLC 
free light chain 
GCP 
good clinical practice 
G-CSF 
granulocyte colony stimulating factor 
GHS 
global health status 
GLP 
good laboratory practice 
GvHD 
graft versus host disease 
H2 blocker 
histamine 2 blocker 
HbA1c 
glycosylated hemoglobin 
HepBsAg 
hepatitis B surface antigen 
HepCAb 
hepatitis C virus antibody 
HHCS 
home health care service 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
HSCT 
hematopoietic stem cell transplantation 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IFN- 
interferon- 
Ig 
immunoglobulin 


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Abbreviation or Term 
Definition/Explanation 
IL 
interleukin 
IMiD 
immunomodulator 
IMWG 
International Myeloma Working Group  
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
institutional review board 
ISS 
International Staging System 
IUD 
intrauterine device 
IV 
intravenous(ly)  
IVSS 
intravenous solution stabilizer 
KM 
Kaplan-Meier 
LDH 
lactase dehydrogenase 
LTFU 
long-term follow-up 
MDE 
myeloma defining event 
MDSCs 
myeloid derived suppressor cells 
MGUS 
monoclonal gammopathy of undetermined clinical significance 
MR 
minimal response 
MRD 
minimal residual disease  
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
 
 
NIMP 
non-investigational medicinal products 
NK cells 
natural killer cells 
NOD/SCID 
non-obese diabetic/severe combined immunodeficiency 
ORR 
overall response rate 
OS 
overall survival 
PB 
peripheral blood 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PF 
physical functioning 


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Abbreviation or Term 
Definition/Explanation 
PFS 
progression-free survival 
PI 
proteasome inhibitor 
PK 
pharmacokinetic(s) 
POEMS   
POEMS syndrome:  polyneuropathy, organomegaly, endocrinopathy, 
monoclonal protein, and skin changes 
PR 
partial response 
PRO 
Patient-Reported Outcomes 
PRO-CTCAE 
Patient-Reported Outcomes version of the Common Terminology 
Criteria for Adverse Events 
PSA 
prostate specific antigen 
PR interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG or partial response 
QoL 
Quality of Life 
QRS interval 
QRS interval is the interval between the Q wave and the S wave in 
the heart's electrical cycle as measured by ECG; represents the time 
it takes for the depolarization of the ventricles 
QTcF 
Fridericia's Correction Formula 
QTc interval  
QT interval corrected for heart rate using accepted methodology 
RRMM 
Relapsed and/or refractory multiple myeloma 
SARS-COV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous(ly) 
sFLC 
serum free light chain 
SFU 
safety follow-up 
SPD 
bi-dimensional lesion measurements (sum of the products of the 
maximal perpendicular diameters of measured lesions) 
SPEP 
serum protein electrophoresis 
t1/2 
half-life 
TACI 
transmembrane activator and calcium modulator 
TB 
tuberculosis 
TBL 
total bilirubin 
TFI 
treatment-free interval 
TLS 
tumor lysis syndrome 
TNF 
tumor necrosis factor 
TPI 
toxicity probability interval 
Treg cells 
regulatory T cells 
UIFE 
urine immunofixation 


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Abbreviation or Term 
Definition/Explanation 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
VAS 
visual analog scale 
VGPR 
very good partial response 
WFI 
Water for Injection 
 


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12.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 12-1 will be performed by the central laboratory and/or by the 
local laboratory.  Additional analyte test results may be reported by the local or 
central laboratory, in accordance with standard laboratory procedures (eg, 
components of a hematology panel). 
The date and exact time of sample collection will be recorded in the source documents 
at the site (do not use the time that the samples were frozen or any other time point). 
If blood samples are collected on the same day on which the infusion bag is being 
changed, the blood samples must be collected before the infusion bag is changed.  
Blood draws should not be done via central venous access.  Exception:  if a permanent 
central line with more than one lumen is used, blood draws can be done via the lumen 
that is not used for AMG 420 drug administration.   
The test results are to be recorded on the electronic case report forms (eCRFs).  Missed 
test(s) that are not done must be reported as such on the eCRFs. 
Refer to the laboratory manual and/or Amgen-provided training materials for detailed 
collection, processing, and shipping instructions. 
Additional procedures (eg, collection of an unscheduled blood sample to measure 
cytokine levels) deemed necessary as part of standard of care or as required by local 
laws and regulations may be performed at the investigator’s discretion. 
Where required by local laws or regulations, additional assessments are defined in a 
country-specific protocol supplement at the end of the Appendix Section of protocol.    


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Table 12-1.  Analyte Listing 
Local Laboratory 
Central 
Laboratory 
Chemistry 
Hematology 
Coagulation 
Urinalysis 
Other  
 
Sodium 
Potassium 
Chloride 
Bicarbonate 
(HCO3) or 
Total CO2 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatininea 
Uric acid 
Total 
bilirubin 
Direct 
bilirubin 
ALP 
ALT (SGPT) 
AST (SGOT) 
Amylase 
Lipase 
LDH 
Ferritin 
CRP 
ANC 
Hemoglobin 
Hematocrit 
MCH 
MCHC 
MCV 
Platelets 
RBC 
WBC Differential 
• 
Total 
neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Plasma cells 
 
PT or INR 
PTT  
Fibrinogen 
D-Dimer 
 
 
Specific 
gravity 
pH 
Blood 
Protein 
Ketones 
Glucose 
Bilirubin 
Leucocytes 
esterase 
(WBC) 
Microscopic 
exam 
(only 
needed for 
positive 
dipstick and 
should 
include the 
following): 
Epithelial, 
Bacteria, 
Casts, 
Crystal, 
RBC, WBC 
 
 
Serology (Hep B, 
Hep C) 
Latent tuberculosis 
test 
Urine or serum 
pregnancy testb 
Immunoglobulins 
(IgA, IgM, IgG) 
BM 
FISH/karyotyping  
 
 
 
PK sampling 
 
 
 
 
 
MRD 
 
 
 
 
 
 
 
% MM 
involvement 
sCR 
SPEP 
UPEP 
sFLC 
sβ-
2 microglobulin 
 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; 
AST = aspartate aminotransferase; 
; BSA = body surface area; BUN = blood urea 
nitrogen; CRP = C-reactive protein; 
; FISH = fluorescent in-situ hybridization; 
Ig = immunoglobulin; INR = international normalized ratio; LDH = lactase dehydrogenase; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 
volume; MM = multiple myeloma; MRD = minimal residual disease; PB = peripheral blood; 
PK = pharmacokinetics; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cells; 
; sFLC = serum free light chain; SGOT = serum glutamic 
oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; SPEP = serum protein 
electrophoresis; UPEP = urine protein electrophoresis; WBC = white blood cells sCR= stringent Complete 
Response 
a Creatinine clearance will be calculated using the Cockcroft-Gault equation: 
(140 - age [years] x weight [kg] x 0.85 if female) / (72 x creatinine mg/dL), adjusted for BSA by 1.73 m2/BSA.   
b A pregnancy test will be performed locally at each site on all women unless they are surgically sterile or 
≥ 2 years postmenopausal. 
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.  


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12.3 
Appendix 3.  Study Governance Considerations 
Committee(s) 
Dose Level Review Team 
Dose level review team (DLRT) meetings will be held to review data, monitor safety, and 
make recommendations on dose escalation/change, changes in dosing schedule, and 
minimum hospitalization.  In phase 1b, the DLRT will convene and review all available 
safety, laboratory, and PK data at the following scheduled time points: 
 
After at least 10 subjects in phase 1b cohort 1 (400 g/day dose level) have had the 
opportunity to complete the 4-week infusion period of the first treatment cycle:  On 
the basis of this review, the DLRT will make a recommendation regarding the 
initiation of phase 1b cohort 2 (600 g/day dose level).   
 
After at least 3 subjects with extramedullary (EM) relapsed disease in phase 1b 
cohort 1 (400 g/day dose level) have had the opportunity to complete the 4-week 
infusion period of the first treatment cycle:  On the basis of this review, the DLRT will 
make a recommendation regarding the appropriateness of continued enrollment of 
subjects with EM relapsed disease in phase 1b cohort 2 (600 g/day dose level).  
Please note that enrollment of subjects with EM relapsed disease in phase 1b 
cohort 2 will not be allowed until this safety review of the first 3 subjects with EM 
disease is completed by the DLRT.   
 
After the first 3 subjects have been dosed with AMG 420 at 600 g/day for the full 
4-week infusion cycle in phase 1b cohort 2. 
The DLRT may also convene ad hoc meetings any time to review safety data if deemed 
necessary.  The DLRT will be composed of the investigators or designees, and the 
following Amgen representatives:  early development lead or designee, global safety 
officer or designee, clinical study manager, biostatistician, pharmacokinetics (PK) 
scientist (optional), and other functional area representatives as appropriate.  The 
following members are responsible for DLRT recommendations:  investigators, Amgen 
early development lead or designee, and global safety officer or designee. 
A quorum must be in attendance for the dose level review meeting (DLRM).  The 
quorum is defined as  50% of the participating investigators or their qualified designee 
(ie, sub-investigator or research nurse or study coordinator), as well as > 50% of Amgen 
representatives listed above.  Investigators that are not able to participate in the meeting 
(eg, due to time difference) may also provide their recommendations in writing after 
review of the data discussed at the meeting.  The early development lead or designee 
and the global safety officer or designee must attend for the quorum to be reached.  The 
DLRM will be rescheduled if a quorum is not reached.   


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Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure, and other relevant documents (eg, subject recruitment advertisements) must 
be submitted to an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
by the investigator and reviewed and approved by the IRB/IEC.  A copy of the written 
approval of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document that Amgen distributes to the site.  
The investigator must send a copy of the approval letter from the IRB/IEC and amended 
protocol Investigator’s Signature page to Amgen prior to implementation of the protocol 
amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Recruitment Procedures 
Site staff may identify potential subjects from their existing patient population and/or may 
seek referral patients through existing professional networks or other community 


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sources.  All patient-facing materials must be reviewed/approved by the sponsor 
(Amgen Inc.) and the local IRB/IEC prior to use. 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, and 
the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 


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The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  Subject 
withdrawal of consent or discontinuation from study treatment and/or procedures must 
also be documented in the subject’s medical records; refer to Section 8. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 21 days from the previous informed consent form signature 
date. 
The informed consent form (ICF) will contain a separate section that addresses the use 
of remaining mandatory samples for optional future research.  The investigator or 
authorized designee will explain to each subject the objectives of the future research.  
Subjects will be told that they are free to refuse to participate and may withdraw their 
specimens at any time and for any reason during the storage period.  A separate 
signature will be required to document a subject’s agreement to allow any remaining 
specimens to be used for future research.  Subjects who decline to participate will not 
provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 


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Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On eCRF demographics page, in addition to the unique subject identification number, 
include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  


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Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement 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.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above.  Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.  Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An Investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or eCRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  


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The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit function (or designees).  Inspection of site facilities 
(eg, pharmacy, protocol-required therapy storage areas, laboratories) and review of 
study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Case report forms (CRF) must be completed in English.  TRADENAMES (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 


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Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the 
Interactive Response Technology (IRT) system (if used, such as subject ID and 
randomization number) and CRF entries if the CRF is the site of the original recording 
(ie, there is no other written or electronic record of data, such as paper questionnaires 
for a clinical outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the [IRB/IEC] 
and Amgen 
 
Investigational product-related correspondence including [Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 


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Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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12.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device or procedure. 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered 
clinically significant in the medical and scientific judgment of the investigator 
(ie, not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
For situations when an adverse event or serious adverse event is due to multiple 
myeloma report all known signs and symptoms.  Death due to disease progression 
in the absence of signs and symptoms should be reported as the primary tumor 
type (eg, multiple myeloma).  Note:  The term “disease progression” should not be 
used to describe the adverse event. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as adverse event or 
serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event.  


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Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence 
that, meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are an adverse event.  If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the adverse event is to be considered 
serious.  Hospitalization for elective treatment of a pre-existing condition that did 
not worsen from baseline is not considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) which 
may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 


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A Serious Adverse Event is defined as any untoward medical occurrence 
that, meets at least 1 of the following serious criteria: 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious 
adverse event reporting is 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 medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition.  
These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event eCRF. 
 
The investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Did the event start prior to first dose of investigational product; 
o Assessment of seriousness 
o Severity (or toxicity defined below); 
o Assessment of relatedness to investigational product, other protocol-required 
therapies, study-mandated procedures; 
o Action taken; and  
o Outcome of event. 
 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record a single event for each level of severity on the Event CRF  
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to sponsor in lieu of completion of the Event CRF page. 


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Adverse Event and Serious Adverse Event Recording 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on:  
The Common Terminology Criteria for Adverse Events, version 5 which is available at 
the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
with the exception of cytokine release syndrome (CRS), which must be graded using 
the criteria referenced in the publication by Lee et al, 2014 (see Section 7.4.2.1.2.5) 
and tumor lysis syndrome (TLS), which must be graded according to the Cairo Bishop 
criteria referenced in the publication by Coiffier et al, 2008 (see Section 12.12).   
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product, protocol-required therapies or study-mandated procedure and each 
occurrence of each adverse event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 


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very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized 
follow-up period as defined in Section 9.2.3.1.1, the investigator will provide 
Amgen with a copy of any post-mortem findings including histopathology. 
 
New or updated information will be recorded in the originally completed Event 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
within 24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system via the Safety Report Form.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using an electronic Serious Adverse Contingency Report 
Form (see Figure 12-1) within 24 hours of the investigator’s knowledge of the 
event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC has been taken off-line, then the site can report this information on a paper 
Serious Adverse Event Report Form. 


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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report Form 
 


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12.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for male and female of childbearing potential 
are outlined in Section 6.2. 
Male and female subjects of childbearing potential must receive pregnancy prevention 
counseling and be advised of the risk to the fetus if they become pregnant or father a 
child during treatment and for 6 weeks (or for 14 weeks a male subject's female partner) 
after the last dose of protocol-required therapies. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  1) review 
of subject’s medical records; 2) subject’s medical examination; or 3) subject’s medical 
history interview. 
 
Premenarchal female 
 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment 
Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note:  Failure rate of < 1% per year when used consistently and correctly. 


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 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Contraception Methods for Male Subjects  
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject)  
 
Use a condom during treatment and for an additional 14 weeks after the last dose of 
protocol-required therapies 
The female partner should consider using an acceptable method of effective 
contraception such as:  hormonal, IUD, IUS, female barrier method (diaphragm, cap, 
sponge [a female condom is not an option because there is a risk of tearing when both 
partners use a condom]). 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 


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Unacceptable Methods of Birth Control for Male and Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 6 weeks after the last 
dose of AMG 420. 
 Information will be recorded on the Pregnancy Notification Worksheet 
(see Figure 12-2).  The worksheet must be submitted to Amgen Global Patient 
Safety within 24 hours of learning of a subject’s pregnancy.  (Note:  Sites are not 
required to provide any information on the Pregnancy Notification Worksheet that 
violates the country or regions local privacy laws). 
 After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant 
health information and complete the pregnancy questionnaire for any female subject 
who becomes pregnant while taking protocol-required therapies through 6 weeks 
after the last dose of AMG 420 of the study drug.  This information will be forwarded 
to Amgen Global Patient Safety.  Generally, infant follow-up will be conducted up to 
12 months after the birth of the child (if applicable). 
 Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
 If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
 Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 12.4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  


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 Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 8.1 for details). 
Male Subjects With Partners Who Become Pregnant  
 In the event a male subject fathers a child during treatment, and for an additional 
14 weeks after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Worksheet.   
 The worksheet (see Figure 12-2) must be submitted to Amgen Global Patient Safety 
within 24 hours of the site’s awareness of the pregnancy.  (Note:  Sites are not 
required to provide any information on the Pregnancy Notification Worksheet that 
violates the country or regions local privacy laws). 
 The investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
 Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
 Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 6 weeks after the last dose of 
AMG 420. 
 
Information will be recorded on the Lactation Notification Worksheet (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 224. 
 
With the female subjects signed authorization for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through 6 weeks after the last dose of 
AMG 420 after discontinuing protocol-required therapies. 


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Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 


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12.6 
Appendix 6.  Sample Storage and Destruction 
Any blood, saliva, or bone marrow (BM) sample collected according to the Schedule of 
Activities (Section 2.2) can be analyzed for any of the tests outlined in the protocol and 
for any tests necessary to minimize risks to study subjects.  This includes testing to 
ensure analytical methods produce reliable and valid data throughout the course of the 
study.  This can also include, but is not limited to, investigation of unexpected results, 
incurred sample reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
multiple myeloma, the dose response and/or prediction of response to AMG 420, 
characterize antibody response, and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the 
 or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood, saliva, or BM samples and any other components from the cells can be located 
and destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 


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appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 12.3 for subject confidentiality. 


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12.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomyolosis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible 
drug-induced liver injury (DILI) according to recommendations in the last section of this 
appendix.  


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Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
 3x ULN  
at any time 
 2x ULN 
 
 
OR 
INR 
-- 
 1.5x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
 8x ULN at any time 
 5x ULN but  8x ULN for  2 weeks 
 5x ULN but  8x ULN and unable to 
adhere to enhanced monitoring schedule 
 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
 3x ULN (when baseline was  ULN) 
 
OR 
 
ALP 
 8x ULN at any time 
-- 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; 
INR  international normalized ratio; TBL  total bilirubin; ULN  upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen investigational product is to be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Table 12-2) are never to be rechallenged. 
 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 


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To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate Case Report Form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 12.4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 12-2 or who experience AST or ALT elevations  3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a periossd of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.   
Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, bilirubin (BIL) (total and direct), and INR within 24 hours  
 
In cases of TBL  2x ULN or INR  1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 


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 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral blood 
smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.  


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 153 of 169 
CONFIDENTIAL 
 
 
12.8 
Appendix 8.  International Working Group Response Criteria for 
Multiple Myeloma (IMWG-URC) 
Response criteriaa 
Standard IMWG response criteriab 
sCR 
 
CR as defined below AND 
 
Normal FLC ratioc AND 
 
Absence of clonal cells in BM biopsy by immunohistochemistry κ/ ratio 
 4:1 or  1:2 for κ and  patients, respectively, after counting  100 plasma 
cellsd 
CR 
 
Negative immunofixation on the serum and urine AND 
 
Disappearance of any soft tissue plasmacytomas AND 
 
 5 plasma cells in BM aspirates 
 
In patients with baseline measurable disease only by sFLC, a normal FLC 
ratio is required 
VGPR 
 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis  
OR  
 
 90 reduction in serum M-protein plus urine M-protein 
level  100 mg/24 hours 
 
In patients with baseline measurable disease only by sFLC, a 
 90 decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria. 
 
In patients achieving a VGPR by other criteria, a soft tissue plasmacytoma 
must decrease by more than 90 in the SPD compared with baseline 
PR 
 
 50 reduction of serum M-protein and reduction in 24-hour urinary 
M-protein by  90 or to  200 mg/24 hours   
 
In patients with baseline measurable disease only by sFLC, a 
 50 decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria. 
 
If serum and urine M-protein are unmeasurable, and serum free light assay is 
also unmeasurable,  50 reduction in plasma cells is required in place of 
M-protein, provided baseline BM cell percentage was  30. 
 
If present at baseline, a  50 reduction in the size (SPD)e of soft tissue 
plasmacytomas is also required. 
MR 
 
 25 but  49 reduction of serum M-protein and reduction in 24-hr urine M-
protein by 50 to 89 
 
In patients with baseline measurable disease only by sFLC, a 25 but 
 49 decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria 
 
If present at baseline, a  50 reduction in the size of soft tissue 
plasmacytomas (SPD)e is also required. 
Stable 
disease 
 
Not recommended for use as an indicator of response 
 
Stability of disease is best described by providing the time-to-progression 
estimates 
 
Not meeting criteria for sCR, CR, VGPR, PR, minimal response, or PD 
Page 1 of 2 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 154 of 169 
CONFIDENTIAL 
 
 
Footnotes are defined on last page of this table 
Response criteriaa 
Standard IMWG response criteriab (Continued) 
PDf,g 
 
Any 1 or more of the following criteria: 
 
Increase of 25 from lowest confirmed response value in 1 or more of the 
following criteria: 
 
Serum M-protein (absolute increase must be  0.5 g/dL); 
o 
Serum M-protein increase 1 g/dL, if the lowest M component was 
 5 g/dL; 
o 
Urine M-protein (absolute increase must be  200 mg/24 hr); 
o 
In patients without measurable serum and urine M-protein levels, the 
difference between involved and uninvolved FLC levels (absolute 
increase must be  10 mg/dL); 
 
In patients without measurable serum and urine M-protein levels and 
without measurable involved FLC levels, BM plasma-cell percentage 
irrespective of baseline status (absolute increase must be  10); 
 
Appearance of a new lesion(s),  50 increase from nadir in SPDe of 
 1 lesion, or  50 increase in the longest diameter of a previous lesion 
 1 cm in short axis; 
 
 50 increase in circulating plasma cells (minimum of 200 cells per μL) if 
this is the only measure of disease 
IMWG MRD criteria (requires a CR as defined above) 
Sustained 
MRD-neg
ative 
 
MRD negativity in the marrow (NGS) and by imaging as defined below, 
confirmed minimum of 1 year apart.  
 
Subsequent evaluations can be used to further specify the duration of 
negativity (eg, MRD-negative at 5 years)h 
Sequencin
g MRD-
negative 
 
Absence of clonal plasma cells by NGS on BM aspirate in which presence of 
a clone is defined as less than 2 identical sequencing reads obtained after 
DNA sequencing of BM aspirates using the LymphoSIGHT platform (or 
validated equivalent method) with a minimum sensitivity of 1 in 10⁵ nucleated 
cellsi or higher 
Imaging 
plus MRD-
negative 
 
MRD negativity as defined by NGS plus disappearance of every area of 
increased tracer uptake found at baseline or a preceding PET/CT or decrease 
to less mediastinal blood pool SUV or decrease to less than that of 
surrounding normal tissuej 
Page 2 of 2 
Footnotes are defined on last page of this table 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 155 of 169 
CONFIDENTIAL 
 
 
ASCT  autologous stem cell transplantation; BM  bone marrow; CR  complete response; CRAB 
features  calcium elevation, renal failure, anaemia, or lytic bone lesions; CT  computed tomography; 
FLC  free light chain; IMWG  International Myeloma Working Group; MR  minimal disease; 
MRD  minimal residual disease; MRI  magnetic resonance imaging; NGS  next generation sequencing; 
PD  progressive disease; PET  positron emission tomography; PFS  progression-free survival; 
PR  partial response; sCR  stringent complete response; SPD  sum of the products of the maximal 
perpendicular diameters of measured lesions; SUV  standardized uptake value; VGPR  very good partial 
response 
a All response categories require 2 consecutive assessments made any time before starting any new 
therapy; for MRD there is no need for 2 consecutive assessments, but information on MRD after each 
treatment stage is recommended (eg, after induction, high-dose therapy/ASCT, consolidation, maintenance).  
MRD tests should be initiated only at the time of suspected CR.  All categories of response and MRD require 
no known evidence of progressive or new bone lesions if radiographic studies were performed.  However, 
radiographic studies are not required to satisfy these response requirements except for the requirement of 
FDG PET if imaging MRD-negative status is reported. 
b Derived from international uniform response criteria for multiple myeloma.  Minor response definition and 
clarifications derived from Rajkumar and colleagues.  When the only method to measure disease is by 
serum FLC levels:  CR can be defined as a normal FLC ratio of 0.26 to 1.65 in addition to the CR criteria 
listed previously.  Very good PR in such patients requires a  90 decrease in the difference between 
involved and uninvolved FLC levels.  All response categories require 2 consecutive assessments made at 
any time before the institution of any new therapy; all categories also require no known evidence of 
progressive or new bone lesions or extramedullary plasmacytomas if radiographic studies were performed.  
Radiographic studies are not required to satisfy these response requirements.  Bone marrow assessments 
do not need to be confirmed.  Each category, except for stable disease, will be considered unconfirmed until 
the confirmatory test is performed.  The date of the initial test is considered as the date of response for 
evaluation of time dependent outcomes such as duration of response. 
c All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on results 
obtained with the validated Freelite test (Binding Site, Birmingham, UK). 
d Presence/absence of clonal cells on immunohistochemistry is based upon the κ//L ratio.  An abnormal κ/ 
ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis.  An abnormal ratio 
reflecting presence of an abnormal clone is κ/ of  4:1 or  1:2.  
e Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or 
dedicated CT scans where applicable.  For patients with only skin involvement, skin lesions should be 
measured with a ruler.  Measurement of tumor size will be determined by the SPD. 
f Positive immunofixation alone in a patient previously classified as achieving a CR will not be considered 
progression.  For purposes of calculating time to progression and PFS, patients who have achieved a CR 
and are MRD-negative should be evaluated using criteria listed for progressive disease.  Criteria for relapse 
from a CR or relapse from MRD should be used only when calculating disease-free survival. 
g In the case where a value is felt to be a spurious result per physician discretion (eg, a possible laboratory 
error), that value will not be considered when determining the lowest value. 
h Sustained MRD negativity when reported should also annotate the method used (eg, sustained flow 
MRD-negative, sustained sequencing MRD-negative). 
i DNA sequencing assay on BM aspirate should use a validated assay such as LymphoSIGHT (Sequenta). 
j Criteria used by Zamagni and colleagues, and expert panel (IMPetUs; Italian Myeloma criteria for PET 
Use).  Baseline positive lesions were identified by presence of focal areas of increased uptake within bones, 
with or without any underlying lesion identified by CT and present on at least 2 consecutive slices.  
Alternatively, an SUVmax  2.5 within osteolytic CT areas  1 cm in size, or SUVmax  1.5 within osteolytic CT 
areas  1 cm in size were considered positive.  Imaging should be performed once MRD negativity is 
determined by NGS. 
Source:  International Myeloma Working Group consensus criteria for response and minimal residual 
disease assessment in MM (Kumar et al, 2016); modified for protocol purposes 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 156 of 169 
CONFIDENTIAL 
 
 
12.9 
Appendix 9.  Clarification on Eligibility Criteria:  Definition of 
Relapsed or Refractory Disease and Line of Treatment 
Refractory multiple myeloma is defined as disease that is nonresponsive while on 
primary or salvage therapy, or progresses within 60 days of last therapy:  Nonresponsive 
disease is defined as either failure to achieve minimal response (MR).  There are 
2 categories of refractory multiple myeloma:  
 
Relapsed and refractory multiple myeloma.  Relapsed and refractory multiple 
myeloma is defined as disease that is nonresponsive while on salvage therapy, or 
progresses within 60 days of last therapy in patients who have achieved MR or better 
at some point previously before then progressing in their disease course. 
 
Primary refractory multiple myeloma.  Primary refractory multiple myeloma is 
defined as disease that is nonresponsive in patients who have never achieved a MR 
or better with any therapy.  It includes patients who never achieve MR or better in 
whom there is no significant change in M-protein and no evidence of clinical 
progression as well as primary refractory, PD where patients meet criteria for true 
PD. 
Relapsed multiple myeloma is defined as previously treated multiple myeloma that 
progresses and requires the initiation of salvage therapy but does not meet criteria for 
either “primary refractory myeloma” or “relapsed-and-refractory multiple myeloma” 
categories. 
A line of therapy is defined as 1 or more cycles of a planned treatment program.  This 
may consist of 1 or more planned cycles of single-agent therapy or combination therapy, 
as well as a sequence of treatments administered in a planned manner.  
For example, a planned treatment approach of induction therapy followed by autologous 
stem cell transplantation, followed by maintenance is considered 1 line of therapy 
(Rajkumar et al, 2011).  


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 157 of 169 
CONFIDENTIAL 
 
 
12.10 
Appendix 10.  Medications That May Cause QTc Prolongation 
A list of medications known to cause QTc interval prolongation is available at the 
following link:  https://crediblemeds.org/index.php/login/dlcheck  
If a participant in this study does not have access to the internet, they can contact the 
institution investigational pharmacy or contact their study physician to obtain a list. 
Table 12-3 presents a list of drugs that may prolong QTc.  This is not an inclusive list of 
drugs and is provided for guidance only.  The participant is encouraged to follow the list 
in this link above for the most up-to-date information.  These drugs are prohibited during 
the study.  Washout period is based on roughly 5 half-lives and rounded to a convenient 
interval.  This list includes (but is not limited to) the following: 
Table 12-3.  Medications That May Cause QTc Prolongation 
Compounds 
Compound Half-Life 
Possible 
Washout   
Period - Hours 
Possible 
Washout    
Period - Days 
Alfuzosin 
 10 hours 
 
7 
Amantadine 
17  4 hours (10-25) 
 
4 
Amiodarone 
(cordarone) 
58 days (15-142) 
36 days (active metabolite) 
 
180 
Amitriptyline* 
 24 hours, wide interpatient variability 
 
 
Arsenic trioxide 
not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hours (26-64) 
 
10 
Chloral hydrate 
readily converted to trichloroethanol 
(active metabolite T½  7-10 hours) 
48 
 
Chloroquine 
prolonged (days to weeks) 
 
 
Chlorpromazine 
30  7 hours 
 
 
Clarithromycin 
non-linear PK 3-4 hours (250 mg Q12) 
5-7 hours (500 mg Q12) 
36 
 
Chloroquine 
6-60 days; mean 20 days 
 
 
Desipramine* 
 24 hours, wide interpatient variability 
 
 
Disopyramide 
6.7 hours (4-10) 
36 
 
Dofetilide 
10 hours 
48 
 
Dolasetron 
8.1 hours 
 
 
Domperidone 
7-8 hours 
48 
 
Doxepin* 
 24 hours, wide interpatient variability 
 
 
Droperidol 
2.2 hours 
10 
 
Page 1 of 3 
Footnotes defined on last page of this table 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 158 of 169 
CONFIDENTIAL 
 
 
Table 12-3.  Medications That May Cause QTc Prolongation 
Compounds 
Compound Half-Life 
Possible 
Washout  
Period – Hours 
Possible 
Washout   
Period - Days 
Erythromycin 
*each salt form has different half-life* 
 
 
Felbamate 
20-23 hours 
 
5 
Flecainide 
20 hours (12-27) 
 
5 
Foscarnet 
87.5  41.8 hours 
*distribution and release from bone* 
 
20 
Fosphenytoin 
12-29 hours 
 
6 
Gatifloxacin 
7-14 hours 
48 
 
Gemifloxacin 
7 hours 
48 
 
Grepafloxacin 
16 hours 
 
3 
Halofantrine 
6-10 days (variable among individual) 
 
45 
Haloperidol 
18  5 hours 
 
5 
Ibutilide 
6 hours (2-12) *variable among 
subject* 
36 
 
Imipramine* 
 24 hours, wide interpatient 
variability 
 
 
Indapamide 
14 hours (biphasic elimination) 
 
3 
Isradipine 
8 hours (multiple metabolites) 
48 
 
Levofloxacin 
6-8 hours 
48 
 
Levomethadyl 
multiple compartment PK with active 
metabolite 
2.6 days for LAAM, 2 days for 
nor-LAAM, 4 days for dinor-LAAM 
 
20 
Lithium 
24 hours (10-50) 
 
7 
Mesoridazine 
24-48 hours (animal study) 
 
10 
Methadone 
15-30 hours 
 
7 
Moexipril/HCTZ 
2-9 hours (include active metabolite) 
for moexipril; 5.6-14.8 hours for 
HCTZ 
48 
 
Moxifloxacin 
12  1.3 hours 
72 
 
Naratriptan 
6 hours 
36 
 
Nicardipine 
 2 hours post IV infusion 
12 
 
Nortriptyline* 
 24 hours, wide interpatient 
variability 
 
 
Octreotide 
1.7 hours 
12 
 
Ofloxacin 
5-7.5 hours 
 
2 
Ondansetron 
4 hours (IV/IM); 3 hours (PO) 
 
1 to 3 
Pentamidine 
6.4  1.3 hours 
36 
 
Pimozide 
55 hours 
 
10 
Page 2 of 3 
Footnotes defined on last page of this table 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 159 of 169 
CONFIDENTIAL 
 
 
Table 12-3.  Medications That May Cause QTc Prolongation 
Compounds 
Compound Half-Life 
Possible  
Washout     
Period – Hours 
Possible 
Washout     
Period - Days 
Procainamide 
3-4 hours for PA and NAPA (active 
metabolite) 
24 
 
Protriptyline* 
 24 hours, wide interpatient variability 
 
 
Quetiapine 
6 hours 
36 
 
Quinidine 
6-8 hours in adult; 3-4 hours in 
children 
36 
 
Quinine 
4-5 hours 
 
 
Risperidone 
3-20 hours (extensive to poor 
metabolizer) 
9-hydroxyrisperidone (active 
metabolite) T½  21-30 hours 
(extensive to poor metabolizer) 
 
4 
Salmeterol 
5.5 hours (only 1 datum) 
36 
 
Sotalol 
12 hours 
72 
 
Sparfloxacin 
20 hours (16-30) 
 
4 
Sumatriptan 
2.5 hours 
12 
 
Tacrolimus 
 34 hours in healthy;  19 hours in 
kidney transplant 
 
7 
Tamoxifen 
5-7 days (biphasic) 
 
30 
Telithromycin 
2-3 hours 
24 
 
Thioridazine 
20-40 hours (phenothiazines) 
 
7 
Tizanidine 
2.5 hours 
12 
 
Vardenafil 
4-5 hours 
 
 
Venlafaxine 
5  2 hours for parent comp. 
11  2 hours for OVD (active 
metabolite) 
60 
 
Voriconazole 
6 hours; dose dependent 
 
 
Ziprasidone 
7 hours 
36 
 
Zolmitriptan 
2.8-3.7 hours (higher in female) 
18 
 
Page 3 of 3 
* Weakly associated with Torsades de pointes and/or QT prolongation, but that are unlikely to be a risk for 
Torsades de pointes when used in usual recommended dosages and in patients without other risk factors 
(eg, concomitant QT prolonged drugs, bradycardia, electrolyte disturbances, congenital long QT syndrome, 
concomitant drugs that inhibit metabolism). 
Sources:  Drug Facts and Comparison 2006, 2005; Physician’s Desk Reference, 2002; Goodman & 
Gilman’s the Pharmacological Basis of Therapeutics, 1996. 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 160 of 169 
CONFIDENTIAL 
 
 
12.11 
Appendix 11.  Schedule of Activities in Case of Requirement for Dose Step 
Table 12-4.  Phase 1b Screening and Treatment Cycle 1 With Dose Step 
  
SCR 
Treatment Period 
Cycle 
  
1 
Infusion-
free 
Intervala 
Cycle Day 
-
21 to 
-1 
1 
2 
3 
4 
5 
6 
8 15 22 
29 
36 
Hours 
  
Pre-
dose 
Relative to start of infusion  
Pre
-
ste
p 
Relative to start of infusion  
  
  
EOI
  
0 
1 
2 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
0.
5 
1 
2 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
  
  
  
  
  
  
GENERAL AND SAFETY ASSESSMENTS 
  
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   
  
In-/Exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   
  
Demographics/Medic
al history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   
  
Hospitalizationb 
 
6 days 
 
 
 
 
 
Concomitant 
medications 
----------------------------------------     continually from informed consent until SFU     --------------------------------------------------- 
SAE review 
----------------------------------------     continually from informed consent until SFU     ---------------------------------------------------
AE review 
 
 
--------------------------------------     continually from first dose of AMG 420 until SFU     -----------------------------------------------
Physical examination 
X 
X 
  
  
  
  
  
  
  
  
  
X 
X 
X 
  
  
  
  
  
  
  
  
  
X X X 
X 
X 
X 
X 
Peripheral 
neuropathy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance 
status 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital signs, pulse 
oximetryc 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
ECG triplicate 
measurementc 
X 
X 
  
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X X 
 
 
 
X 
 
Page 1 of 4 
Footnotes defined after last page of table. 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
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CONFIDENTIAL 
 
 
Table 12-4.  Phase 1b Screening and Treatment Cycle 1 With Dose Step 
  
SCR 
Treatment Period 
Cycle 
  
1 
Infusion-
free 
Intervala 
Cycle Day 
-
21 t
o -1 
1 
2 
3 
4 
5 
6 
8 15 2
2 
29 
36 
Hours 
  
Pre-
dose 
Relative to start of infusion   
Pre
-
ste
p 
Relative to start of infusion  
  
  
 EOI 
  
0 
1 
2 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
0.
5 
1 
2 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
  
  
  
  
  
  
LABORATORY ASSESSMENTS 
  
Pregnancy testd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulatione 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
X X 
X 
X 
X 
X 
X 
Hematology, 
chemistrye  
X 
X 
 
 
 
 
 
X  
 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
X X 
X 
X 
X 
X 
X 
Creatinine Clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ferritinf 
 
X 
       continue monitoring in case of CRS only       
Hepatitis serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Latent TB test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Ig:  IgA, IgM, IgG 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK ASSESSMENTS 
AMG 420 PK 
collectiong 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X X 
X 
X 
 
Xg 
 
Page 2 of 4 
Footnotes defined after last page of table. 


Product:  AMG 420 
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CONFIDENTIAL 
 
 
Table 12-4.  Phase 1b Screening and Treatment Cycle 1 With Dose Step 
  
SCR 
Treatment Period 
Cycle 
  
1 
Infusion-
free 
Intervala  
Cycle Day 
-21 to 
-1 
1 
2 
3 
4 
5 
6 
8 15 2
2 
29 
36 
Hours 
  
Pre-
dose 
Relative to start of infusion    
Pre
-
ste
p 
Relative to start of infusion    
  
  
EOI 
  
0 
1 
2 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
0.5 1 
2 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
  
  
  
  
  
  
DISEASE ASSESSMENTS 
SPEP/SIFEh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
UPEP/UIFEh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
s-2 microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
sFLC (ĸ/ʎ) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
BM aspirate/biopsyi  
X 
At initial suspected CR and at 6 (after 4 cycles) months and repeat at 12 months for subjects who continue to appear to be in CR and 
recommended in case of PD/relapse 
 MM involvementi 
X 
At initial suspected CR and at 6 (after 4 cycles) months and repeat at 12 months for subjects who continue to appear to be in CR and 
recommended in case of PD/relapse 
BM 
FISH/karyotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extramedullary 
plasmacytoma 
assessmentsj  
X 
        repeat only to confirm a PR or better only if measurable plasmacytoma present at baseline, every 12 weeks ( 2 weeks), 
as clinically indicated   
Skeletal surveyj 
X 
                                                   repeat only as clinically indicated                                                    
Page 3 of 4 
Footnotes defined after last page of table. 


Product:  AMG 420 
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Date: 17 September 2021 
Page 163 of 169 
CONFIDENTIAL 
 
 
Table 12-4.  Phase 1b Screening and Treatment Cycle 1 With Dose Step 
  
SCR 
Treatment Period 
Cycle 
  
1 
Infusion-
free 
Intervala  
Cycle Day 
-
21 t
o -1 
1 
2 
3 
4 
5 
6 
8 15 2
2 
29 
36 
Hours 
  
Pre-
dose 
Relative to start of infusion    
Pre
-
ste
p 
Relative to start of infusion    
  
  
EOI 
  
0 
1 
2 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
0.5 1 
2 
4 
6 
8 
1
2 
1
6 
2
0 
2
4 
4
8 
  
  
  
  
  
  
BIOMARKER ASSESSMENTS 
  
INVESTIGATIONAL PRODUCT DOSING 
AMG 420 cIV infusion 
 
 
---------------------------------------------------------------------------------------------------------------------------------------------- 
 
Premedicationo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 4 of 4 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 164 of 169 
CONFIDENTIAL 
 
 
Footnotes defined on next page 
AE  adverse event;
 cIV  continuous intravenous; CR  complete response; CRS  cytokine release syndrome; CT  computed tomography; 
 ECG  electrocardiogram; ECOG  Eastern Cooperative Oncology Group; EOI  end of infusion; FISH  fluorescent in situ 
hybridization; Ig  immunoglobulins; MDSCs  myeloid derived suppressor cells; MM  multiple myeloma; MRD  minimal residual disease; MRI  magnetic resonance 
imaging;
;
 PD  progressive disease; PET  positron emission tomography;
; 
PK  pharmacokinetics; PR  partial response; SAE  serious adverse event;
; SCR  screening; sFLC (ĸ/ʎ)  serum free 
light chain (kappa/lambda); SFU  safety follow-up; SIFE  serum immunofixation; SPEP  serum protein electrophoresis; TB  tuberculosis; UIFE  urine 
immunofixation; UPEP  urine protein electrophoresis  
a Infusion-free interval  days 30 to 42, day 43  day 1 of subsequent cycle.   
b See Section 7.1.1.4.1 for details on hospitalization requirements. 
c ECGs and vital signs should be performed approximately 15 min prior to any invasive procedures including IV bag change, if applicable, and approximately 15 min 
prior to EOI.  ECGs are only required in cycle 1 and 2.  
d Refer to Section 9.2.4.1 for details of required pregnancy testing. 
e As indicated in Section 12.2, hematology and chemistry panels include differential cell counts and comprehensive metabolic profile, as well as serum uric acid and 
phosphorous levels, and liver function tests.  Coagulation panel includes prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and D-dimer. 
f If ferritin value after CRS is abnormal, continue monitoring until values are back to baseline/event is resolved. 
g Time schedule for PK sampling cycle 1 day 29:  approximately 15 min prior to EOI and 4, 8, 24, and 48 hours after EOI. 
h Serum and urine immunofixation (IFE) for M-protein measurements.  Urine IFE to be followed up only if positive for M-protein at baseline. 
j Baseline imaging is required at screening (if done within 30 days prior to screening for standard of care, no need to repeat) to evaluate for extramedullary (EM) relapse 
using whole body MRI or PET/CT and should be repeated during treatment only to confirm a PR or better only if measurable plasmacytoma are present at baseline 
every 12 weeks ( 2 weeks) and as clinically indicated.  Skeletal survey does not need to be performed at screening if CT or PET-CT performed and does not need to 
be repeated after screening unless clinically indicated.   
k MRD and 
 
o See Section 7.1.4 for details on premedication requirements.


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 165 of 169 
CONFIDENTIAL 
 
 
12.12 
Appendix 12.  Cairo-Bishop Clinical Tumor Lysis Syndrome 
Definition and Grading 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 classifies tumor 
lysis syndrome (TLS) in grade 3 (present), grade 4 (life threatening consequences; 
urgent intervention indicated) and grade 5 (death).  Presence of TLS is not clearly 
defined by CTCAE version 4.0.  Cairo and Bishop developed a system for defining and 
grading TLS based on Hande-Garrow classification of laboratory or clinical TLS 
(Coiffier et al, 2008).  For this trial the Cairo-Bishop classification will be used to define 
presence of TLS, ie, presence of laboratory TLS (see Table 12-5) and clinical TLS 
(see Table 12-6) including grading as detailed below.  
Based on the Cairo and Bishop system, laboratory TLS is present when levels of 2 or 
more serum values of uric acid, potassium, phosphorus, or calcium are more than or 
less than normal at presentation or if they change by 25 within 3 days before or 7 days 
after initiation of treatment (Table 12-5). 
Table 12-5.  Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (TLS) 
Element 
Value 
Change from Baseline 
Uric acid 
 476 mol/L or 8 mg/dL 
25 increase 
Potassium 
 6.0 mmol/L or 6 mg/L 
25 increase 
Phosphorus 
 2.1 mmol/L for children or 
 1.45 mmol/L for adults 
25 increase 
Calcium 
 1.75 mmol/L 
25 decrease 
Note:  2 or more laboratory changes within 3 days before or 7 days after cytotoxic therapy will constitute 
laboratory TLS. 
Clinical TLS requires the presence of laboratory TLS in addition to 1 or more of the 
following significant complications:  renal insufficiency, cardiac arrhythmias/sudden 
death, and seizures (Table 12-6).  The grade of clinical TLS is defined by the maximal 
grade of the clinical manifestations as detailed in Table 12-6.  


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 166 of 169 
CONFIDENTIAL 
 
 
Table 12-6.  Cairo-Bishop Clinical Tumor Lysis Syndrome Definition and Grading 
Grade 
Creatininea, b 
Cardiac Arrhythmiaa 
Seizurea 
0 
 1.5 x ULN 
n1 
n1 
1 
1.5 x ULN 
intervention not indicated 
-- 
2 
 1.5 – 3.0 x ULN 
non urgent medical 
intervention indicated 
one brief, generalized seizure; 
seizure(s) well controlled by 
anticonvulsants or infrequent focal 
motor seizures not interfering with 
ADL 
3 
 3.0 – 6.0 x ULN 
symptomatic and 
incompletely controlled 
medically or controlled 
with device (eg, 
defibrillator)  
seizure in which consciousness is 
altered; poorly controlled seizure 
disorder; with breakthrough 
generalized seizures despite medical 
intervention 
4 
 6.0 x ULN 
life-threatening (eg, 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
seizure of any kind which are 
prolonged, repetitive or difficult to 
control (eg, status epilepticus, 
intractable epilepsy) 
5 
Death 
death 
death 
Note:  Laboratory TLS and at least 1 clinical complication will constitute clinical TLS. 
ADL  activities of daily living; CHF  congestive heart failure; TLS  tumor lysis syndrome; ULN  upper 
limit of normal 
a not directly or probably attributable to therapeutic agent 
b if no institutional ULN is specified, age/sex ULN creatinine may be defined as follows:   1 to  12 years of 
age, both male and female, 61.6 mol/L;  12 to  16 years, both male and female, 88 mol/L;  16 years, 
female 105.6 mol/L, male 114.4 mol/L


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 167 of 169 
CONFIDENTIAL 
 
 
12.13 
Appendix 13.  Performance Status According to Eastern Cooperative 
Oncology Group (ECOG) Scale 
ECOG Performance Status Scale 
Grade 
Descriptions 
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 housework, office work). 
2 
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50 of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50 of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead. 
Source:  Oken et al, 1982 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 168 of 169 
CONFIDENTIAL 
 
 
12.14 
Appendix 14.  Protocol-specific Anticipated Serious Adverse Events 
Anticipated serious adverse events are events that are anticipated to occur in the study 
population at some frequency independent of investigational product exposure and do 
not need to be reported individually as a Food and Drug Administation (FDA) 
Investigational New Drug (IND) safety report by the sponsor.  Identification and reporting 
of anticipated serious adverse events is the responsibility of the sponsor; the investigator 
is responsible for reporting adverse events and serious adverse events as described in 
Section 12.4. 
Table 12-7.  Anticipated Serious Adverse Events for Study 20160370 
Preferred Terma 
Preferred Terma 
anaemia 
immunoglobulin level increased 
anaemia of malignant disease 
infection in an immunocompromised host 
back pain 
leukopenia 
blood albumin abnormal 
malaise 
blood albumin decreased 
nephrotic syndrome 
blood albumin increased 
neutropenia 
blood calcium increased 
oliguria 
bone pain 
osteopenia 
chronic kidney disease 
osteoporosis 
creatinine increased 
pain in extremity 
electrophoresis abnormal 
plasma cell myeloma 
electrophoresis protein abnormal 
plasma cell myeloma recurrent 
end stage renal disease 
plasmacytoma 
fatigue 
pathological fracture 
fracture 
platelet count decreased 
hemoglobin decrease 
protein total increased 
hyperalbuminemia 
renal failure 
hypercalcemia 
skeletal pain 
hypercalcemia of malignancy 
thrombocytopenia 
hyperproteinaemia 
urine electrophoresis abnormal 
hyperviscosity syndrome 
venous thrombosis 
hypoalbuminaemia 
white blood cell count decreased 
immunoglobulin level decreased 
 
a MedDRA Version 21 


Product:  AMG 420 
Protocol Number: 20160370 
Date: 17 September 2021 
Page 169 of 169 
CONFIDENTIAL 
 
 
12.15 
Appendix 15.  Peripheral Neuropathy Assessment 
TNSr Items 
0 
1 
2 
3 
4 
Symptom extension 
(tingling, 
numbness, 
neuropathic pain)a 
none 
symptoms 
limited to 
fingers or 
toes  
symptoms 
extend to 
ankle or wrist 
symptoms 
extend to knee 
or elbow 
symptoms 
above knees 
or elbows or 
functionally 
disability  
Pin sensibility 
normal 
reduced in 
fingers/toes 
reduced up 
to wrist/ankle 
reduced up to 
elbow/knee 
reduced up 
to above 
elbow/knee 
Vibration sensibility 
normal 
reduced in 
fingers/toes 
reduced up 
to wrist/ankle 
reduced up to 
elbow/knee 
reduced up 
to above 
elbow/knee 
Strengthb 
normal 
mild 
weakness 
moderate 
weakness 
severe 
weakness 
paralysis 
Tendon reflexes 
normal 
ankle reflex 
reduced 
ankle reflex 
absent 
ankle reflex 
absent/others 
reduced 
all reflexes 
absent 
TNSr  total neuropathy score-reduced 
a The worse score of the 3 subcomponents (tingling/paresthesia, numbness, and neuropathic pain proximal 
extension) was used as the subjective symptom extension score. 
b The muscle with the worse score is used as the strength score (toe, ankle, wrist and finger extensors and 
flexors, quadriceps, hamstrings, biceps, and triceps).  TNSr and pain items were adapted with permission 
(Smith et al, 2010). 


Product:  AMG 420 
Protocol Number:  20160370 
Date:  17 September 2021 
Page 1 of 21 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0   
Amendment 5 
Protocol Title:  A Phase 1b Multicenter, Open-label, Expansion Study to Assess 
the Safety and Efficacy of AMG 420 in Subjects With Relapsed and/or Refractory 
Multiple Myeloma 
Amgen Protocol Number AMG 420 20160370 
Amendment Date: 
17 September 2021 
Rationale: 
The rationale for this protocol amendment are: 
 
To put clarifications around delays of treatment cycles in place 
(Section 7.1.1.2, 7.4.2.1.2.2 and 9.1.2) 
 
To add clarity around treatment free intervals (Section 7.1.1.3) 
 
To remove second course treatment in the protocol as it is no longer warranted for 
study conduct due to termination of the program and no further supply of AMG 
420 (Section 5.1.1, 6.2, 7.4.2.1.3, 9.1.3, 10.2.1, and Appendix 13) 
 
To add table for management of COVID infection (Section 7.4.2.1.2.4) 
 
To add SARS-COV-9 vaccination criteria under Section 7.1.8 
 
Several sections of the protocol have been updated to include required alignments 
with current Amgen protocol template (Sections 2.2, 7.1.6, 9.2.3.1.1.2, 9.2.3.1.1.3, 
12.2, 12.3, and 12.4). 
 
Administrative and editorial changes (including grammatical, typographical, and 
formatting) have been made throughout the protocol. 


Product:  AMG 420 
Protocol Number:  20160370 
Date:  20 May 2020 
Page 1 of 101 
CONFIDENTIAL 
 
 
Amendment 4 
Protocol Title:  A Phase 1b Multicenter, Open-label, Expansion Study to Assess 
the Safety and Efficacy of AMG 420 in Subjects With Relapsed and/or Refractory 
Multiple Myeloma 
 
Amgen Protocol Number (AMG 420) 20160370 
NCT Number:  NCT03836053 
 
Amendment 4 Date: 
20 May 2020 
 
Rationale: 
This protocol was amended to address the following: 
• 
Removal of Phase 1b Part 2 (combination cohort) and Phase 2 text globally 
• 
Updated restart guidance after adverse event to correct inconsistency within 
Table 7-5  
Approved 
 
 


Product:  AMG 420 
Protocol Number:  20160370 
Date:  22 May 2019 
Page 1 of 123 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Phase 1b/2 Multicenter, Open-label, Expansion Study to Assess 
the Safety and Efficacy of AMG 420 in Subjects With Relapsed and/or Refractory 
Multiple Myeloma (ParadigMM-1A) 
 
Amgen Protocol Number (AMG 420) 20160370 
NCT Number:  NCT03836053 
 
Amendment Date: 
22 May 2019 
 
Rationale: 
This protocol is being amended to: 
• 
Include new phase 1b part 2 combination cohort 
 
, maximum 20 additional subjects to be enrolled in this 
cohort). 
• 
Addition of adverse event management guidance for phase 2 study, including dose 
reduction and discontinuation parameters for discrete event occurring on treatment. 
• 
Changes made to clarify guidance on infusion reactions and tumor lysis syndrome. 
• 
Adjustment made to platelet count eligibility criteria. 
• 
Addition of patient interviews for phase 1b study and patient reported outcome 
measurement tools to phase 2 study. 
• 
Updated timing of imaging assessments for extramedullary disease, providing option 
for multiple assessments while responders remain on treatment. 
• 
Updated statement of hypothesis added and revisions to statistical analysis plan 
(Section 10) made to provide sample size justification for the phase 2 study.  
• 
Change primary analysis time point. 
• 
Remove expired Amgen template language to ensure compliance with current 
Amgen template, including removal of disease related events as a subcategory of 
adverse events. 
Approved 
 
 


Product:  AMG 420
Protocol Number: 20160370
Date: 12 December 2018
Page 1 of 3
CONFIDENTIAL
Amendment 2
Title:  A Phase 1b/2 Multicenter, Open-label, Expansion Study to Assess the Safety 
and Efficacy of AMG 420 as Monotherapy in Subjects With Relapsed and/or 
Refractory Multiple Myeloma
AMG 420
Amgen Protocol Number 20160370
IND number BB-IND 134608
Amendment Date:
12-December-2018
Rationale:  
This protocol is being amended based on comments received from the FDA during a 
Type C meeting, and also to align with changes to the protocol for the BI 836909 FIH 
trial. 
The following changes were made to Protocol Amendment 1, dated 11 October 2018:

Inclusion Criteria # 103 was modified to incorporate FDA feedback on:
o
The requirement for subjects to be relapsed and/or refractory to ≥ 3 lines 
of therapy which must include a CD38-directed monoclonal antibody.  
o
The inclusion of subjects who could not tolerate PIs, IMiDs, or CD38-
directed monoclonal antibody.

Language added regarding management of patients who develop fevers during 
treatment with AMG 420

The table of contents and all references are updated accordingly.
Approved 
 
 


Product:  AMG 420 
Protocol Number:  20160370 
Date:  11 October 2018 
Page 1 of 12 
CONFIDENTIAL 
 
 
Amendment 1 
Title:  A Phase 1b/2 Multicenter, Open-label, Expansion Study to Assess the Safety 
and Efficacy of AMG 420 as Monotherapy in Subjects With Relapsed and/or 
Refractory Multiple Myeloma 
 
AMG 420 
Amgen Protocol Number 20160370 
IND number BB-IND 134608 
 
Amendment Date: 
11-October-2018 
Rationale:  This protocol is being amended based on comments received from the FDA 
upon submission of the US IND on August 31, 2018.  All updates are in line with 
changes requested by the agency. 
The following changes were made to the original protocol, dated 15 August 2018: 
 
DLT criteria was revised to specify the grade and time to resolution for the DLT 
exceptions of headache, insomnia, and fever. 
 
Removed exclusion for Grade 3 neurological events tht improve to Grade 0 or 
Grade 1 within 14 days from DLT evaluation 
 
Clarification added to indicate mandatory dose interruption for Grade 4 adverse 
events (AMG 420 related or non-related) and restart after improvement of the 
toxicity to a specified lower grade. 
 
Incorporated Phase 2 stopping rules that apply to Grade 4 or higher drug-related 
adverse events, excluding lymphopenia (or reduced lymphocyte counts).   
 
Stopping rules for Phase 2 adjusted to be applied by the DRT after every 
20 subjects have had the chance to receive at least 1 cycle of treatment at the 
determined dose level. 
 
Clarifications/minor corrections for consistency throughout protocol 
 
Clarifications/minor corrections to Schedule of Assessments 
 
The table of contents and all references are updated accordingly. 
Approved 
 
 

SAP_001.pdf: 
Product:  AMG 420 
Protocol Number:  20160370 
Date:  12 June 2020 
Page 1 of 39 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1b Multicenter, Open-label, Expansion 
Study to Assess the Safety and Efficacy of 
AMG 420 as Monotherapy in Subjects With 
Relapsed and/or Refractory Multiple Myeloma 
Short Protocol Title: 
A Phase 1b Study to Assess AMG 420 Monotherapy 
in Subjects with Relapsed and/or Refractory Multiple 
Myeloma 
Protocol Number: 
20160370 
NCT Number: 
NCT03836053 
Authors: 
 
Biostatistician II, IQVIA 
 
Biostatistics Director, Amgen Inc 
Sponsor: 
Amgen Inc 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
SAP Date: 
Document Version 
Date 
Amendment 1 (v[2.0]) 
12 June 2020 
ANIGEN~ 


Product:  AMG 420 
Protocol Number:  20160370 
Date:  12 June 2020 
Page 2 of 39 
CONFIDENTIAL  
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
11JAN2019 
NA 
Amendment 1 (v2.0) 
12Jun2020 
 
Removal of Phase 1b Part 2 
(combination cohort) and Phase 2 text 
globally 
ANIGEN~ 


Product:  AMG 420 
Protocol Number:  20160370 
Date:  12 June 2020 
Page 3 of 39 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ............................................................................................................ 3 
1. 
Introduction ............................................................................................................. 9 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 9 
2.1 
Objectives and Endpoints ............................................................................ 9 
2.2 
Hypotheses and/or Estimations ................................................................. 11 
3. 
Study Overview .................................................................................................... 11 
3.1 
Study Design ............................................................................................. 11 
3.2 
Sample Size .............................................................................................. 13 
3.3 
Adaptive Design ........................................................................................ 13 
4. 
Covariates and Subgroups ................................................................................... 13 
4.1 
Planned Covariates ................................................................................... 13 
4.2 
Subgroups ................................................................................................. 13 
5. 
Definitions ............................................................................................................. 14 
6. 
Analysis Sets ........................................................................................................ 20 
6.1 
Safety Analysis Set ................................................................................... 20 
6.2 
Dose Limiting Toxicity Evaluable Analysis Set .......................................... 20 
6.3 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) ................................ 20 
6.4 
Retreatment Analysis Set .......................................................................... 21 
7. 
Planned Analyses ................................................................................................. 21 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 21 
7.1.1 
Interim Analyses ........................................................................ 21 
7.1.2 
Dose Level Review Team .......................................................... 21 
7.2 
Primary Analysis ....................................................................................... 21 
7.3 
Final Analysis ............................................................................................ 21 
8. 
Data Screening and Acceptance ........................................................................... 21 
8.1 
General Principles ..................................................................................... 21 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 21 
8.3 
Handling of Missing and Incomplete Data ................................................. 21 
8.4 
Detection of Bias ....................................................................................... 22 
8.5 
Outliers ..................................................................................................... 22 
8.6 
Distributional Characteristics ..................................................................... 22 
8.7 
Validation of Statistical Analyses ............................................................... 22 
9. 
Statistical Methods of Analysis.............................................................................. 22 
9.1 
General Considerations ............................................................................. 22 
9.2 
Subject Accountability ............................................................................... 23 
9.3 
Important Protocol Deviations ................................................................... 23 
9.4 
Demographic and Baseline Characteristics ............................................... 23 
AMGEN~ 


Product:  AMG 420 
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Date:  12 June 2020 
Page 4 of 39 
CONFIDENTIAL  
 
 
9.5 
Efficacy Analyses ...................................................................................... 24 
9.5.1 
Analyses of Key Secondary Efficacy Endpoint(s) ...................... 24 
9.5.1.1 
Overall Response Rate ........................................... 24 
9.5.1.2 
Duration of Response .............................................. 24 
9.5.1.3 
MRD Negativity at CR ............................................. 24 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 24 
9.5.2.1 
Progression-free Survival ........................................ 24 
9.5.2.2 
Overall Survival ....................................................... 24 
9.5.2.3 
Time to Response ................................................... 25 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 25 
9.6 
Safety Analyses ........................................................................................ 25 
9.6.1 
Analyses of Safety Endpoint(s) .................................................. 25 
9.6.2 
Adverse Events ......................................................................... 25 
9.6.3 
Laboratory Test Results ............................................................ 27 
9.6.4 
Vital Signs ................................................................................. 27 
9.6.5 
Physical Measurements ............................................................ 28 
9.6.6 
Electrocardiogram ..................................................................... 28 
 
 ................................................................... 28 
9.6.8 
Exposure to Investigational Product .......................................... 28 
9.6.9 
Exposure to Concomitant Medication ........................................ 28 
9.7 
Other Analyses ......................................................................................... 29 
9.7.1 
PK Analyses .............................................................................. 29 
9.7.2 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 29 
9.7.3 
Analyses of Clinical Outcome Assessments .............................. 29 
9.7.4 
Analyses of Health Economic Endpoints ................................... 29 
9.7.5 
Analyses of Biomarker Endpoints .............................................. 29 
10. 
Changes From Protocol-specified Analyses.......................................................... 29 
11. 
Literature Citations / References ........................................................................... 30 
12. 
Prioritization of Analyses....................................................................................... 31 
13. 
Data Not Covered by This Plan............................................................................. 31 
14. 
Appendices ........................................................................................................... 32 
Appendix A.  Reference Values/Toxicity Grades ................................................... 33 
Appendix B.  Guidance for Response Confirmation .............................................. 35 
Appendix C.  Clinical Outcome Assessment Forms/Instruments ........................... 37 
Appendix D.  Health Economic Forms/Instruments ............................................... 38 
Appendix E.  Details of PK or PK/PD Methods for Modeling ................................. 39 
 
ANIGEN~ 


Product:  AMG 420 
Protocol Number:  20160370 
Date:  12 June 2020 
Page 5 of 39 
CONFIDENTIAL  
 
 
List of Tables 
Table 1.  Rules for Holding Enrollment in Phase 1b ....................................................... 12 
Table 2.  Conventions for Censoring for PFS and DOR ................................................. 17 
 
ANIGEN~ 


Product:  AMG 420 
Protocol Number:  20160370 
Date:  12 June 2020 
Page 6 of 39 
CONFIDENTIAL  
 
 
List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
ANC 
absolute neutrophil count 
APRIL 
a proliferation-inducing ligand 
AST 
aspartate aminotransferase  
AUClast 
area under the concentration-time curve from time 0 to the last 
measurable concentration 
BAFF 
B-cell activating factor 
BAFF-R 
B-cell activating factor receptor 
 
 
BiTE® 
bispecific T-cell engager 
BM 
bone marrow 
BOR 
best overall response 
CAR 
chimeric antigen receptor 
cIV 
continuous intravenous 
Cmax 
maximum concentration 
CR 
complete response 
Css 
steady-state concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLRM 
dose level review meeting 
DLRT 
dose level review team 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EM 
Extramedullary 
EOI 
end of infusion 
EOS 
end of study 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FISH 
fluorescent in situ hybridization 
ANIGEN~ 


Product:  AMG 420 
Protocol Number:  20160370 
Date:  12 June 2020 
Page 7 of 39 
CONFIDENTIAL  
 
 
Abbreviation or Term 
Definition/Explanation 
FLC 
free light chain 
IMiD 
Immunomodulator 
IMWG 
International Myeloma Working Group  
ISS 
International Staging System 
IV 
intravenous(ly)  
KM 
Kaplan-Meier 
LTFU 
long-term follow-up 
MR 
minimal response 
MRD 
minimal residual disease  
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 
 
 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PI 
proteasome inhibitor 
PK 
pharmacokinetic(s) 
PR 
partial response 
PR interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG or partial response 
QRS interval 
QRS interval is the interval between the Q wave and the S wave in the 
heart's electrical cycle as measured by ECG; represents the time it 
takes for the depolarization of the ventricles 
QTc interval  
QT interval corrected for heart rate using accepted methodology 
RRMM 
Relapsed and/or refractory multiple myeloma 
 
 
SC 
subcutaneous(ly) 
sCR 
stringent complete response 
sFLC 
serum free light chain 
SFU 
safety follow-up 
SPEP 
serum protein electrophoresis 
t1/2 
half-life 
TBL 
total bilirubin 
TFI 
treatment-free interval 
TLS 
tumor lysis syndrome 
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Abbreviation or Term 
Definition/Explanation 
TNF 
tumor necrosis factor 
TPI 
toxicity probability interval 
Treg cells 
regulatory T cells 
UIFE 
urine immunofixation 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
US 
United States 
VGPR 
very good partial response 
 
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1.
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical
analyses that have been outlined within the protocol amendment 4 for study 20160370,
AMG 420 dated 20 May 2020. The scope of this plan includes the interim analysis,
primary analysis and final analysis that are planned and will be executed by the Amgen
Global Biostatistical Science department unless otherwise specified.
2.
Objectives, Endpoints and Hypotheses
2.1 
Objectives and Endpoints
Objectives 
Endpoints 
Phase 1b 
Primary 

Establish the safety and
tolerability of AMG 420 at dose
levels of 400 g/day and 600
g/day in subjects with relapsed
and/or refractory multiple
myeloma (RRMM)

Dose-limiting toxicities (DLTs),
treatment-emergent adverse
events, treatment-related adverse
events and changes in vital signs,
electrocardiograms (ECGs), and
clinical laboratory tests
Key Secondary 
•
Estimate overall response rate (ORR)
and duration of response (DOR) of
AMG 420 in subjects with RRMM

ORR

DOR

Evaluate the rate of minimal residual
disease (MRD)-negativity at the time
of CR

MRD negativity at the time of CR
Secondary 

Establish the safety and tolerability of
AMG 420 in subjects with
extramedullary relapsed multiple
myeloma

DLTs, treatment-emergent adverse
events, treatment-related adverse
events, and changes in vital signs,
ECGs, and clinical laboratory tests

Characterize the pharmacokinetics
(PK) of AMG 420 when administered
as 4-week continuous intravenous
(cIV) infusion

AMG 420 PK parameters including,
but not limited to, half-life (t1/2),
clearance, and apparent Css

Evaluate other measures of
anti-myeloma activity of AMG 420 in
subjects with RRMM:

Efficacy parameters according to
International Myeloma Working Group
(IMWG) response criteria, per
investigator assessment:
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Objectives 
Endpoints 
Secondary (Continued) 
 
Time to response 
 
Progression-free survival (PFS) 
 
Overall survival (OS) 
 
Best overall response (BOR) 
 
Time to response 
 
PFS 
 
OS 
 
BOR 
Exploratory for Phase1b 
 Enter Exploratory Objectives Endpoints 
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2.2 
Hypotheses and/or Estimations 
The ORR according to IMWG response criteria along with 95% CI will be calculated per 
investigator assessment for subjects with RRMM. The lower bound of the binomial 
2-sided 95% confidence interval for ORR not lower than 35% is considered clinically 
meaningful. 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 1b, multicenter, non-randomized, open-label expansion study.  AMG 420 
will be evaluated in adult subjects with RRMM.   
The study will consist of up to a 21-day screening, a treatment, safety follow-up (SFU), 
and long-term follow-up (LTFU) period.  In the treatment period, treatment will be 
continued until progressive disease (PD) or relapse as defined by IMWG response 
criteria, unacceptable safety events, next anti-multiple myeloma treatment, or other 
reason for permanent treatment discontinuation.  All subjects will be assessed for 
anti-myeloma activity according to the IMWG response criteria.  An SFU visit will be 
conducted 30 (+3) days after last administration of AMG 420, and an LTFU period that 
will begin after the SFU visit is completed.  The total duration of the LTFU will be up to 
5 years from the first dose of AMG 420 as described in Study Schema of protocol 
section 2.1. 
Phase 1b (Monotherapy Dose Confirmation) 
In phase 1b, approximately 10 subjects will be treated at the 400 g/day dose 
(comprising cohort 1).  Approximately 10 subjects will be treated at the 600 g/day dose 
level (cohort 2).  Each subject in phase 1b will have at least a 30-day SFU.   
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The dose level review team (DLRT) will convene and review all available safety, 
laboratory, and pharmacokinetic (PK) data at the following scheduled time points: 
 
After at least 10 subjects in cohort 1 (400 g/day dose level) in phase 1b have had 
the opportunity to complete the 4-week infusion period of the first treatment cycle: On 
the basis of this review, the DLRT will make a recommendation regarding the 
initiation of the 600 g/day dose level (cohort 2) in phase 1b. 
 
After at least 3 subjects with extramedullary (EM) relapsed disease in cohort 1 
(400 g/day dose level) have had the opportunity to complete the 4-week infusion 
period of the first treatment cycle: On the basis of this review, the DLRT will make a 
recommendation regarding the appropriateness of continued enrollment of subjects 
with EM relapsed disease to cohort 2 in phase 1b (600 g/day dose level).  Please 
note that enrollment of subjects with EM relapsed disease to cohort 2 in phase 1b 
will not be allowed until this safety review of the first 3 subjects with EM disease is 
completed by the DLRT. 
 
After the first 3 subjects have been dosed with AMG 420 at 600 g/day for the full 
4-week infusion cycle. 
The safety data will be reviewed on an ongoing basis and enrollment may be terminated 
at any time.  To further reduce the risk of overdose to ongoing and future subjects, 
protocol-defined enrollment holding rules will be used.  These rules are based on a 
modified Toxicity Probability Interval (mTPI), where the target Toxicity Probability Interval 
(TPI) is a dose-limiting toxicity (DLT) probability from 20% to 33% and the overdose TPI 
is > 33% DLT probability.  Enrollment to the ongoing dose level/schedule will be paused 
per the following rules during enrollment into phase 1b cohort 1 and 2. 
Table 1.  Rules for Holding Enrollment in Phase 1b 
Number of DLTs 
 2 
 3 
 4 
Number of Treated Subjects 
 4 
 6 
 8 
If the rules for pausing enrollment are met, no further enrollment to the respective dose 
level/schedule will be allowed until after a careful review of all safety data by the DLRT.  
Additionally, enrollment will not resume until the protocol has been amended to include 
additional safeguards for subject safety (eg, modifications to dose level and schedule).  
Subjects with EM disease will be able to enroll into cohort 2 after the safety evaluation is 
complete for 3 subjects with EM disease treated at 400 µg/day (cohort 1). 
An investigator will review efficacy data and assess outcomes in accordance with 
IMWG criteria.  Investigator assessments will be used for efficacy analysis. 
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3.2 
Sample Size 
Approximately 20 subjects will be enrolled in this study. 
3.3 
Adaptive Design 
The rules for halting enrollment are based on an mTPI design. The mTPI models the 
probability of toxicity for each dose level using a Bayesian model where each dose level 
has the same prior on the probability of toxicity, a Beta (1,1). When subjects are treated 
at the current dose level, the posterior probability of toxicity is updated using the 
observed data from this level. Enrollment recommendations are made based on this 
posterior probability of toxicity, using three toxicity probability intervals (TPI). 
 
Under-dosing TPI: DLT rate from 0 to < 20% 
 
Target TPI: DLT rate from 20% to 33% 
 
Over-dosing TPI: DLT rate > 33% 
For the current dose level and after adjusting for the width of each TPI interval, if the 
DLT rate is most likely in the under-dosing TPI or most likely in the target TPI then the 
recommendation is to continue enrollment at the current level. If the DLT rate is most 
likely in the over-dosing TPI then the recommendation is to halt enrollment. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
There are no planned covariates in this study. 
4.2 
Subgroups 
The baseline variables for the subgroup analyses may include: 
 
baseline demographics and characteristics: 
 
age (< 65, 65-74, ≥ 75 years) 
 
sex (female, male) 
 
race (White, Asian, other) 
 
baseline disease characteristics:  
 
revised International Staging System (ISS) stage (Stage I, Stages II or III) 
 
BM percent of plasma cells (< 50%, ≥ 50%) 
 
 
 
extramedullary disease (yes, no). Until safety evaluation is complete for 3 subjects 
with EM disease, imaging evaluation at screening will be used to document EM 
disease status. 
 
number of prior lines of therapy (only 3, > 3) 
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 
prior allogeneic HSCT (yes, no) 
 
refractory to 
 
IMiD (yes, no) 
 
PI (yes, no) 
 
IMiD + PI (yes, no) 
 
daratumumab or other CD 38-targeting antibody (yes, no) 
Subgroup analysis will not be performed due to each sub group may not have 
justifiable count as less number of sample size. 
5. 
Definitions 
Adverse Event (AE) 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject. The event does not necessarily have a causal relationship with study treatment. 
The definition of adverse events includes worsening of a preexisting medical condition. A 
preexisting condition that has not worsened during the study, or involves an intervention, 
is not considered an adverse event. 
Age at Enrollment 
Subject age at enrollment will be determined using the age in years reported in the 
clinical database. 
Baseline 
For any variable, unless otherwise specified the baseline is the last assessment taken 
prior to the first administration of AMG 420. For parameters/assessments not scheduled 
to be performed (or scheduled but not performed) on the same day as the first 
administration of AMG 420, the baseline value is the value from the screening period 
measured closest to the day of first administration of AMG 420. 
Baseline ECG Values in Triplicate 
For the three sets of triplicate pre-dose ECG, the mean of values in a triplicate should be 
calculated before taking the mean of the three sets of averages.  For all post-baseline 
ECG, the mean value for measurements taken at the same assessment will be 
calculated and used in the analysis.  When an ECG is missing within a triplicate, all 
available data will be averaged for that time point. 
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Death Date 
For subjects who die during the study, the death date will be recorded on the end of 
study CRF in the date subject ended study field. Incomplete death dates where only the 
day of death date is missing will be imputed using the following rules: 
Day 1 of the month will be used if year and month indicate that death happened in 
different month from last known alive date; 
One day after last known alive date will be used if death happened in the same month as 
last known alive date. 
The imputed death date will be used in calculation of duration of response, progression-
free survival and overall survival.  
Dose-limiting Toxicities (DLTs) 
Investigators determine whether a TEAE qualifies as a DLT per the definition described 
in protocol Section 7.4.1. For an adverse event to qualify as a DLT, the start date must 
be within 28 days from the date of the first dose of investigational product. 
Best Overall Response 
Best overall response for a subject is the best observed post baseline disease response 
per the International Myeloma Working Group Uniform Response Criteria for Multiple 
Myeloma (IMWG-URC). The detailed algorithm is provided in Appendix B.  
Overall Response Rate (ORR) 
ORR refers to the proportion of subjects with an objective response. Objective response 
refers to any of the following responses per the International Myeloma Working Group 
Uniform Response Criteria for Multiple Myeloma (IMWG-URC): (sCR, CR, VGPR or PR) 
Per IMWG-URC, any response requires 2 consecutive assessments made any time 
before starting any new therapy. Subjects who do not experience a sCR/CR/VGPR/PR 
or do not have any follow-up tumor assessments will be regarded as non-responders. 
Duration of Response (DOR) 
Duration of response (DOR) will be calculated for subjects who achieve a PR or better. 
For such subjects, the duration of overall response is defined as the time (months) from 
first documentation of response to disease progression or death due to any cause. 
Dates of progression and censoring will be determined as described for the analysis of 
PFS. 
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 DOR (in months)  (Earliest date of disease progression, death, censor - Date of first 
                                observation of PR or better before confirmation  1)/30.4 
Subjects who have not ended their response at the time of analysis will have DOR 
censored on the date of their latest evaluable assessment. 
Time to response 
Time to response applies for subjects who achieved best overall response of PR, VGPR, 
CR or sCR. Time to response is calculated as the number of months 
(one mont   30.4 days) from the first administration of AMG 420 to the first objective 
assessment of response (ie, date of the first detection of response) as per IMWG-URC.  
TTR (in months)  (Date of objective response – Date of first dose  1)/30.4 
MRD Negativity (MRD-) 
MRD- is defined as a response of CR or sCR accompanied by any of the following types 
of MRD negativity. 
 
Sustained MRD- 
 
Sequencing MRD- 
 
Imaging plus MRD- 
Subjects who do not experience a MRD negativity or do not have any evaluable follow-
up assessments will be regarded as MRD non-responders. 
Progression-free survival (PFS) 
Progression free survival (PFS) is defined as number of months between start of 
treatment and first evidence of documented disease progression or death (due to any 
cause), whichever occurs first.  
PFS (in months)  (Earliest date of disease progression, death, censor – Date of first 
                            dose  1)/30.4  
Progression-free survival will be right-censored for subjects who meet one of the 
following conditions: 1) no post baseline disease assessments, 2) non-protocol systemic 
anticancer treatment started before documentation of PD or death, 3) death or disease 
progression after more than 1 missed disease assessment visit or 4) alive and does not 
have documentation of PD before a data analysis cutoff date. For such subjects, the 
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primary analysis of PFS will be right-censored according to the conventions described in 
Table 2. 
Table 2.  Conventions for Censoring for PFS and DOR 
Situation 
Date of Progression or Censoring 
Outcome 
No post baseline disease 
assessments** 
Date of first dose 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last evaluable disease 
assessment prior to start of new 
anticancer therapy 
Censored 
Death or PD immediately after more 
than 1 consecutively missed disease 
assessment visit* 
Date of last evaluable disease 
assessment visit before the first 
missed visit 
Censored 
Alive and without PD documentation 
(including lost to follow-up without PD) 
Date of last evaluable disease 
assessment 
Censored 
Death or PD between planned disease 
assessments 
Date of death or first disease 
assessment showing PD, whichever 
occurs first 
Progressed 
Death before first disease assessment 
Date of death 
Progressed 
* If death or PD is more than 84 days after previous disease assessment, or Study Day 1 if there is no 
previous disease assessment. 
** Only apply to PFS. 
Overall survival (OS) 
Overall survival is defined as the interval from Study Day 1 until death due to any cause; 
otherwise, OS is censored on the last recorded date on which the subject was alive.  
Last Evaluable Disease Assessment Date 
For responses assessed by investigator, last disease assessment date is the last 
evaluable response assessment date collected using IMWG Response CRF (except the 
response assessment date of Inevaluable) before confirmed PD, on or before new anti-
cancer therapies or procedures. 
Last Known Alive Date 
For subjects not known to have died, their last date known to be alive will be 
determined as the latest date associated with clinic visits before data cutoff date 
including, for example, but not limited to the following: 
 
Date of Enrollment on Subject Enrollment CRF 
 
Date First Taken, Date Last Taken on Concomitant Medications CRF 
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
Date Performed on ECOG Performance Status, Vital Signs, Electrocardiogram,
Procedures CRFs

Admission Date, Discharge Date on Hospitalizations CRF

Date of Examination on Physical Measurement CRF

Date Collected on Reproductive Status and Pregnancy Test (Local Lab),
Chemistry (Local Lab), Hematology (Local Lab), Coagulation (Local Lab),
Urinalysis (local Lab), Immunology (Local lab)  CRFs and in central lab data

Date of Assessment on IMWG Response for Time Point, Peripheral Neuropathy
Assessment CRFs

Start Date and End Date on Investigational Product Administration CRF

Date Started and Date Ended or Resulted in Death on Events CRF

Start date, Stop date on Anti-Myeloma / Anti-Cancer Therapies, Other Protocol
Required Therapy (GLUCOCORTICOID), Other Protocol Required Therapy
(Tocilizumad), Hematopoietic Stem Cell Transplantation Autologous,
Hematopoietic Stem Cell Transplantation Allogenic CRFs

Subject Status Date if status is Alive on Survival Status CRF

Assessment Date on Skeletal Survey and Plasmacytoma Assessment CRF

End of study date if the subject’s primary reason for ending study is not
“Lost to follow-up”
Fridericia-corrected QT Interval (QTcF) 
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec), as follows: 
QTcFQT/(RR/1000)1/3 
Change From Baseline 
Change from Baseline is the arithmetic difference between post-dose assessments and 
Baseline value. 
Change (absolute) from Baseline  (Post-baseline Value – Baseline Value) 
Change (percent) from Baseline 
        [(Post-baseline Value – Baseline Value)/Baseline Value] x 100 
Investigational Product (IP) 
The term ‘investigational product’ is used in reference to AMG 420. 
Primary Completion: 
The primary completion date is defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the primary endpoint(s), for the 
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purposes of conducting the primary analysis, whether the study concluded as planned in 
the protocol or was terminated early. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study 
The end of study (EOS) date is defined as the date when the last subject across all sites 
is assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, LTFU), as applicable. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  The following actions 
must be taken if a subject fails to return to the clinic for a required study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
is able to continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts are 
to be documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
For subjects who are lost to follow-up, the investigator can search publicly 
available records where permitted to ascertain survival status.  This ensures that 
the data set(s) produced as an outcome of the study is/are as comprehensive as 
possible. 
Study Day 
Post study day: study day (date - date of Study Day 1)  1 
Pre study day: study day (date – date of Study Day 1) 
Study Day 1 
It is defined as the first day that protocol-specified investigational product is administered 
to the subject. 
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Treatment-emergent Adverse Event (TEAE) 
A treatment-emergent adverse event is any adverse event starting on or after the first 
administration of investigational product, as determined by the flag indicating if the 
adverse event started prior to the first dose on the Events CRF, and up to and including 
33 days after the last IP dose date or EOS date, whichever occurs first. The severity of 
each adverse event will be graded using the CTCAE version 5.0 with exception of CRS 
which will be graded according to adopted grading system in Lee et al, 2014 and TLS 
that will be graded according to Cairo-Bishop criteria (refer to protocol Appendix 12). 
Adverse events will be coded using MedDRA. 
Safety Follow-up 
SFU visit will be conducted 30 (3) days after last administration of AMG 420. 
Long-term Follow-up 
LTFU period begin after the SFU visit is completed.  The total duration of the LTFU 
will be up to 5 years from the first dose of AMG 420, or until subject death, 
whichever is first.” 
6. 
Analysis Sets 
6.1 
Safety Analysis Set 
Safety Analysis Set defined as all subjects that are enrolled and receive at least 1 dose 
of AMG 420. 
6.2 
Dose Limiting Toxicity Evaluable Analysis Set 
The analysis of DLT will be restricted to DLT-evaluable subjects. DLT evaluable 
analysis set includes subjects who complete the DLT evaluable period or 
experienced a DLT anytime during the DLT evaluable period. A subject will be not 
DLT evaluable if he/she drops out before completion of the DLT-evaluable period for 
reasons other than a DLT prior to completing the 4 weeks of AMG420 treatment. 
The DLT window may also be extended to assess events starting within the window in 
case the DLT definition is time dependent. 
6.3 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) 
The PK Analysis Set will contain all subjects who have received at least 1 dose of the 
investigational product and have at least 1 PK sample collected.  These subjects will be 
evaluated for PK analysis unless the number of data points required for analysis is not 
enough, or significant protocol deviations have affected the data, or if key dosing or 
sampling information is missing. 
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6.4 
Retreatment Analysis Set 
Retreatment analysis set defined as subjects that are enrolled and receive at least one 
dose of AMG 420 during the second course of treatment after attaining CR and 
subsequently have disease progression while off-therapy. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
7.1.1 
Interim Analyses 
No specific interim analysis planned. 
7.1.2 
Dose Level Review Team 
DLRT will be responsible for monitoring safety and making recommendations regarding 
termination of enrollment and dose level/schedule escalation/changes.  See Protocol 
Section 12.3 for further details of DLRT responsibilities. 
7.2 
Primary Analysis 
The primary analysis will occur when the target enrollment is complete and each subject 
has had the chance to be treated for at least 6 months. 
7.3 
Final Analysis 
A final analysis is planned after all subjects have ended the study. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality and statistical 
characteristics of the data relative to the requirements of the planned analyses.  The 
database will be subject to edit checks outlined in the data management plan (DMP) by 
Amgen Clinical Data Management (CDM) department. Data inconsistencies and 
suspicious values will be reviewed and resolved before the database is locked. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
The following imputation for missing or incomplete data will be performed if required: 
Incomplete adverse event and concomitant medication dates missing data will be 
imputed as described in Appendix A. 
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Non-pharmacokinetic measurements (eg, biomarker data) that are below the lower limit 
of quantification will be considered equal to half of the lower limit of quantification for all 
analyses unless specified otherwise. 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations in each cohort.  
The clinical study team will identify and document the criteria for important protocol 
deviations. 
8.5 
Outliers 
Outlier data will not be excluded unless scientifically justified. 
Pharmacokinetic (PK) serum concentration data will be evaluated for outliers by visual 
inspection, and decisions to re-assay individual samples will be made in accordance with 
standard pharmacokinetic evaluation practice. 
8.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures. 
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs. 
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety, PK, 
pharmacodynamic and biomarker data by dose, dose schedule, and time as appropriate.  
Descriptive statistics on continuous data will include means, medians, standard 
deviations and ranges, while categorical data will be summarized using frequency 
counts and percentages.  Time to event endpoints will be summarized with Kaplan-Meier 
(KM) proportions at select time points, KM quartiles (when estimable), the number of 
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subjects with events, the number of subjects censored, and censoring reasons.  
Duration of follow-up for time to event endpoints will be estimated using the reverse 
Kaplan Meier method (Schemper and Smith, 1996).  Point estimates for efficacy 
endpoints will be accompanied by 2-sided 95% confidence intervals including KM 
quartiles (Klein and Moeschberger, 1997), KM proportions (Kalbfleisch and 
Prentice, 1980), and binomial proportions (Clopper and Pearson, 1934).  Graphical 
summaries of the data may also be presented.   
9.2 
Subject Accountability 
The following subject disposition information will be summarized as follows 
 
Number of screened subjects 
 
Number of subjects in Safety Analysis Set 
 
Number (%) of subjects who discontinued treatment 
 
Number (%) of subjects who discontinued the study 
 
Primary reason for ending treatment 
 
Primary reason for study discontinuation 
The percentages are based on the number of subjects enrolled in the study.  
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study. Eligibility deviations are defined 
in the protocol. 
9.4 
Demographic and Baseline Characteristics 
The following descriptive summaries of the demographic and baseline characteristics will 
be produced: Demographic (ie, age, age groups [< 65, 65-74 and >= 75], sex, race, 
ethnicity), prior line of therapies (median, range) and baseline characteristics (height, 
weight, Eastern Cooperative Oncology Group (ECOG) Performance Status will be 
summarized using descriptive statistics. If multiple races have been reported for a 
subject, the subject will be categorized as multiple. 
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9.5 
Efficacy Analyses 
9.5.1 
Analyses of Key Secondary Efficacy Endpoint(s) 
9.5.1.1 
Overall Response Rate 
The number () of subjects with a best overall response of sCR, CR, VGPR, PR, MR, 
SD, PD or IE will be summarized. 
Overall response rate is defined as the proportion of subjects for whom the best overall 
response is sCR, CR, VGPR, or PR as determined by International Myeloma Working 
Group Uniform Response Criteria (IMWG-URC). The ORR along with the associated 
95 exact binomial confidence interval (Clopper-Pearson method) will be determined. 
9.5.1.2 
Duration of Response 
Kaplan-Meier methods will be used to estimate the distribution of DOR. And the median 
and other quartiles in addition to the corresponding two-sided 95 confidence intervals 
will be calculated. 
A Kaplan-Meier figure showing the estimated DOR distribution will be provided. 
9.5.1.3 
MRD Negativity at CR 
MRD negativity analysis will be performed for all subjects included in the safety analysis 
set. Number of MRD[-] responders at CR along with exact 2-sided 95 will be provided 
by using Clopper & Pearson method  
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
9.5.2.1 
Progression-free Survival 
PFS analysis will be performed for all subjects included in the safety analysis set. The 
Kaplan-Meier curve will be generated. PFS rate at 3-month intervals and the median and 
other quartiles in addition to the corresponding two-sided 95 confidence intervals will 
be provided. Disease progression determined by using IMWG-URC will be used for the 
analysis. 
9.5.2.2 
Overall Survival 
OS analysis will be performed for all subjects included in the safety analysis set. The 
Kaplan-Meier curve will be generated. Overall survival rate at 3-month intervals, the 
median and other quartiles in addition to the corresponding two-sided 95 confidence 
intervals will be calculated.  
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9.5.2.3 
Time to Response 
Time to response will be calculated for subjects who achieved best overall response of 
PR, VGPR, CR or sCR. Time to response is calculated as the number of months from 
the first administration of AMG 420 to the first objective assessment of response (ie, 
date of the first detection of response) as per IMWG-URC. 
Time to response will be descriptively analyzed, summary statistics of the number, 
mean, standard deviation, median, and range will be reported. 
Listings will be produced for all subjects indicating the MRD negativity, OS, PFS, time to 
response, and duration of response. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
9.6 
Safety Analyses 
9.6.1 
Analyses of Safety Endpoint(s) 
Statistical analyses on safety endpoints will be done using subjects from the Safety 
Analysis Set (except the analysis of the DLT endpoint, which will be based on 
subjects from the DLT evaluable set), which includes subjects that are enrolled and 
received at least 1 dose of AMG 420. 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 or later will be 
used to code all adverse events to a system organ class and a preferred term. The 
severity of each adverse event will be graded using CTCAE version 5.0 criteria with 
exception of CRS which will be graded according to adopted grading system in 
Lee et al, 2014 and TLS graded according to Cairo-Bishop criteria (refer to protocol 
Appendix 12).  Where appropriate the tables will also be presented by worst grade. 
Treatment-emergent adverse events will be summarized based on the number (%) 
of subjects experiencing events by MedDRA SOC and PT. The denominator for the 
percentage will be based on the number of subjects in the safety analysis set. 
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The subject incidence of adverse events will be summarized for 
 
TEAE 
o All treatment-emergent AEs 
o Grade 3 or higher treatment-emergent AEs 
o Treatment-emergent SAEs 
o Treatment-emergent AEs leading to interruption of investigational 
product 
o Treatment-emergent AEs leading to withdrawal of investigational 
product 
o Fatal treatment-emergent AEs 
 
Treatment-related AEs 
o All treatment-related AEs 
o Grade 3 or higher treatment-related AEs 
o Treatment-related SAEs 
o Treatment-related AEs leading to interruption of investigational 
product 
o Treatment-related AEs leading to withdrawal of investigational 
product 
o Fatal treatment-related AEs 
The summaries that are displayed by SOC, PT and grade will be ordered by 
descending order of incidence of SOC, PT and grade with in each SOC for the 
total group. 
Then summary of TEAEs, summary of TEAEs, TESAEs, Treatment-related TEAEs, 
and Treatment-related SAEs by SOC, PT and Grade will be generated for 
extramedullary subjects. 
The above adverse event tables will not be created if two or fewer subjects experience 
the adverse event.  
Dose Limiting Toxicities  
The analysis of the probability of DLTs will include data from DLT-evaluable subjects 
(see Protocol Section 7.4.1 for definition of DLT-evaluable).  The primary analysis will 
only include DLTs that occur during the DLT evaluation period.  If DLTs occur outside 
the DLT evaluation period, a sensitivity analysis will be performed where DLTs occurring 
outside of the specified time interval are included.  The number and percentage of 
subjects reporting DLTs will be evaluated overall and by AMG 420 dose level. 
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9.6.3 
Laboratory Test Results 
Chemistry, Hematology and Coagulation 
Actual values and change from baseline for selected chemistry and hematology 
parameters will be summarized descriptively for each scheduled visit based on 
the safety analysis set. 
Chemistry 
Hematology 
Coagulation 
Total bilirubin 
ANC 
PT or INR 
ALT (SGPT) 
Hemoglobin 
APTT 
AST (SGOT) 
Platelets 
 
Alkaline phosphatase 
WBC 
 
Creatinine 
Lymphocyte 
 
Phosphate 
 
 
Calcium (Corrected) 
 
 
Potassium 
 
 
Sodium 
 
 
Albumin 
 
 
Glucose 
 
 
Amylase 
 
 
Lipase 
 
 
Shift tables will be presented for the baseline toxicity grade by the worst on-study 
toxicity grade in a table form for selected parameters mentioned above if 
applicable. CTCAE version 5.0 will be used for toxicity grading for the above 
mentioned parameters excluding Total bilirubin, ALT (SGPT), AST (SGOT) and 
Alkaline phosphatase (CTCAE version 4.03 will be used for toxicity grading). 
Potential Hy’s law cases may be summarized. 
9.6.4 
Vital Signs 
The analyses of vital signs include summary statistics over time and/or changes from 
baseline over time. 
9.6.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics at baseline.  
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9.6.6 
Electrocardiogram 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters. Subjects' maximum post baseline values will be categorized and the 
number and percentage of subjects in each group will be summarized. 
9.6.8 
Exposure to Investigational Product 
The average dose administration (g), cumulative dose (g), number of cycles, duration 
of treatment, number and percentage of subjects with dose modifications, reasons for 
modification will be summarized using descriptive statistics. Subject-level data may be 
provided instead of the summary if the subject incidence is low or single dose is given.  
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group. 
Extent of exposure to study treatments will be summarized for Safety population 
 
Duration of treatment (days) 
o Defined as the duration (in weeks) from the date of the first dose to the date of 
the last dose of study drug + 1 
 
Total number of treatment cycles started  
o Defined as the total number of treatment cycles in which at least one dose of 
study drug is administered. 
 
Cumulative dose received of AMG420 across all cycles, defined as the cumulative 
dose of AMG 420. 
 
Average dose of AMG420, defined as the total dose received divided by the number 
of days on treatment administered . 
9.6.9 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term for each treatment group as coded by the World Health Organization 
Drug dictionary. 
9.7 
Other Analyses 
9.7.1 
PK Analyses 
The PK parameters of AMG 420 including, but not limited to, average Css, clearance, 
and half-life (t1/2) for serum AMG 420 will be estimated using non-compartmental 
methods and summarized by dose level using means, geometric means, standard 
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deviations, coefficients of variation, medians, minimums, and maximums.  Individual 
concentration-time profiles will be summarized by dose level.  Plasma AMG 420 
concentrations at each time point along with PK parameter values may be listed for each 
subject. Summary statistics will be computed for each sampling time and parameter as 
appropriate. The relationship between AMG 420 exposure and efficacy/safety may be 
conducted. 
9.7.2 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
PK/PD analyses will be provided by the Department of Clinical Pharmacology, Modeling 
& Simulation (CPMS). Actual collection times of PK samples will be recorded to assess 
the plasma concentration. The PK parameter estimates for AMG420 will be summarized. 
Exploratory analyses may be performed to evaluate the relationship between the 
estimated PK parameters and selected safety, biomarker, or clinical effect endpoints. In 
addition, the population modeling program may be used to fit a nonlinear mixed effects 
model to estimate PK parameters. Details regarding the analyses will be provided in a 
separate analysis plan by CPMS. 
9.7.3 
Analyses of Clinical Outcome Assessments 
Analysis of clinical outcome assessments is not planned for this study. 
9.7.4 
Analyses of Health Economic Endpoints 
Analyses of Health Economic Endpoints are not planned for this study. 
9.7.5 
Analyses of Biomarker Endpoints 
The analysis of Biomarker will be described and performed by Clinical Biomarker Group. 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 
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11.
Literature Citations / References
Clopper CJ, Pearson ES.  The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika.  1934;26(4):404-413. 
Ji Y, Liu P, Li Y, Bekele BN.  A modified toxicity probability interval method for dose-
finding trials.  Clin Trials.  2010;7(6):653-663.  
Kalbfleisch JD, Prentice RL.  The Statistical Analysis of Failure Time Data, Hoboken, 
New Jersey: John Wiley & Sons; 1980. 
Klein JP, Moeschberger ML.  Survival Analysis: Techniques for Censored and Truncated 
Data, New York: Springer-Verlag; 1997.   
Kumar S, Paiva B, Anderson KC, et al.  International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple 
myeloma.  Lancet Oncol.  2016;17(8):e328-346.  
Schemper M, Smith TL.  A note on quantifying follow-up in studies of failure time. 
Control Clin Trials. 1996;17(4):343–46.   
Lee JJ, Liu DD.  A predictive probability design for phase II cancer clinical trials.  Clinical 
Trials.  2008;5(2):93-106. 
Thall P, Simon R, Estey E. Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes Statistics in Medicine. 1995;14:357-379 
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12. 
Prioritization of Analyses 
No Priority of outputs planned for this study 
13. 
Data Not Covered by This Plan 
The analysis of Biomarkers (except MRD) is not covered in this plan. 
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14. 
Appendices 
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Appendix A.  Reference Values/Toxicity Grades 
The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 is available at the 
following link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Technical Detail and Supplemental Information Regarding Statistical Procedures 
and Programs 
Imputation Rules for Partial or Missing Stop Dates 
If the month and year are present, impute the last day of the month. If only the year is 
present, impute December 31 of that year.  If the stop date is entirely missing, assume 
the event or medication is ongoing. 
Imputation Rules for Partial or Missing Start Dates 
 
Stop Date 
 
 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
Start 
Date 
 
1st 
Dose 
1st 
Dose 
1st 
Dose 
yyyymm 
1st 
Dose 
yyyymm 
1st 
Dose 
yyyy 
1st 
Dose 
yyyy 
Partial: 
yyyymm 
1st 
Dose 
yyyymm 
N/A 
1 
N/A 
1 
N/A 
1 
1 
 1st 
Dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
1st 
Dose 
yyyy 
N/A 
1 
N/A 
1 
N/A 
1 
1 
 1st 
Dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1  Impute the date of first dose 
2  Impute the first day of the month 
3  Impute January 1 of the year 
4  Impute January 1 of the stop year 
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Note: For subjects who were never treated (first dose date is missing), partial start dates 
will be set to the first day of the partial month. 
Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date. 
Imputation rules for stop date: 
For partial stop date mmyyyy, impute the last day of the month. 
For partial stop date yyyy, impute December 31 of the year. 
For completely missing stop date, do not impute. 
If the stop date imputation leads to a stop date that is after the death date, then 
impute the stop date as the death date. 
If the stop date imputation leads to a stop date that is before the start date, then 
there is a data error and do not impute the stop date. (ie. set the stop date as 
missing). 
Code Fragments: 
Provisional Code Fragments for calculating a confidence interval using the Clopper 
Pearson Method. The following example SAS code will be utilized for the response rate 
analysis providing the proportion of subjects responding to treatment with corresponding 
80 confidence intervals. 
data propci (keep  ns p low_ci upp_ci); 
nxx; * total n within the treatment group; 
do ns xx; *number of responders; 
pns/n; * response rate; 
q1-p; 
lowFFINV(0.1, 2*ns, 2*(n-ns1)); /* use for 2-sided 80 CI */ 
UppFFINV(1-0.1, 2*(ns1), 2*(n-ns)); /* use for 2-sided 80 CI */ 
low_ci  1 / (1(n-ns1) / (ns*lowf)); * lower CI for response rate; 
upp_ci  1 / (1(n-ns) / ((ns1)*uppf)); *upper CI for response rate; 
if p1 then upp_ci1; 
if p0 then low_ci 0; 
output; 
end;run; 
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Appendix B.  Guidance for Response Confirmation 
For responses assessed by investigator, the following table and notes will be used to 
confirm the responses: 
Confirmation of Response Assessed by Investigator at Each Visit (applicable to 
MR or better and PD) 
“Has response 
been 
confirmed” 
Entered on 
IMWG Response 
CRF for the 
current 
assessment 
(Yes/No) 
‘Has response 
been confirmed’ 
Entered on 
IMWG Response 
CRF for the next 
assessment 
(Yes/No) 
Response Category of the current 
and the next assessments 
Confirmation 
of the current 
assessment 
Yes 
- 
- 
Confirmed 
No 
Yes 
If the current assessment is MR or 
better, and the next assessment is 
no worse than the current one, keep 
the current response status as is. 
Confirmed 
If the current assessment is MR or 
better, and the next assessment is 
worse than the current one but also 
is MR or better, select the response 
status same as the next assessment. 
Confirmed 
If the current assessment is PD, and 
the next assessment is also PD, 
keep the current response status as 
is. 
Confirmed 
If the current assessment is PD, but 
the next assessment is not PD, keep 
the current response status as is. 
Unconfirmed 
No 
Leave the response as is. 
Unconfirmed 
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Note:  
Response assessments done after initiation of new anti-cancer therapy will be 
excluded. But if new anti-cancer therapy is started before confirmed progressive 
disease, additional testing during subsequent therapy can be used to confirm 
progressive disease (PD), as long as this testing is within 35 days from the last 
disease assessment on study. 
Stable disease (SD) means the response does not fulfil criteria for a confirmed 
MR, PR, VGPR, CR, sCR, or PD.  An assessment of SD does not need to be 
confirmed, however it should be remains same at least 6 weeks. A response of SD 
is not upgraded until there is a confirmed response of sCR, CR, VGPR, PR, MR or 
PD. 
For subjects that do not qualify for a confirmed response or stable disease (SD), 
the BOR will be not evaluable 
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Appendix C.  Clinical Outcome Assessment Forms/Instruments 
Not applicable 
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Appendix D.  Health Economic Forms/Instruments 
Not applicable 
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Appendix E.  Details of PK or PK/PD Methods for Modeling 
CPMS group will be responsible for PK/PD modeling. 
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