Clinical trial NCT03859427
Conditions: Relapsed or Refractory Multiple Myeloma
Keywords: Bone Marrow Cancer
Sponsor: Amgen
Start date: 2019-05-08; Completion date: 2023-03-31
Enrollment: 454 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Compare efficacy of 56 mg/m2 carfilzomib administered once-weekly in combination with lenalidomide and dexamethasone (KRd 56 mg/m2) to 27 mg/m2 carfilzomib administered twice-weekly in combination with lenalidomide and dexamethasone (KRd 27 mg/m2) in subjects with relapsed or refractory multiple myeloma (RRMM) with 1 to 3 prior lines of therapy.

Detailed description:

Arms: arm 1: Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using once-weekly carfilzomib 56 mg/m2 arm 2: Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using twice-weekly carfilzomib 27 mg/m2
Interventions: intervention 1: Carfilzomib intervention 2: Carfilzomib intervention 3: Lenalidomide intervention 4: Dexamethasone
Intervention descriptions: intervention 1: Once weekly IV over 30 minutes on day 1, 8 and 15 of each 28 day cycle. The dose will be 20 mg/m2 on cycle 1 day 1 and 56 mg/m2 beginning with cycle 1 day 8 and thereafter. 12 cycles or until progression, unacceptable toxicity, death, loss to follow up or withdrawal of consent. intervention 2: Twice weekly IV over 10 minutes on day 1, 2, 8, 9, 15 and 16 of each 28 day cycle. The dose will be 20 mg/m2 on cycle 1 days 1 and 2 and 27 mg/m2 beginning with cycle 1 day 8 and thereafter. 12 cycles or until progression, unacceptable toxicity, death, loss to follow up or withdrawal of consent. intervention 3: Once daily orally 25 mg days 1 to 21 of each cycle. 12 cycles or until progression, unacceptable toxicity, death, loss to follow up or withdrawal of consent intervention 4: Once daily orally or by IV 40 mg days 1, 8 and 15 of each cycle. Also day 22 of cycles 1 to 9. 12 cycles or until progression, unacceptable toxicity, death, loss to follow up or withdrawal of consent

Protocol documents:
Prot_000.pdf: 
Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
Page 1 of 145 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
Title Page 
Protocol Title: 
A Randomized, Open-label, Phase 3 Study 
Comparing Once-weekly vs Twice-weekly 
Carfilzomib in Combination With Lenalidomide 
and Dexamethasone in Subjects With Relapsed 
or Refractory Multiple Myeloma (A.R.R.O.W.2)  
Short Protocol Title: 
A Study Comparing Once-weekly vs 
Twice-weekly Carfilzomib in Combination with 
Lenalidomide and Dexamethasone in Subjects 
With Relapsed or Refractory Multiple Myeloma 
Protocol Number: 
20180015 
Investigational Product: 
Carfilzomib 
Trade Name: 
Kyprolis 
Sponsor 
Name of Sponsor: 
Amgen Inc.   
Address: 
One Amgen Center Drive  
Thousand Oaks, CA 91320, United States 
Telephone Number: 
1-805-447-1000 
Key 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive  
Thousand Oaks, CA 91320, United States 
Telephone Number: 
 
Email Address: 
 
EudraCT Number: 
2018‐000665‐36 
NCT Number: 
03859427 
Protocol Date: 
Document Version 
Date 
Original 
04 October 2018 
Amendment 1 
10 October 2019 
Amendment 2 
24 August 2020 
Amendment 3 
12 August 2021 
Superseding 
Amendment 3 
02 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.  The format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (ICH E6). 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
Page 2 of 145 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
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:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
Page 3 of 145 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Randomized, Open-label, Phase 3 Study 
Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination With Lenalidomide 
and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma 
(A.R.R.O.W.2) , dated 02 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 
sub-investigators (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:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
Page 4 of 145 
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FORM-001520, v.22, 05 February 2018 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Synopsis ................................................................................................. 10 
2. 
Study Schema and Schedule of Activities ............................................................. 18 
2.1 
Study Schema ........................................................................................... 18 
2.2 
Schedule of Activities ................................................................................ 19 
3. 
Introduction ........................................................................................................... 28 
3.1 
Study Rationale ......................................................................................... 28 
3.1.1 
Justification for Primary Endpoint .............................................. 29 
3.1.2 
Justification for the Clinical Outcome Assessments 
Endpoints .................................................................................. 30 
3.2 
Background ............................................................................................... 31 
3.2.1 
Disease ..................................................................................... 31 
3.2.2 
Amgen Investigational Product Background:  
Carfilzomib ................................................................................ 31 
3.3 
Benefit/Risk Assessment ........................................................................... 32 
3.3.1 
Therapeutic Context .................................................................. 32 
3.3.2 
Key Benefits .............................................................................. 33 
3.3.3 
Key Risks .................................................................................. 34 
3.3.3.1 
Risks ....................................................................... 35 
4. 
Objectives, Endpoints and Hypotheses ................................................................. 38 
4.1 
Objectives and Endpoints .......................................................................... 38 
4.2 
Hypotheses ............................................................................................... 41 
5. 
Study Design ........................................................................................................ 41 
5.1 
Overall Design .......................................................................................... 41 
5.2 
Number of Subjects ................................................................................... 43 
5.2.1 
Replacement of Subjects ........................................................... 43 
5.2.2 
Number of Sites ......................................................................... 43 
5.3 
End of Study ............................................................................................. 43 
5.3.1 
End of Study Definition .............................................................. 43 
5.3.2 
Study Duration for Subjects ....................................................... 44 
5.4 
Justification for Investigational Product Dose ............................................ 44 
5.5 
Patient Input on Study Design ................................................................... 45 
6. 
Study Population .................................................................................................. 45 
6.1 
Inclusion Criteria  ...................................................................................... 46 
6.2 
Exclusion Criteria  ..................................................................................... 47 
6.3 
Subject Enrollment .................................................................................... 50 
6.4 
Screen Failures ......................................................................................... 51 
7. 
Treatments ........................................................................................................... 51 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
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7.1 
Treatment Procedures............................................................................... 52 
7.1.1 
Investigational Product: Carfilzomib ........................................... 52 
7.1.1.1 
Dosage Formulation ................................................ 52 
7.1.1.2 
Dosage, Administration, and Schedule .................... 52 
7.1.1.3 
Intravenous Prehydration ........................................ 53 
7.1.1.4 
Starting Dose in Hepatic Insufficiency ..................... 54 
7.1.2 
Non-investigational Products ..................................................... 54 
7.1.2.1 
Dexamethasone:  Dosage, Administration, 
and Schedule .......................................................... 54 
7.1.2.2 
Lenalidomide ........................................................... 54 
7.1.3 
Medical Devices ........................................................................ 55 
7.1.4 
Other Protocol-required Therapies ............................................ 55 
7.1.4.1 
Antiviral Prophylaxis ................................................ 56 
7.1.4.2 
Prophylaxis for Hepatitis B Reactivation .................. 56 
7.1.4.3 
Thromboprophylaxis ................................................ 56 
7.1.4.4 
Tumor Lysis Syndrome Prophylaxis ........................ 56 
7.1.4.5 
Proton-pump Inhibitor .............................................. 56 
7.1.4.6 
Bisphosphonate or Monoclonal Antibody 
Therapy ................................................................... 56 
7.1.4.7 
Prophylaxis for Pneumocystis Jirovenci................... 57 
7.1.5 
Other Treatment Procedures ..................................................... 57 
7.1.6 
Product Complaints ................................................................... 57 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 57 
7.1.7.1 
Anticancer Therapeutic or Radiation ....................... 57 
7.1.7.2 
Corticosteroids ........................................................ 58 
7.1.7.3 
Plasmapheresis ....................................................... 58 
7.1.7.4 
Myeloid Growth Factors .......................................... 58 
7.2 
Method of Treatment Assignment ............................................................. 58 
7.3 
Blinding ..................................................................................................... 59 
7.4 
Dose Modification ...................................................................................... 59 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 59 
7.4.1.1 
Amgen Investigational Product:  
Carfilzomib .............................................................. 59 
7.4.1.2 
Non-Amgen Non-Investigational Product:  
Lenalidomide ........................................................... 63 
7.4.1.3 
Non-Amgen Non-Investigational Product:  
Dexamethasone ...................................................... 64 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 64 
7.6 
Treatment Compliance .............................................................................. 64 
7.7 
Treatment of Overdose ............................................................................. 64 
7.8 
Prior and Concomitant Treatment ............................................................. 64 
7.8.1 
Prior Treatment ......................................................................... 64 


Product:  Carfilzomib 
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7.8.2 
Concomitant Treatment ............................................................. 65 
8. 
Discontinuation Criteria ......................................................................................... 65 
8.1 
Discontinuation of Study Treatment........................................................... 65 
8.2 
Discontinuation From the Study ................................................................ 66 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 67 
8.2.2 
Reasons for Removal From Study ............................................. 67 
8.3 
Lost to Follow-up ....................................................................................... 67 
9. 
Study Assessments and Procedures .................................................................... 68 
9.1 
General Study Periods .............................................................................. 68 
9.1.1 
Screening, Enrollment and/or Randomization ............................ 68 
9.1.2 
Treatment Period ....................................................................... 68 
9.1.3 
Safety Follow-up ........................................................................ 69 
9.1.4 
Long-term Follow-up .................................................................. 69 
9.1.5 
End of Study .............................................................................. 69 
9.2 
Description of General Study Assessments and Procedures ..................... 70 
9.2.1 
General Assessments ............................................................... 70 
9.2.1.1 
Informed Consent .................................................... 70 
9.2.1.2 
Demographics ......................................................... 70 
9.2.1.3 
Medical History ........................................................ 70 
9.2.1.4 
Physical Examination .............................................. 70 
9.2.1.5 
Physical Measurements .......................................... 71 
9.2.1.6 
Substance Abuse History ........................................ 71 
9.2.1.7 
Performance Status................................................. 71 
9.2.2 
Efficacy Assessments ................................................................ 71 
9.2.2.1 
SPEP, UPEP, SFLC, SIFE, and UIFE ..................... 71 
9.2.2.2 
Bone Marrow Sample Evaluation Including 
FISH and MRD[-]CR Assessment ........................... 72 
9.2.2.3 
Bone Lesion Assessment (Skeletal 
Survey, CT, or PET/CT) .......................................... 73 
9.2.2.4 
Extramedullary Plasmacytoma ................................ 73 
9.2.2.5 
Progressive Disease Assessment ........................... 74 
9.2.3 
Safety Assessments .................................................................. 74 
9.2.3.1 
Adverse Events ....................................................... 74 
9.2.3.2 
Vital Signs ............................................................... 77 
9.2.3.3 
Electrocardiograms (ECGs) ..................................... 77 
9.2.3.4 
Other Safety ............................................................ 78 
9.2.4 
Clinical Laboratory Assessments ............................................... 79 
9.2.4.1 
Pregnancy Testing .................................................. 79 
9.2.4.2 
Prespecified Biomarker Assessments ..................... 80 
9.2.5 
Pharmacokinetic Assessments .................................................. 80 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
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9.2.6 
Pharmacodynamic Assessments (Only for Subjects 
Participating in the Optional Intensive PK/PDn 
Substudy) .................................................................................. 80 
9.2.7 
Clinical Outcome Assessments ................................................. 80 
9.2.7.1 
EORTC QLQ-C30 ................................................... 80 
9.2.7.3 
Patient-reported Convenience With 
Carfilzomib-dosing Schedule Question .................... 81 
9.2.7.5 
Cancer Therapy Satisfaction 
Questionnaire (CTSQ) ............................................. 81 
9.2.9 
Optional Substudies .................................................................. 83 
9.2.9.1 
Intensive 
Pharmacokinetic/Pharmacodynamic 
Substudy ................................................................. 83 
9.2.10 
Other Assessments ................................................................... 83 
10. 
Statistical Considerations ...................................................................................... 83 
10.1 
Sample Size Determination ....................................................................... 83 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 84 
10.2.1 
Analysis Sets ............................................................................. 84 
10.2.1.1 
Intent-to-Treat Population ........................................ 84 
10.2.1.2 
Safety Population .................................................... 84 
10.2.1.3 
Per-Protocol Population .......................................... 84 
10.2.2 
Covariates ................................................................................. 84 
10.2.3 
Subgroups ................................................................................. 85 
10.2.4 
Handling of Missing and Incomplete Data .................................. 85 
10.3 
Statistical Analyses ................................................................................... 86 
10.3.1 
Planned Analyses ...................................................................... 86 
10.3.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 86 
10.3.1.2 
Primary Analysis ..................................................... 87 
10.3.1.3 
Final Analysis .......................................................... 87 
10.3.2 
Methods of Analyses ................................................................. 87 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
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10.3.2.1 
General Considerations ........................................... 87 
10.3.2.2 
Efficacy Analyses .................................................... 88 
10.3.2.3 
Safety Analyses ...................................................... 89 
11. 
References ........................................................................................................... 91 
12. 
Appendices ........................................................................................................... 95 
12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 96 
12.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 99 
12.3 
Appendix 3.  Study Governance Considerations ..................................... 102 
Data Monitoring Committees and Independent Review 
Committee ............................................................................... 102 
Regulatory and Ethical Considerations .................................................... 103 
Recruitment Procedures .......................................................................... 103 
Informed Consent Process ...................................................................... 104 
Data Protection/Subject Confidentiality ................................................... 106 
Publication Policy .................................................................................... 106 
Investigator Signatory Obligations ........................................................... 107 
Data Quality Assurance ........................................................................... 107 
Source Documents .................................................................................. 109 
Study and Site Closure............................................................................ 110 
Compensation ......................................................................................... 110 
12.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 111 
Definition of Adverse Event ..................................................................... 111 
Definition of Serious Adverse Event ........................................................ 112 
Recording Adverse Events and Serious Adverse Events ........................ 113 
Evaluating Adverse Events and Serious Adverse Events ........................ 114 
Reporting of Serious Adverse Event ........................................................ 115 
12.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 121 
12.5.1 
Risks Associated With Pregnancy ........................................... 121 
12.5.2 
Counseling .............................................................................. 121 
12.5.2.1 
Female Subjects of Childbearing Potential ............ 121 
12.5.2.2 
Female Subjects Not of Childbearing 
Potential ................................................................ 122 
12.5.2.3 
Male Subjects: ....................................................... 122 
12.5.3 
Definition of Females of Childbearing Potential ....................... 122 
12.5.4 
Contraception Methods ........................................................... 123 
12.5.4.1 
Contraception Methods for Female 
Subjects ................................................................ 123 
12.5.4.2 
Contraception Methods for Male Subjects ............. 124 
12.5.4.3 
Unacceptable Methods of Birth Control for 
Male and Female Subjects .................................... 125 


Product:  Carfilzomib 
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12.5.5 
Pregnancy Testing................................................................... 125 
12.5.5.1 
Female Subjects ................................................... 125 
12.5.5.2 
Male Subjects: ....................................................... 126 
12.5.6 
Additional Precautions ............................................................. 126 
12.5.7 
Collection of Pregnancy Information ........................................ 126 
12.5.8 
Collection of Lactation Information ........................................... 128 
12.6 
Appendix 6.  Sample Storage and Destruction ........................................ 131 
12.7 
Appendix 7.  Hepatotoxicity Stopping Rules: Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 133 
12.8 
Appendix 8.  Guidelines for Documenting Prior Treatment ...................... 134 
12.9 
Appendix 9.  ECOG Performance Status ................................................ 135 
12.10 Appendix 10.  2018 ESH/ESC Office Blood Pressure 
Measurement .......................................................................................... 136 
12.11 Appendix 11.  Summary of International Myeloma Working 
Group - Uniform Response Criteria ......................................................... 137 
12.12 Appendix 12.  Patient-reported Convenience With 
Carfilzomib-dosing Schedule Question .................................................... 140 
 
List of Tables 
Table 2-1.  Schedule of Activities ................................................................................... 19 
Table 7-1.  Dose Decrements for Carfilzomib ................................................................ 59 
Table 7-2.  Dose Modification Guidelines for Thrombocytopenia and 
Neutropenia ............................................................................................ 60 
Table 7-3.  Dose Modification Guidelines for Nonhematologic Toxicities ....................... 61 
Table 12-1.  Analyte Listing ......................................................................................... 100 
List of Figures 
Figure 2-1.  Study Schema ............................................................................................ 18 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form ..................................................................................................... 116 
Figure 12-2.  Pregnancy and Lactation Notification Forms ........................................... 129 
 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
Page 10 of 145 
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FORM-001520, v.22, 05 February 2018 
 
1. 
Protocol Synopsis 
Protocol Title: A Randomized, Open-label, Phase 3 Study Comparing Once-weekly vs 
Twice-weekly Carfilzomib in Combination With Lenalidomide and Dexamethasone in 
Subjects With Relapsed or Refractory Multiple Myeloma (A.R.R.O.W.2)  
Short Protocol Title: A Study Comparing Once-weekly vs Twice-weekly Carfilzomib in 
Combination with Lenalidomide and Dexamethasone in Subjects With Relapsed or 
Refractory Multiple Myeloma 
Study Phase: 3 
Indication: relapsed or refractory multiple myeloma (RRMM) 
Rationale 
The ASPIRE study demonstrated the superiority of the combination of carfilzomib 
(Kyprolis) with lenalidomide and dexamethasone (KRd; 27 mg/m2 twice-weekly) over 
lenalidomide with dexamethasone (Rd).  Superiority of the KRd regimen was 
demonstrated in terms of median progression-free survival (PFS) (26.3 vs 17.6 months, 
hazard ratio [HR] = 0.69), overall response rate (ORR) (87.1% vs 66.7%, odds 
ratio [OR] = 3.47) (Stewart et al, 2015), health-related quality-of-life (Stewart et al, 2016), 
as well as overall survival (OS) (median OS: 48.3 vs 40.4 months, HR = 0.79 
[Siegel et al, 2018]). 
Safety results from the final analysis were consistent with the known safety profile of 
carfilzomib, with no new safety signals observed after extended follow-up.  
Despite the favorable benefit-risk profile of the KRd regimen, as demonstrated in the 
ASPIRE study, compliance with the currently available twice-weekly KRd dosing 
schedule may be less than optimal because of the convenience-related attributes of this 
regimen.   
The purpose of this study is to:  
 
Compare efficacy of a once-weekly combination of KRd (56 mg/m2) with the on-label 
twice-weekly combination of KRd (27 mg/m2)  
 
Compare PFS, patient-reported convenience and other patient-reported outcomes, 
OS, and minimal residual disease (MRD) rate between the 2 regimens 
 
Describe the safety profile of once-weekly KRd 56 mg/m2 and twice-weekly 
KRd 27 mg/m2 in subjects with RRMM with 1 to 3 prior lines of therapy.  


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
Page 11 of 145 
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Objectives/Endpoints 
 
Objectives 
Endpoints 
Primary 
 
compare efficacy of 
56 mg/m2 carfilzomib administered 
once-weekly in combination with 
lenalidomide and dexamethasone 
(KRd 56 mg/m2) to 
27 mg/m2 carfilzomib administered 
twice-weekly in combination with 
lenalidomide and dexamethasone 
(KRd 27 mg/m2) in subjects with 
relapsed or refractory multiple 
myeloma (RRMM) with 1 to 3 prior 
lines of therapy 
 
overall response, defined as the best 
overall response of stringent complete 
response [sCR], complete response 
[CR], very good partial response 
[VGPR], and partial response [PR] per 
International Myeloma Working Group 
Uniform Response Criteria 
[IMWG-URC] over the duration of the 
study 
Key Secondary 
 
compare progression-free survival 
(PFS) between treatment arms 
 
PFS over the duration of the study 
 
compare patient-reported 
convenience with carfilzomib-dosing 
schedule between treatment arms 
 
convenience as measured by the 
Patient-reported Convenience With 
Carfilzomib-dosing Schedule Question 
after cycle 4 of treatment 
Secondary 
 
describe safety and tolerability in 
treatment arms  
 
incidence of treatment-emergent 
adverse events  
 
compare additional efficacy 
parameters between treatment arms  
 
time to response (TTR)  
 
duration of response (DOR)  
 
time to progression (TTP)  
 
compare overall survival (OS) 
between treatment arms 
 
OS over the duration of the study 
 
compare rate of minimal residual 
disease negative (MRD[-]) in bone 
marrow aspirates between treatment 
arms  
 
MRD[-]CR, defined as achievement of 
CR or better by Independent Review 
Committee (IRC) per IMWG-URC and 
achievement of MRD negativity as 
assessed by next-generation 
sequencing method at a 10-5 
threshold over the duration of the 
study 
 
MRD[-] status at 12 months, defined 
as achievement of MRD negativity at 
12 months (± 4 weeks) from 
randomization, as assessed by 
next-generation sequencing method 
at a 10-5 threshold  


Product:  Carfilzomib 
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Objectives 
Endpoints 
Secondary (continued) 
 
compare patient-reported physical 
functioning and role functioning 
between treatment arms 
 
physical functioning and role 
functioning over time as measured by 
the Physical Functioning and Role 
Functioning scales of the European 
Organization for Research and 
Treatment of Cancer Quality-of-life 
Questionnaire Core 30 
(EORTC QLQ-C30) over the duration 
of the study 
 
compare patient-reported treatment 
satisfaction between treatment arms 
 
treatment satisfaction as measured by 
the Satisfaction With Therapy (SWT) 
scale of the Cancer Therapy 
Satisfaction Questionnaire (CTSQ) 
after cycle 4 of treatment 
 
Hypotheses 
Once-weekly KRd 56 mg/m2 is non-inferior in terms of efficacy when compared with 
twice-weekly KRd 27 mg/m2.   
Overall Design 
This is a phase 3, multicenter, open-label, randomized study in subjects with RRMM who 
have received 1 to 3 prior therapies.  The study will consist of a screening period of up to 
28 days, a treatment duration of up to 12 cycles of 28 days, and a 30-day safety 
follow-up period.    
Subjects will receive the study drug(s) determined by randomization for a maximum of 
12 cycles.  No crossover between the treatment arms is allowed.  After discontinuation 
of study drug(s) subjects will have a safety follow-up visit 30 (+3) days after the last dose 
of all study drug(s).  After end of study, subjects may continue treatment per local 
standard of care at the discretion of the investigator.   
All subjects will be assessed for multiple myeloma disease response according to the 
International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) 
(Section 12.11) every 28 ± 7 days from cycle 1 day 1 through the end of cycle 12 or 
disease progression until death, loss to follow-up, withdrawal of full consent , or until first 
subsequent antimyeloma treatment (whichever occurs first), regardless of cycle duration, 
dose delays or treatment discontinuation.     
Subjects who end study drug(s) before completing 12 cycles without confirmed 
progressive disease (PD) are required to complete disease response assessments and 
report new antimyeloma treatment every 28 ± 7 days until 12 months after 
randomization, first subsequent antimyeloma treatment, death, loss to follow-up, 
withdrawal of full consent, or confirmed PD, whichever occurs first.  For applicable study 
subjects, long term follow-up will commence after the 30-day safety follow-up visit.  All 
subjects with confirmed disease progression within 12 months of randomization will be 
followed for survival every 28  7 days until 12 months after randomization, death, loss 
to follow-up, or withdrawal of full consent, whichever comes first (Section 9.1.4).  For 
applicable study subjects, long-term follow-up will commence 28 days after the safety 
follow-up visit. 


Product:  Carfilzomib 
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Date:  02 September 2021 
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FORM-001520, v.22, 05 February 2018 
 
The disease assessment schedule is independent of treatment schedules.   
Subjects will be randomized in a 1:1 ratio to 1 of 2 arms: 
 
Arm 1:  KRd using once-weekly carfilzomib 56 mg/m2  
 
Arm 2:  KRd using twice-weekly carfilzomib 27 mg/m2  
Randomization will be performed using an interactive voice/web response system 
(IxRS).  Subjects will be stratified based on the following criteria:  original (not revised) 
International Staging System (ISS) stage at the time of study entry (stage 1 or 2 vs stage 
3), prior lenalidomide treatment (yes vs no), prior proteasome inhibitor (PI) treatment 
(yes vs no), prior anti-CD38 exposure (yes vs no).   
All subjects enrolled will have pharmacokinetic samples assessed.  Approximately 
15 subjects in each arm will be invited to participate in the intensive pharmacokinetics 
(PK)/pharmacodynamics (PDn) substudy at selected sites.  Sparse PK samples will be 
collected from the rest of the subjects, eg, subjects who do not consent to participate in 
the intensive PK/PDn substudy.  See Sections 9.2.5 and 9.2.6 for more details. 
An independent data monitoring committee (DMC) will be convened for this study and 
will act in an advisory capacity to the sponsor with respect to safeguarding the interests 
of study subjects, assessing interim data, monitoring the overall conduct of the study, 
and providing with recommendations relating to continuing, modifying, or stopping the 
study based on these findings (International Council for Harmonisation Good Clinical 
Practice [ICH GCP 5.5.2]).  Details of the DMC will be described in the DMC Charter.  
The initial assessment from this committee will be planned after 30 subjects 
(approximately 15 for the experimental arm and 15 for the control arm) have been 
enrolled and have finished the first cycle of treatment to ensure safety of all arms.  
A provision will be made allowing an early follow-up DMC meeting to be decided at the 
time of the initial assessment.  The DMC will meet approximately every 6 months to 
review safety data on a regular basis, and once to review the efficacy data for futility.  
The interim analysis for futility is planned to occur when the first 230 subjects have been 
randomized and had a best overall response (BOR) assessed by the date when 
treatment was completed, confirmed PD or death occurred, subject was lost to follow-up, 
withdrew consent, or started new therapy, whichever occurred first.   
The individual subject disease response and disease progression for this study will be 
independently assessed by an Independent Review Committee (IRC) in accordance with 
the IMWG-URC (Section 12.11).  The membership criteria and operational details of the 
IRC will be described in the IRC Charter.  The IRC will centrally review the disease-
related tests and assessments (Section 9.2.2) to evaluate disease progressions and 
responses without the knowledge of randomization assignments or Investigator’s 
disease assessments.  The IRC assessment will be used for the primary analysis of 
efficacy endpoints except for MRD rate and clinical outcome assessments (COA) 
endpoints.    
Number of Subjects 
Approximately 460 subjects will be enrolled in the study, with approximately 230 subjects 
per each arm.   
Summary of Subject Eligibility Criteria 
This study will enroll adults ≥ 18 years of age with RRMM.  Subjects must have 
measurable disease per IMWG consensus criteria for response assessment in multiple 
myeloma, Eastern Cooperative Oncology Group Performance Status (ECOG PS) of  2, 


Product:  Carfilzomib 
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Date:  02 September 2021 
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and at least partial response (PR) to at least 1 line of prior therapy.  Subjects must also 
have received at least 1 but not more than 3 prior lines of therapy for multiple myeloma 
including relapse or progression after the most recent myeloma treatment prior to 
enrollment.   
 
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.2. 
Treatments 
For both arms 
Each subject’s first dose of carfilzomib will be calculated based upon baseline body 
surface area (BSA) using the Mosteller formula.  In subjects with BSA > 2.2 m2, the dose 
should be capped based on a BSA of 2.2 m2.  The dose for each subject should not be 
revised unless the subject has a change in body weight of > 20% (gain or loss) in which 
case the BSA should be recalculated.  Carfilzomib dose is to be recalculated using the 
updated BSA and applied until such time that any future weight change requires further 
BSA recalculation.  The dose can also be modified in response to toxicity following the 
dose modification guideline tables using the most current BSA if this has been 
recalculated since the first cycle due to weight change.  
In subjects with normal renal function, lenalidomide will be taken once-daily orally on 
days 1 to 21 of each cycle at a dose of 25 mg.  In subjects with renal impairment (mild to 
moderate or severe), please refer to the regional product label.   
Dexamethasone should be taken weekly orally or by intravenous (IV) infusion at a dose 
of 40 mg.  When dexamethasone is administered on the same day as carfilzomib, it 
should be started and completed within at least 4 hours of the start of carfilzomib 
infusion.  A 30 minute interval between the end of the dexamethasone infusion and the 
start of the carfilzomib infusion is recommended.  All doses should be administered on 
the scheduled days  2 days.   
Arm 1 (once-weekly KRd 56 mg/m2): 
Carfilzomib will be administered once-weekly IV as a 30 ± 5 minute infusion using an 
infusion pump on days 1, 8, and 15 of each 28-day cycle.  The dose will be 20 mg/m2 on 
day 1 of the first cycle and 56 mg/m2 beginning with day 8 of cycle 1 and thereafter.  All 
carfilzomib doses should be administered on the scheduled day  2 days, and the day 8 
and 15 doses should have at least a 5-day treatment-free interval.  Dose delays > 2 
days are only permitted during the start of a new cycle (for more information see Section 
7.4.1). 
Arm 2 (twice-weekly KRd 27 mg/m2): 
Carfilzomib will be administered twice-weekly IV as a 10 ± 5 minute infusion using an 
infusion pump on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle.  The dose will be 
20 mg/m2 on days 1 and 2 of the first cycle and 27 mg/m2 beginning with day 8 of cycle 1 
and thereafter.   
Every effort should be made to maintain the days 1, 2, 8, 9, 15, and 16 every 28-day 
schedule.  If this is not possible, then priority should be to maintain consecutive 
dosing days.  For example, if day 1 of a new cycle is started 2 days later than originally 
scheduled, the entire cycle should shift by 2 days, such that the new days 1, 2, 8, 9, 15, 
and 16 of the next cycle are maintained.  There must always be at least 5 days between 
the second dose of 1 week and the first dose of the following week (ie, between days 2 
and 8, and days 9 and 15).  Mid-cycle doses that are missed should not be made up, 
unless these parameters are maintained. 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
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Procedures 
Written informed consent must be obtained from all subjects or legally acceptable 
representatives before any study-specific screening procedures are performed.  The 
following procedures will occur per the Schedule of Assessments:  demographics, 
medical history, substance use history, complete physical examination, physical 
measurements, 12-lead electrocardiogram (ECG) with QTc interval, vital signs, ECOG 
PS, echocardiogram (ECHO), review of adverse events and serious adverse events, 
recording of concomitant medications and antimyeloma therapies.  Imaging studies will 
be performed for bone lesions (all subjects) and soft tissue plasmacytoma evaluation (if 
clinically indicated).  Central laboratory testing will be performed to confirm disease 
status and/or stage, including collection of bone marrow samples for minimal residual 
disease negative (MRD[-]) testing, cytomorphology, fluorescence in situ hybridization 
(FISH), and for confirmation of CR or sCR.  Additional central laboratory testing will 
include hematology, serum chemistry, hepatic and renal function.  Eligibility labs are to 
be confirmed by central laboratory prior to enrollment.  Samples will also be taken to 
perform PK and PDn assessments.  Local laboratory testing will include coagulation 
factors, hepatitis B serology and hepatitis B virus (HBV) DNA testing, and pregnancy 
testing for females of childbearing potential.  Clinical outcome assessments will be 
measured using questionnaires and individual questions.   
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 Table 2-1. 
Statistical Considerations 
The sample size was determined so that the primary objective could be tested via 
synthesis method at 1-sided 2.5% significance level with 80% power, including an 
interim analysis for futility when the first 230 subjects have been randomized and had a 
BOR assessed by the date when treatment was completed, PD/death occurred, patient 
dropped out or started new therapy, whichever occurred first. 
A sample size of 460 subjects is needed to achieve 80% power for demonstrating that 
once weekly- KRd 56 mg/m2 preserves at least 60% of twice-weekly KRd 27 mg/m2 
effect in terms of ORR at a 1-sided 2.5% significance level using the synthesis method.  
This calculation assumes a true relative risk (RR) of 1 with ORR = 86.6% for both arms 
(once weekly- KRd 56 mg/m2 vs twice-weekly KRd 27 mg/m2), and an interim analysis 
for futility at 50% information fraction using O’Brien-Fleming beta-spending function.  
The reference ORR = 86.6% was determined based on the BOR observed by the end of 
12 cycles of treatment in ASPIRE study (Amgen data on file).   
The hypotheses for the primary and key secondary objectives (ORR, PFS, and 
convenience after cycle 4 of treatment) will be tested using a fixed sequence hierarchical 
testing procedure to control the family-wise type I error rate at 1-sided 0.025 level.  The 
testing is ordered as follows: non-inferiority of ORR, non-inferiority of PFS, and 
superiority of patient-reported convenience after cycle 4 of treatment.  Starting with the 
hypothesis of ORR, if any hypothesis in the sequence is rejected at a 1-sided 
significance level of 0.025, then the subsequent hypothesis will be tested.  Otherwise, if 
any hypothesis failed to be rejected, then the subsequent hypotheses will not be tested.  
Primary/final analyses of efficacy endpoints will be based on the intent-to-treat 
population, which includes all randomized subjects.  


Product:  Carfilzomib 
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Date:  02 September 2021 
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FORM-001520, v.22, 05 February 2018 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Overall response over the duration of the study:  Clopper-Pearson 
method for by treatment overall response rate (ORR) estimate and 
CI.  Mantel-Haenszel stratified RR for the inference of treatment 
effect.  
The synthesis approach will be used to show that once-weekly 
KRd 56 mg/m2 preserves at least 60% of twice-weekly KRd 
27 mg/m2 effect vs Rd.  
Secondary 
PFS over the duration of the study: Kaplan-Meier (KM) estimates 
for PFS distribution by treatment and PFS rates and CI at 6 and 12 
months, stratified Cox proportional hazards (PH) model for HR and 
CI estimate.  The synthesis approach will be used to show that 
once-weekly KRd 56 mg/m2 preserves at least 50% of twice-weekly 
KRd 27 mg/m2 effect vs Rd. 
Patient-reported convenience after cycle 4 of treatment:  
Cochran-Mantel-Haenszel method will be used to evaluate the 
treatment effect (OR) for whether carfilzomib dosing is reported as 
convenient or inconvenient; a logistic regression model including 
the randomization stratification factors and treatment group will be 
considered for sensitivity analysis 
Time to response: mean, SD, median, minimum and maximum 
among responders.  
Duration of response (DOR): KM method among responders. 
Time to progression (TTP): KM method and stratified Cox PH 
model.  
OS over the duration of the study: KM estimates for OS distribution 
by treatment and OS rates and CI at 6 and 12 months, stratified 
Cox PH model for HR and CI estimate. 
MRD[-]CR: proportion of MRD[-]CR will be reported with CI 
calculated using Clopper-Pearson method. 
MRD[-] status at 12 months from randomization: proportion of 
MRD[-] will be reported with CI calculated using Clopper-Pearson 
method. 
Physical functioning and role functioning (EORTC QLQ-C30) over 
time: repeated measures analysis of covariance adjusting for the 
baseline covariates.  A restricted maximum likelihood-based mixed 
model for repeated measures (MMRM) will be considered as 
sensitivity analysis.  
Patient-reported treatment satisfaction (CTSQ) after cycle 4 of 
treatment: analysis of covariance at the corresponding fixed time 
point. 
Exploratory 
Will be described in the statistical analysis plan finalized before 
database lock. 
Safety analyses will be based on the safety population (defined as all randomized 
subjects who have received at least 1 dose of any study treatment [carfilzomib, 
lenalidomide, or dexamethasone]).  The number and percentage of subjects 
experiencing 1 or more adverse events will be summarized by treatment group, 
relationship to study treatment, and severity.  Changes from baseline and shift in toxicity 
grade in safety laboratory test results, left ventricular ejection fraction and vital signs will 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
Page 17 of 145 
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FORM-001520, v.22, 05 February 2018 
 
be summarized using descriptive statistics.  Adverse events and safety laboratory test 
results will be graded for severity using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.  
Subjects’ demographics and disease characteristics, in addition to prior and concomitant 
medications and study treatment exposure, will be summarized descriptively for each 
treatment group.   
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name: Amgen Inc.  


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
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FORM-001520, v.22, 05 February 2018 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema 
Safety follow-up
C1D1
30 days after 
last dose of all 
study drug(s)
Screening (up to 28 days)
Randomization 1:1
C12D1
Twelve 28-day cycles:
KRd56 once-weekly (N ~ 230)
K  (20/56 mg/m2 IV 30 min): days 1, 8, 15
Twelve 28-day cycles:
KRd27 twice-weekly (N ~ 230)
K (20/27 mg/m2 IV 10 min): days 1, 2, 8, 9, 15, 16
C6D1
For both arms:
Lenalidomide (25 mg): days 1-21; Dexamethasone (40 mg weekly; oral or IV)
Open-label Treatment Period
Stratified by:
• ISS stage
• Prior lenalidomide
• Prior proteasome inhibitor
• Prior anti-CD38 exposure
LTFU/EOS
Up to 12 
months after 
randomization
 
CxDx = cycle X day X; d = dexamethasone; EOS = End of Study; IV = intravenously; K = Kyprolis (carfilzomib); LTFU = long-term follow-up; R = lenalidomide. 
 


Product:  Carfilzomib 
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Date:  02 September 2021 
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2.2 
Schedule of Activities 
Table 2-1.  Schedule of Activities 
PROCEDURE 
Scree 
ninga  
(up to 
28 days 
before 
rand) 
Treatment Period 
Cycles 1 to 12 
Safety FU 
(30 [+3] 
days after 
last dose) 
LTFUb 
(every 28  
7 days) 
Notes 
Day 1 
2 
8 
9 
15 
16 
22 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Including multiple myeloma history 
Substance use 
X 
 
 
 
 
 
 
 
 
 
Tobacco only 
Complete physical examination  
X 
 
 
 
 
 
 
 
X 
 
 
Physical 
measurem
ents 
Height 
X 
 
 
 
 
 
 
 
 
 
 
BSA 
X 
(X) 
 
 
 
 
 
 
 
 
BSA should be calculated during screening per Mosteller 
formula and utilized to calculate required study drug doses.  
BSA should be recalculated if weight changes by more than 
20% (gain or loss) from weight used at the most recent BSA 
calculation. 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG with 
QTc interval
 
 
 
X 
(X) 
 
 
Screening and as clinically indicated. 
cycle 1 
 
 
 
X 
 
 
 
 
 
 
To be performed at the end of carfilzomib infusion 
cycle 2  
 
X 
 
 
 
 
 
 
 
 
Vital signs (once-weekly arm) 
X 
X 
 
X 
 
X 
 
 
X 
 
Checked prior to administration of carfilzomib in all cycles.  In 
cycles 1 and 6, an additional blood pressure measurement 
post-carfilzomib infusion will be collected (within 30 minutes of 
the end of infusion). 
Vital signs (twice-weekly arm) 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
X 
 
 
Echocardiogram  
X 
(X) 
 
 
 
 
 
 
X 
 
During treatment every 6 months (± 2 weeks) from C1D1 until 
SFU and additionally as clinically indicated.  An ECHO must 
be performed within 72 hours of the onset of a suspected 
cardiac failure event. 
Page 1 of 8 
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Product:  Carfilzomib 
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Table 2-1.  Schedule of Activities 
PROCEDURE 
Scree 
ninga  
(up to 
28 days 
before 
rand) 
Treatment Period 
Cycles 1 to 12 
Safety FU 
(30 [+3] 
days after 
last dose) 
LTFUb 
(every 28  
7 days) 
Notes 
Day 1 
2 
8 
9 
15 
16 
22 
Survival 
 
 
 
 
 
 
 
 
 
(X) 
Subjects who terminate early from study treatment (less than 
12 complete cycles) will be followed every 28 ± 7 days after 
safety follow-up visit until 12 months after randomization, 
death, loss to follow-up or withdrawal of full consent, 
whichever comes first. 
Subsequent antimyeloma therapies 
 
 
 
 
 
 
 
 
 
(X) 
All subjects who have ended study treatment without a 
confirmed PD will be followed every 28 ± 7 days until 12 
months after randomization, first subsequent antimyeloma, 
death, loss to follow-up, withdrawal of full consent, or 
confirmed PD, whichever comes first. 
Adverse events/serious adverse eventsc 
Continuous 
 
 
Concomitant therapies review 
Continuous 
 
 
LABORATORY ASSESSMENTS 
Pregnancy 
test (FCBP 
only) 
Serum  
X 
 
 
 
 
 
 
 
X 
 
At screening: 10 to 14 days prior to C1D1 
Urine or serum cycle 1 
(predose) 
 
X 
 
X 
 
X 
 
X 
 
 
Within 24 hours prior to dose of lenalidomide. 
Urine or serum cycle 2 to 
12 (predose; regular 
menses) 
 
X 
 
 
 
 
 
 
 
 
Urine or serum cycle 2 to 
12 (irregular menses) 
 
X 
 
 
 
X 
 
 
 
 
Hematology 
X 
X 
 
 
 
 
 
 
X 
 
Hematology and chemistry samples from screening may be 
used for C1D1 if taken within 3 days prior to C1D1.  
Hematology and chemistry samples taken within 48 hours of 
D1 of subsequent cycles may be used for treatment 
decisions.   Laboratory results must be evaluated for 
potential dose modification assessment prior to dosing. 
Chemistry 
X 
X 
 
 
 
 
 
 
X 
 
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Product:  Carfilzomib 
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Date:  02 September 2021 
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Table 2-1.  Schedule of Activities 
PROCEDURE 
Scree 
ninga  
(up to 
28 days 
before 
rand) 
Treatment Period 
Cycles 1 to 12 
Safety FU 
(30 [+3] 
days after 
last dose) 
LTFUb 
(every 28  
7 days) 
Notes 
Day 1 
2 
8 
9 
15 
16 
22 
LABORATORY ASSESSMENTS (CONTINUED) 
Screening laboratory assessments 
X 
 
 
 
Assessments must be done within 28 days prior to 
randomization 
See Table 12-1 for more details.   
Coagulation tests 
X 
 
 
 
 
2 microglobulin 
X 
(X) 
 
 
At screening and as clinically indicated. 
NT-proBNP 
X 
 
 
 
At screening.  
Quantitative immunoglobulins 
X 
(X) 
 
 
During screening, assessments must be done within 28 days 
prior to randomization. 
To be repeated only in case of clinical need, such as recurrent 
infections 
Hepatitis B virus 
X 
(X) 
(X) 
 
For subjects with unknown hepatitis serology status or who 
have not had hepatitis serology tested within 6 months of 
screening: perform local serology testing for HBsAg, anti-HBs, 
and anti-HBc.   
Local testing for HBV DNA will be performed for subjects with 
any of the following:  a known history of hepatitis B, positive 
serology, or who seroconvert to positive status during 
treatment.  HBV DNA testing will be repeated every 12 weeks 
( 2 weeks) or more frequently if clinically indicated through 
SFU.  An appropriate specialist should be consulted for all 
subjects who test positive. 
See Section 9.2.3.4.3  
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Product:  Carfilzomib 
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Date:  02 September 2021 
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Table 2-1.  Schedule of Activities 
PROCEDURE 
Scree 
ninga  
(up to 
28 days 
before 
rand) 
Treatment Period 
Cycles 1 to 12 
Safety FU 
(30 [+3] 
days after 
last dose) 
LTFUb 
(every 28  
7 days) 
Notes 
Day 1 
2 
8 
9 
15 
16 
22 
DISEASE-SPECIFIC ASSESSMENTS 
SPEP/UPEP/SFLC/SIFE/UIFEd 
X 
(X) 
X 
(X) 
Screening disease-specific assessments must be done within 
28 day screening window and repeated on C1D1 if not 
performed within 14 days (of C1D1).  See Section 9.2.2.1. 
 
Disease assessments at the safety follow-up visit and during 
LTFU are not required for subjects with confirmed PD or have 
started new antimyeloma therapy or if assessments were 
performed within 14 days prior to the safety follow-up visit. 
Serum calcium 
Bone lesion assessment 
X 
(X) 
 
(X) 
A standard of care bone lesion radiographic assessment 
performed within 45 days of Cycle 1 Day 1 may be used as 
the Screening assessment, and does not need to be repeated, 
unless standard of care method of assessment is different 
from as specified above, ie, MRI bone lesion assessment 
would not be allowed to substitute for the Screening bone 
lesion assessment.  It will be repeated if worsening clinical 
symptoms suggest PD or as clinically indicated.  Not required 
during LTFU for subjects with confirmed PD. 
Plasmacytoma evaluation 
(X) 
(X) 
 
(X) 
Will be done at screening only if clinically suspected.  
Screening evaluation may be done within the 28 day 
screening window, if performed as a part of standard of care.   
For subjects with a history of plasmacytoma, clinical 
assessment will be performed locally every 28 ( 7) days from 
C1D1.  Radiological exam will be performed only to confirm a 
response of PR or better, or to confirm PD, or as clinically 
indicated (see  
Section 9.2.2.4 for more detail) 
Not required during LTFU for subjects with confirmed PD. 
Page 4 of 8 
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Product:  Carfilzomib 
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Date:  02 September 2021 
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FORM-001520, v.22, 05 February 2018 
 
Table 2-1.  Schedule of Activities 
PROCEDURE 
Scree 
ninga  
(up to 
28 days 
before 
rand) 
Treatment Period 
Cycles 1 to 12 
Safety FU 
(30 [+3] 
days after 
last dose) 
LTFUb 
(every 28  
7 days) 
Notes 
Day 1 
2 
8 
9 
15 
16 
22 
DISEASE-SPECIFIC ASSESSMENTS (CONTINUED) 
Bone 
marrow 
sample 
For MRD[-] assessment  
X 
(X) 
 
 
Within the 28-day screening window, at CR or better, and at 
12 months from randomization (± 4 weeks) for all subjects 
regardless of cycles.  A bone marrow aspirate is required for 
MRD analysis.  MRD sample is sent frozen (12-month 
sample may be omitted if an MRD analysis with confirmed 
results was performed within 4 months of the scheduled test 
at 12 months from randomization, or if the subject has started 
new anti-myeloma therapy prior to 12-month landmark, or if 
disease progression is recorded). 
Cytomorphology 
X 
(X) 
 
(X) 
Screening, bone marrow aspirate slides for cytomorphology 
obtained be used as baseline if taken within 45 days prior to 
randomization and are sent to the central laboratory for 
processing (see Section 9.2.2.2). 
FISH analysis for 
cytogenetic risk  
X 
 
 
 
See Section 9.2.2.2.  A bone marrow aspirate is required and 
will be taken no later than C1D1 predose (ie, during 28-day 
screening period or C1D1). Note: DO NOT FREEZE the 
FISH sample tube.   
Immunohistochemisty to 
confirm sCR 
 
(X) 
 
(X) 
When parameters suggest CR has been reached, collect a 
bone marrow sample: a biopsy or an aspirate clot to enable 
immunohistochemistry to assess sCR.  (At minimum a bone 
marrow aspirate is required for plasma cell% and MRD).  
Page 5 of 8 
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Product:  Carfilzomib 
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Date:  02 September 2021 
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Table 2-1.  Schedule of Activities 
PROCEDURE 
Scree 
ninga  
(up to 
28 days 
before 
rand) 
Treatment Period 
Cycles 1 to 12 
Safety FU 
(30 [+3] 
days after 
last dose) 
LTFUb 
(every 28  
7 days) 
Notes 
Day 1 
2 
8 
9 
15 
16 
22 
SPARSE PHARMACOKINETIC ASSESSMENTS (ONLY FOR SUBJECTS NOT PARTICIPATING IN OPTIONAL INTENSIVE PK/PDN SUBSTUDY) 
Cycle 2 only 
 
X 
 
 
 
 
 
 
 
 
 Predose (within 5 min before the start of infusion) 
 15 minutes after the start of infusion (± 5 min) for once-
weekly arm only 
 Immediately prior to (within 2 min before) the end of 
infusion 
 30 min after the end of infusion (± 5 min) 
INTENSIVE PHARMACOKINETIC ASSESSMENTS (ONLY FOR SUBJECTS IN OPTIONAL INTENSIVE PK/PDN SUBSTUDY) 
Cycle 1  
 
X 
 
X 
 
 
 
 
 
 
Day 1 only: 
 
Predose (within 5 min before the start of infusion) 
 
Immediately prior to (within 2 min before) the end of 
infusion 
Day 8 only: 
 
Predose (within 5 min before the start of infusion) 
 
15 minutes after the start of infusion (± 5 min) for once-
weekly arm only 
 
Immediately prior to (within 2 min before) the end of 
infusion 
 
15 min, 60 min, and 2 hr after the end of infusion 
(± 5 min) 
Cycle 2 
 
X 
 
X 
 
 
 
 
 
 
 
Predose (within 5 min before the start of infusion) 
 
Immediately prior to (within 2 min before) the end of 
infusion 
 
60 minutes after the end of infusion (± 5 min) 
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Product:  Carfilzomib 
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Date:  02 September 2021 
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FORM-001520, v.22, 05 February 2018 
 
Table 2-1.  Schedule of Activities 
PROCEDURE 
Scree 
ninga  
(up to 
28 days 
before 
rand) 
Treatment Period 
Cycles 1 to 12 
Safety FU 
(30 [+3] 
days after 
last dose) 
LTFUb 
(every 28  
7 days) 
Notes 
Day 1 
2 
8 
9 
15 
16 
22 
PHARMACODYNAMIC ASSESSMENTS (ONLY FOR SUBJECTS IN OPTIONAL INTENSIVE PK/PDN SUBSTUDY) 
Cycle 1 
 
X 
 
X 
 
 
 
 
 
 
Day 1 only: 
 
Predose (within 5 min before the start of infusion) 
Day 8 only: 
 
Predose (within 5 min before the start of infusion) 
 
60 minutes (± 5 min) after the end of infusion 
Cycle 2 
 
X 
 
X 
 
X 
 
 
 
 
 
Predose (within 5 min before the start of infusion) 
 
60 min after the end of infusion (± 5 min) 
Cycle 3 to 7 
 
X 
 
 
 
 
 
 
 
 
 
Predose (within 5 min before the start of infusion) 
 
60 min after the end of infusion (± 5 min) 
CLINICAL OUTCOME ASSESSMENTS – TO BE COMPLETED PRIOR TO ANY STUDY PROCEDURE 
EORTC QLQ-C30  
 
(X) 
 
 
 
 
 
 
X 
 
Before dosing on day 1 of cycle 1, 3, 5, 7, 9, and 12   
Patient-reported convenience with 
carfilzomib-dosing schedule  
single-item question 
 
(X) 
 
 
 
 
 
 
X 
 
Before dosing on C2D1, C5D1, and C12D1 for subjects still 
receiving carfilzomib. 
CTSQ  
 
(X) 
 
 
 
 
 
 
X 
 
Before dosing on C2D1, C5D1, and C12D1.   
Page 7 of 8 
Footnotes are defined on the last page of the table. 


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Table 2-1.  Schedule of Activities 
PROCEDURE 
Scree 
ninga  
(up to 
28 days 
before 
rand) 
Treatment Period 
Cycles 1 to 12 
Safety FU 
(30 [+3] 
days after 
last dose) 
LTFUb 
(every 28  
7 days) 
Notes 
Day 1 
2 
8 
9 
15 
16 
22 
STUDY TREATMENT ADMINISTRATION 
Once-weekly arm 
Carfilzomib 
 
X 
 
X 
 
X 
 
 
 
 
Cycle 1: 20 mg/m2 on days 1; 56 mg/m2 on days 8, 15 
Cycles 2-12: 56 mg/m2 each dosing day 
Dexamethasone 
 
X 
 
X 
 
X 
 
(X) 
 
 
40 mg (oral or IV) weekly.  Day 22 administration is for cycles 
1 to 9 only and may be self-administered at home 
IV prehydration 
 
(X) 
 
(X) 
 
(X) 
 
 
 
 
As clinically indicated (Section 7.1.1.3) 
Lenalidomide 
 
Days 1 to 21 
 
 
In subjects with normal renal function, lenalidomide will be 
taken once-daily on days 1 to 21 at a dose of 25 mg.  In 
subjects with renal impairment (mild to moderate or severe), 
please refer to the regional product label. 
Twice-weekly arm 
Carfilzomib 
 
X 
X 
X 
X 
X 
X 
 
 
 
Cycle 1: 20 mg/m2 on days 1 and 2; 27 mg/m2 on  
days 8, 9, 15, and 16 
Cycles 2 to 12: 27 mg/m2 each dosing day 
Dexamethasone  
 
X 
 
X 
 
X 
 
(X) 
 
 
40 mg (oral or IV) weekly.  Day 22 administration is for cycles 
1 to 9 only and may be self-administered at home 
IV prehydration 
 
(X) 
(X) (X) 
(X) 
(X) 
(X) 
 
 
 
As clinically indicated (Section 7.1.1.3) 
Lenalidomide 
 
Days 1 to 21 
 
 
In subjects with normal renal function, lenalidomide will be 
taken once-daily on days 1 to 21 at a dose of 25 mg.  In 
subjects with renal impairment (mild to moderate or severe), 
please refer to the regional product label. 
Page 8 of 8 
anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface antibody; BSA = body surface area; C = cycle; CR = complete response; CTSQ = Cancer Therapy 
Satisfaction Questionnaire; CxDx = cycle X day X; D = day; ECOG = Eastern Cooperative Oncology Group; ECG = electrocardiogram; EORTC = European 
Organization for Research and Treatment of Cancer; EORTC QLQ-C30 = EORTC Quality-of-life Questionnaire Core 30;
 FCBP = females of childbearing potential; 
FISH = fluorescence in-situ hybridization; FU = follow-up; IV = intravenously; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; LTFU = long-term 
follow-up; MRD [-] = minimal residual disease negative; NT-proBNP = N terminal of the prohormone brain natriuretic peptide; PD = progressive disease; 
PDn = pharmacodynamics; PK = pharmacokinetics; PR = partial response; rand = randomization; sCR = stringent complete response;
SFLC = serum-free light chain; SIFE = serum immunofixation; SOC = standard of care; SPEP = serum protein 
electrophoresis; UIFE = urine immunofixation; UPEP = urine protein electrophoresis 
 (X) = Parentheses indicate that the particular test is situational at that time point, as specified in the respective notes. 
a If the assessments are repeated during screening, then the most recent result prior to randomization should be used to determine eligibility. 


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b LTFU is up to 12 months after randomization. 
c If the investigator becomes aware of serious adverse events suspected to be related to IP or fatal serious adverse events (regardless of causality) after completion of 
the protocol-required reporting period, 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.  Please refer to Section 9.2.3.1.1.3 for additional details. 
d.Disease response assessments are to be performed every 28 ± 7 days from C1D1 through the end of C12 or until confirmed PD, whichever comes first, regardless of 
cycle duration, dose delays, or treatment discontinuation.  After discontinuation from study treatment, subjects who do not have confirmed PD are required to 
continue disease response assessments and report new antimyeloma treatment and will be followed every 28 ± 7 days until 12 months after randomization, first 
subsequent antimyeloma treatment, death, loss to follow-up, withdrawal of full consent, or confirmed PD, whichever comes first.    
 


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3. 
Introduction 
3.1 
Study Rationale 
Recently, the International Myeloma Working Group (IMWG) published 
recommendations on management of relapsed multiple myeloma and advocated a 
regimen containing carfilzomib (K), preferably in combination with lenalidomide (R) and 
dexamethasone (d) (Laubach et al, 2016); such a regimen (27 mg/m2 KRd,  
twice-weekly) was approved for treatment of relapsed multiple myeloma based on the 
results of ASPIRE study (Stewart et al, 2015).   
ASPIRE was the first phase 3 randomized study demonstrating that a triplet combining 
non-conventional chemotherapy agents and carfilzomib had significant improvement in 
outcomes when compared with a doublet in patients who had received 1 to 3 prior lines 
of therapy and whose disease had not progressed during treatment with bortezomib or 
lenalidomide plus dexamethasone (if it was their most recent treatment).  In this study, 
the addition of carfilzomib to lenalidomide and dexamethasone reduced the risk of death 
or progression by 31% when compared with lenalidomide and dexamethasone alone 
(hazard ratio [HR] = 0.69, p < 0.0001) which translated into a median progression-free 
survival (PFS) of 26.3 months.  Further, KRd 27 mg/m2 twice-weekly was associated 
with a high overall response rate (ORR) of 87.1% (odds ratio [OR] = 3.47; p < 0.0001) 
(Stewart et al, 2015), increasing rapidly by end of cycle 4 of treatment, and 
demonstrated a statistically significant 8-month improvement in median overall survival 
(OS) (HR = 0.794; p = 0.0045) (Siegel et al, 2018).  Also, the rate of complete or 
stringent complete response (CR/sCR) has a steep increase by end of 12 cycles of KRd 
27 mg/m2 twice-weekly (Dimopoulos et al, 2018).  These positive results were seen 
despite a less intensified carfilzomib dosing after 12 cycles of therapy and limiting 
carfilzomib treatment to the first 18 cycles of therapy.   
For the approved dose schedule of KRd, carfilzomib is administered intravenously (IV) 
on 2 consecutive days for 3 weeks (ie, days 1, 2, 8, 9, 15, and 16) of each 28-day cycle.  
The frequency of dosing in this regimen demands a substantial time commitment and 
potential financial challenges for patients and caregivers, as carfilzomib is generally 
administered in an outpatient clinic.  This time commitment can be particularly 
burdensome for patients with transportation or mobility challenges 
(Barrett-Lee et al, 2007).  As a result, compliance with the currently available twice-
weekly dose schedule for the KRd regimen may be less optimal and can reduce the 
ability to achieve deep responses and the longest possible survival.    


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A more time-efficient once-weekly dosing schedule can help improve patient adherence 
to treatment with antimyeloma IV agents.  Two studies of once-weekly vs twice-weekly 
dosing schedules of bortezomib as combination therapy showed similar efficacy 
between the 2 regimens; however, patients with multiple myeloma treated once-weekly 
were more concordant, received higher doses, had fewer dose reductions, and were 
treated for longer durations compared with patients treated twice-weekly 
(Bringhen et al, 2010; Reeder et al, 2010).  These studies provide clinical evidence that 
a once-weekly schedule can result in improved dosing and longer duration of therapy 
when compared with a twice-weekly schedule, while preserving benefit to the patients 
and allowing for a schedule that is less burdensome.   
Exploring a KRd regimen aimed at improving tolerability, treatment convenience, and 
patient satisfaction while preserving clinical benefit to the patients is expected to address 
the challenges patients may face with the on-label twice-weekly KRd 27 mg/m2 dose 
regimen and is an important consideration for improving treatment outcomes.   
3.1.1 
Justification for Primary Endpoint  
The ORR over the duration of the study is used as the primary endpoint to establish 
non-inferiority in terms of efficacy of a once-weekly KRd regimen (56 mg/m2) when 
compared with weekly KRd dose regimen with the on-label twice-weekly KRd 27 mg/m2 
dose regimen.  A positive correlation between ORR and PFS is supported by ASPIRE 
overall response and PFS rates (Stewart et al, 2015), as well as by the data from 
meta-analysis of 7 phase 3 studies with different treatment regimens for this study 
population (Teng et al, 2018).   
In the pivotal ASPIRE study (the historical study for the non-inferiority analysis), the 
analysis of ORR was statistically significant and consistent with the treatment effect 
observed in PFS (primary endpoint) and OS.  The ORR was 87.1% (95% CI: 83.4, 90.3) 
in the KRd arm versus 66.7% (95% CI: 61.8, 71.3) in the Rd arm (OR [95% CI]: 3.47 
[2.41, 5.00]; p < 0.0001) and corresponded with a 9-month improvement in median PFS 
and an 8-month improvement in OS.  The mean time to response (TTR) was 1.6 months 
in the KRd arm (Siegel et al, 2018; Stewart et al, 2015) and the response rate increased 
rapidly by end of cycle 4 plateauing after that.  By the end of 12 cycles of treatment in 
the ASPIRE study, the best ORR was 86.6% (Amgen data on file), with a CR/ sCR rate 
steeply increasing (Dimopoulos et al, 2018), and Kaplan-Meier event-free rate for PFS 
was 74.6% (HR = 0.55) (Amgen data on file) 


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In the supplementary appendix of the e-publication, Stewart et al present a landmark 
analysis of PFS within the KRd group among patients who achieved partial response 
(PR) or better compared with patients who did not achieve a response of PR or better, 
providing evidence that the responders had significantly longer subsequent PFS than 
nonresponders (p < 0.001).  The Simon-Makuch landmark transient-state method at the 
end of 2 months from randomization was used to minimize the bias in favor of 
responders represented by the time necessary to reach the response (Simon and 
Makuch, 1984).   
Results of an ongoing Study 20140241 (CFZ013) evaluating once-weekly dosing 
regimens of KRd (56 and 70 mg/m2) support the proposed ORR as a primary endpoint.  
After a median treatment time of 39 weeks, ORR was 90% for subjects treated with 
56 mg/m2.  The combined dose cohort, including subjects that were treated with weekly 
doses of 56 and 70 mg/m2 (N = 56) reached an ORR of 89.3% after a median treatment 
time of 33 weeks (Amgen data on file).   
Additional supportive evidence for the appropriateness of the primary endpoint ORR 
involves a model-based meta-analysis of 7 phase 3 studies in subjects with relapsed 
and refractory multiple myeloma (RRMM), which included ASPIRE and ENDEAVOR 
studies (Teng et al, 2018).  This meta-analysis assessed the relationship between ORR 
and PFS.  The results from these phase 3 studies showed that responses are attainable 
within the first 4 months of treatment and demonstrated a linear relationship between 
ORR and median PFS, with a strong correlation (R2 = 0.84) (Teng et al, 2018).  The 
selected studies encompass a broad representation of treatment regimens, with 
12 treatment arms used to evaluate the relationship of ORR and PFS. The median time 
to response (defined as achievement of PR or better) in this meta-analysis was  
4 months in 6 of the 7 studies with available information (Teng et al, 2018).  
These evidences indicate that ORR over duration of the study is an appropriated 
predictor of PFS and will be a suitable indicator of efficacy to establish non-inferiority 
between once-weekly and twice-weekly KRd dose regimens.   
3.1.2 
Justification for the Clinical Outcome Assessments Endpoints  
Treatment convenience and satisfaction are significant endpoints adding to the 
health-related quality-of-life (HRQOL) of RRMM patients (Moreau et al, 2011).  Results 
of the phase 3 A.R.R.O.W. study comparing once-weekly dosing of Kd (70 mg/m2) with 
twice-weekly Kd (27 mg/m2) demonstrated that subjects who were receiving 
once-weekly carfilzomib reported higher odds of convenience and satisfaction than 


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subjects receiving twice-weekly carfilzomib (Study 20140355).  However; this clinical 
outcome assessment (COA) was exploratory and was not corrected for multiplicity.  
Therefore, the same patient-reported convenience with carfilzomib-dosing schedule 
question will be used in this study as a secondary endpoint (corrected for multiplicity) to 
compare patient-reported convenience with carfilzomib-dosing schedule between 
treatment arms.  Response categories include ‘very convenient, convenient, 
inconvenient, and very inconvenient,’ and differ from the response categories to the 
question in ARROW, which also included ‘neutral’ as a response.    
3.2 
Background 
3.2.1 
Disease 
Multiple myeloma, a clonal neoplastic proliferation of plasma cells, is the second most 
common hematologic malignancy and is responsible for approximately 80 000 annual 
deaths worldwide (1% of all cancer deaths).  The estimated incidence of multiple 
myeloma worldwide was 114 000 patients, which represents 0.8% of all cancers.  The 
5-year prevalence of multiple myeloma worldwide was estimated 229 000 persons 
(Ferlay et al, 2015).  Multiple myeloma is a disease of older adults, with a median age at 
diagnosis of 69 years (Noone et al, 2018).  As the world’s older population 
(age  65 years) continues to grow (from 8.5% [617 million] of the world’s population in 
2013 to a projected 17% [1.6 billion] in 2015) (He et al, 2016), the incidence of multiple 
myeloma is expected to increase.   
3.2.2 
Amgen Investigational Product Background:  Carfilzomib 
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor (PI) that binds selectively 
and irreversibly to the 20S proteasome, the proteolytic core particle within the 26S 
proteasome.  Consequently, proteasome function after therapy can only be regained by 
de novo proteasome synthesis.  Specifically, carfilzomib inhibits the chymotrypsin-like 
catalytic activity of the β5 subunit over the caspase-like catalytic activity of the 
β1 subunit or the trypsin-like catalytic activity of the β2 subunit, resulting in the 
accumulation of proteasome substrates and ultimately growth arrest and apoptosis  
(Hoy, 2016).  Carfilzomib extensively penetrates all tissues, but the brain.  It is 
metabolized largely extra-hepatically and rapidly cleared from the circulation by biliary 
and renal excretion (t1/2 = 15 to 30 minutes); < 1% is excreted intact 
(Kortuem and Stewart, 2013). 
Carfilzomib entered clinical studies in September 2005.  On 20 July 2012, Kyprolis® 
(carfilzomib for injection) was granted accelerated approval by the US Food and Drug 


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Administration (FDA) for the treatment of patients with multiple myeloma who have 
received at least 2 prior therapies, including bortezomib and an immunomodulatory 
agents (IMiD), and have demonstrated disease progression on or within 60 days of 
completion of the last therapy.  The initial accelerated approval was based on the results 
of the phase 2 PX-171-003-A1 study in the United States.  Subsequent full approval in 
the United States and globally were based on 2 phase 3 studies: PX-171-009 ASPIRE 
and 2011-003 ENDEAVOR.  Following these approvals, Kyprolis in combination with 
either lenalidomide and dexamethasone or dexamethasone alone is indicated for the 
treatment of RRMM.  The exact indication wording varies by region.  
As of 19 July 2018, an estimated 4132 subjects have been treated with carfilzomib in 
company-sponsored clinical studies since the beginning of the development program 
and approximately 88964 patients have been exposed to carfilzomib in the 
postmarketing setting.   
A detailed description of the chemistry, pharmacology, efficacy, and safety of carfilzomib 
is provided in the Carfilzomib Investigator’s Brochure (IB).   
3.3 
Benefit/Risk Assessment 
The following benefit-risk assessment supports the conduct of this clinical study.  
Reference should be made to the Carfilzomib IB for further data on carfilzomib. 
3.3.1 
Therapeutic Context 
Relapsed or refractory multiple myeloma treatment has evolved rapidly in recent years.  
Progress has been made in autologous stem cell transplantation along with the 
introduction of several breakthrough drugs, including IMiD and PI, which led to a 
significant increase in response rate as well as survival rate (Kumar et al, 2012).  While 
treatment for multiple myeloma will typically 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 and Asimakopoulos, 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 PFS and subsequently 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: 
control disease to prevent or delay associated complications (such as bone fractures, 


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renal insufficiency, and infections), to maintain an acceptable HRQOL, and to provide 
relief of pain and other disease-related symptoms.   
3.3.2 
Key Benefits 
Triplet therapy combining a PI with an IMiD and steroid remains an important and 
commonly used option for many patients with RRMM.  The key benefits of carfilzomib as 
a triplet therapy for patients RRMM include:  increases in OS, PFS, and ORR; as well as 
improvements in quality-of-life. The evidence for these benefits is based on the pivotal, 
phase 3 randomized study (Study PX-171-009 [hereafter referred to as ASPIRE], 
N = 792 subjects) and an ongoing open-label, multicenter, phase 1b dose-finding and 
dose evaluation study (NCT02335983; Study CFZ 013, N = 56).  
ASPIRE evaluated KRd 20/27 mg/m2 twice-weekly vs Rd for treatment of relapsed 
multiple myeloma: the addition of carfilzomib to lenalidomide and dexamethasone 
reduced the risk of death or progression by 31% when compared with lenalidomide and 
dexamethasone alone.  The median PFS with carfilzomib was 26.3 months compared 
with 17.6 months without carfilzomib (HR = 0.69, 95% CI: 0.57, 0.83; p < 0.0001).  
Further, KRd 27 mg/m2, twice-weekly was associated with a higher ORR of 87.1% vs 
66.7% in the control arm (OR = 3.47; p < 0.0001) (Stewart et al, 2015) and improved OS 
by 8-month (median OS 48.3 vs 40.4 months; HR = 0.79; p = 0.0045) 
(Siegel et al, 2018).   
The ongoing Study CFZ013 evaluates once-weekly KRd in patients with RRMM and 
newly diagnosed multiple myeloma (NDMM).  As of data cut-off 22 February 2018, 
available efficacy results from 56 subjects with either RRMM or NDMM treated with 
weekly KRd 56 mg/m2 or KRd 70 mg/m2 has shown similar efficacy (as determined by 
ORR) with either KRd 56 mg/m2 or KRd 70 mg/m2 (90.0% versus 89.1%, respectively) to 
the effect previously reported for twice-weekly KRd (27 mg/m2) in the randomized 
phase 3 ASPIRE study (Biran et al, 2018).  These results complement the significant 
efficacy results of carfilzomib as a triplet therapy.   
The European Organization for Research and Treatment of Cancer Quality-of-life 
Questionnaire Core 30 (EORTC QLQ-C30) instrument with a GHS/QOL subdomain was 
used to assess HRQOL as a secondary endpoint in ASPIRE.  Subjects had higher  
QLQ-C30 global health status/quality of life (GHS/QOL) scores in the KRd group versus 
the Rd group over 18 cycles of treatment (overall treatment difference:  4.23, 95% CI:  
2.09, 6.37 [Stewart et al, 2016]), with a nominal 1-sided p = 0.0001.  Thus, in ASPIRE 
KRd improved overall health and quality-of-life compared with Rd, respectively.     


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3.3.3 
Key Risks 
Multiple important identified and potential risks for carfilzomib have been identified based 
on pooled safety data from completed studies where carfilzomib was used in 
combination (with lenalidomide-dexamethasone, cyclophosphamide dexamethasone, 
melphalan prednisone, or carboplatin etoposide), with dexamethasone alone, or in 
monotherapy studies (n = 2944).  Dose modification instructions for the management of 
toxicities is provided in Section 7.4.   
Although the key identified risks (ie, cardiac failure, acute renal failure, and 
hypertension) are underlying comorbidities in patients with multiple myeloma 
(Kistler et al, 2014; Christiansen et al, 2011; Knauf et al, 2009), these risks were 
identified as key risks with carfilzomib based on a greater incidence and severity of 
adverse events in the carfilzomib treatment groups versus the comparators in the 
randomized clinical studies.  The combination of KRd has been studied in the 
randomized clinical study ASPIRE (A Randomized, Multicenter, Phase 3 Study 
Comparing Carfilzomib, Lenalidomide, and Dexamethasone [KRd] vs Lenalidomide and 
Dexamethasone [Rd] in Subjects with Relapsed Multiple Myeloma).  The information 
about the key risks from this study has been summarized below in Section 3.3.3.1.  
Additional information regarding important identified risks as well as adverse drug 
reactions for carfilzomib are detailed in the Carfilzomib IB.  
Embryo-fetal toxicity is associated with REVLIMID (lenalidomide) treatment.  
Investigators and subjects must comply with the requirements of restricted distribution 
programs if one is present in the local region; (eg, REVLIMID Risk Evaluation and 
Mitigation Strategy [REMS] program in the United States).  Additional information 
regarding risks for lenalidomide are described in REVLIMID United States Prescribing 
Information (USPI) and REVLIMID Summary of Product Characteristics (SmPC) or local 
prescribing information.   
Warnings for dexamethasone include anaphylactoid reactions, cardio-renal toxicities, 
endocrine toxicities, infections, and ophthalmic toxicities.  Dexamethasone is approved 
for the palliative treatment of neoplastic diseases.  Additional details regarding the risks 
of dexamethasone are provided in the prescribing information (Dexamethasone USPI, 
Dexamethasone SmPC).  The risks of dexamethasone in this study are expected to be 
similar with the overall safety profile described in the labeling information.   


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3.3.3.1 
Risks 
3.3.3.1.1 
Cardiac Toxicity 
New onset or worsening of pre-existing cardiac failure (eg, congestive heart failure, 
pulmonary edema, decreased ejection fraction), including fatalities, have occurred after 
administration of carfilzomib.  In clinical studies with carfilzomib, these events occurred 
throughout the course of carfilzomib therapy.   
Incidence of cardiac failure events reported in ASPIRE was as follows: all grades: KRd: 
7.1%, Rd: 4.1%; serious adverse events: KRd: 4.1%, Rd: 2.1%; grade ≥ 3 adverse 
events: KRd: 4.3%, Rd: 2.1%.  Most of the cardiac failure adverse events (all grades) 
were resolved (KRd: 3.3%, Rd: 1.5%) or stabilized/not resolving (KRd: 2.6%, Rd: 1.5%) 
or resolved with sequelae (KRd: 0.5%, Rd: 0%).  Fatal outcomes were reported for 0.8% 
subjects from the KRd group and 1.0% from the Rd group.  Cardiac failure adverse 
events (all grades) leading to discontinuation of any investigational product were 
reported for 0.5% of subjects from the KRd group and 0.8% of subjects from the Rd 
group.   
Once-weekly carfilzomib has been evaluated in A.R.R.O.W study (a randomized 
phase 3 study in 478 subjects with relapsed and refractory multiple myeloma receiving 
carfilzomib in combination with dexamethasone, comparing once-weekly versus 
twice-weekly carfilzomib dosing).  Incidence of cardiac failure events reported in this 
study was as follows: all grades: Kd 20/70 mg/m2 once-weekly: 3.8%, Kd 20/27 mg/m2 
twice-weekly: 5.1%; serious adverse events: Kd 20/70 mg/m2 once-weekly: 3.4%, 
Kd 20/27 mg/m2 twice-weekly 3.4%; grade ≥ 3 adverse events: Kd 20/70 mg/m2  
once-weekly: 2.9%, Kd 20/27 mg/m2 twice-weekly: 4.3%.  Adverse event outcomes were 
reported for serious adverse events only in A.R.R.O.W.  Almost all the cardiac failure 
serious adverse events were resolved (Kd 20/70 mg/m2 once-weekly: 2.9%, 
Kd 20/27 mg/m2 twice-weekly: 1.7%) or not resolved (Kd 20/70 mg/m2 once-weekly: 
0.4%, Kd 20/27 mg/m2 twice-weekly: 1.3%).  One fatal outcome was reported 
(Kd 20/70 mg/m2 once-weekly: 0%, Kd 20/27 mg/m2 twice-weekly: 0.4%).  Cardiac 
failure adverse events (all grades) leading to discontinuation of any investigational 
product were reported for 2.9% of subjects from the Kd 20/70 mg/m2 once-weekly group 
and 2.6% of subjects from the Kd 20/27 mg/m2 twice-weekly group.   
The risk of cardiac failure is increased in elderly patients (≥ 75 years) and in Asian 
patients.  Subjects with New York Heart Association Class III and IV heart failure, recent 
myocardial infarction, and conduction abnormalities uncontrolled by medications were 


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not eligible for the clinical study and may be at greater risk for cardiac complications.  
While adequate hydration is required prior to dosing in cycle 1, all subjects should be 
monitored for evidence of volume overload, especially subjects at risk for cardiac failure.  
The total volume of fluids may be adjusted as clinically indicated in subjects with 
baseline cardiac failure or who are at risk for cardiac failure.   
3.3.3.1.2 
Hypertension 
Hypertension has been reported as one of the common comorbidities in patients with 
multiple myeloma.  Based on the MarketScan claims database, the prevalence of 
hypertension as a comorbidity among multiple myeloma patients is 46.9% 
(Song et al, 2016) and there was a 30% increase in the risk of hypertension in multiple 
myeloma versus non-multiple myeloma patients (Chari et al, 2016).  The incidence of 
hypertension adverse events in ASPIRE was as follows: all grades: KRd: 17.1%, 
Rd: 8.7%, serious adverse events: KRd: 0%, Rd: 0.3%; grade ≥ 3 adverse events: 
KRd: 6.4%, Rd: 2.3%.  The incidence of hypertension (all grades) was higher in subjects 
with a history of hypertension: with history of hypertension: KRd: 20.5%, Rd: 10.7%; 
without history of hypertension: KRd: 13.7%, Rd: 7.1%.  No fatal outcomes for 
hypertension adverse events (all grades) were reported in ASPIRE.  Almost all the 
hypertension adverse events (all grades) were stabilized/not resolving (KRd: 8.7%; 
Rd: 4.4%) or resolved (KRd: 8.4%, Rd: 4.1%); resolved with sequelae was also reported 
(KRd: 0%, Rd: 0.3%).  Hypertension adverse events (all grades) led to discontinuation of 
any investigational product in 0.3% subjects from the KRd and Rd groups each.  
Hypertensive crisis occurred in ≤ 0.5% of subjects (KRd: 0.5%, Rd: 0.3%), all these 
adverse events were ≥ grade 3. 
The incidence of hypertension adverse events in A.R.R.O.W was as follows: all grades: 
Kd 20/70 mg/m2 once-weekly: 21.8%, Kd 20/27 mg/m2 twice-weekly: 21.3%, serious 
adverse events: Kd 20/70 mg/m2 once-weekly: 0%, Kd 20/27 mg/m2 twice-weekly: 0.4%; 
grade ≥ 3 adverse events: Kd 20/70 mg/m2 once-weekly: 5.9%, Kd 20/27 mg/m2 
twice-weekly: 5.5%.  In A.R.R.O.W., the difference in incidence of hypertension (all 
grades) among subjects with or without a history of hypertension was similar between 
treatment groups (with history of hypertension: Kd 20/70 mg/m2 once-weekly: 22.2%, 
Kd 20/27 mg/m2 twice-weekly: 20.6%; subjects without history of hypertension: 
Kd 20/70 mg/m2 once-weekly: 21.6%, Kd 20/27 mg/m2 twice-weekly: 21.9%.  Adverse 
event outcomes were reported for serious adverse events only in A.R.R.O.W. The only 
hypertension serious adverse event was resolved (Kd 20/70 mg/m2 once-weekly: 0%, 


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Kd 20/27 mg/m2 twice-weekly: 0.4%).  Hypertension adverse events (all grades) led to 
discontinuation of any investigational product in 1.3% subjects from the Kd 20/70 mg/m2 
once-weekly and 0% from the Kd 20/27 mg/m2 twice-weekly group.  Hypertensive crisis 
occurred in ≤ 0.5% of subjects (Kd 20/70 mg/m2 once-weekly:  0%, Kd 20/27 mg/m2 
twice-weekly: 0.4%), all these adverse events were ≥ grade 3. 
Blood pressure is monitored while on study and hypertension should be treated as 
needed.  If hypertension cannot be controlled, the carfilzomib dose should be held.  In 
case of hypertensive crisis, carfilzomib should be stopped until the hypertensive crisis 
resolved.  The investigator may consider restarting carfilzomib based on an individual 
benefit-risk assessment.   
3.3.3.1.3 
Acute Renal Failure 
Renal failure is a relatively common problem in patients with multiple myeloma 
(Dimopoulos et al, 2016; Bladé and Rosiñol, 2005).  Acute renal failure occurs most 
often in patients with multiple myeloma who have high rates of production and excretion 
of immunoglobulin (Ig)-free light chains, which may be toxic to the basement membranes 
of the glomeruli and/or the renal tubules and form obstructing tubular casts, particularly if 
the patient is dehydrated (Dimopoulos et al, 2016; Sanders and Booker, 1992). 
Incidence of acute renal failure in ASPIRE was as follows: all grades: KRd: 9.2%, Rd: 
7.7%; serious adverse events: KRd: 2.6%, Rd: 1.8%; grade ≥ 3 adverse events: 
KRd: 3.8%, Rd: 3.3%.  Most of the acute renal failure adverse events (all grades) were 
resolved (KRd: 6.1%, Rd: 5.7%) or stabilized/not resolving (KRd: 2.8%, Rd: 1.8%) or 
resolved with sequelae (KRd: 0.3%, Rd: 0%).  No fatal outcomes were reported for the 
KRd group; in the Rd group, fatal outcomes were reported for 0.3% of the subjects.  
Acute renal failure adverse events (all grades) leading to discontinuation of any 
investigational product were reported for 0.5% subjects in the KRd group and 1.0% in 
the Rd group.     
The incidence of acute renal failure adverse events in A.R.R.O.W was as follows: all 
grades: Kd 20/70 mg/m2 once-weekly: 7.1%, Kd 20/27 mg/m2 twice-weekly: 6.8%, 
serious adverse events: Kd 20/70 mg/m2 once-weekly: 4.6%, Kd 20/27 mg/m2 
twice-weekly:  5.1%; grade ≥ 3 adverse events: Kd 20/70 mg/m2 once-weekly: 3.8%, 
Kd 20/27 mg/m2 twice-weekly: 5.5%. Adverse event outcomes were reported for serious 
adverse events only in A.R.R.O.W.  All of the acute renal failure serious adverse events 
were resolved (Kd 20/70 mg/m2 once-weekly: 3.8%, Kd 20/27 mg/m2 twice-weekly:  
3.8%) or not resolved (Kd 20/70 mg/m2 once-weekly: 0.8%, Kd 20/27 mg/m2  


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twice-weekly: 1.3%).  None were reported as fatal or unknown in either treatment group.  
Acute renal failure adverse events (all grades) leading to discontinuation of any 
investigational product were reported for 2.1% subjects in the Kd 20/70 mg/m2 
once-weekly and Kd 20/27 mg/m2 twice-weekly groups, each.     
Acute renal failure was reported more frequently in patients with advanced RRMM who 
received carfilzomib monotherapy.  The incidence was increased in patients with a 
decrease in estimated creatinine clearance, calculated using Cockcroft and Gault 
equation, prior to receiving carfilzomib.  Renal function should be monitored with regular 
measurement of the serum creatinine and/or estimated creatinine clearance.  Reduce or 
stop dose as described in the dose modification Section 7.4.   
4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
compare efficacy of 
56 mg/m2 carfilzomib administered 
once-weekly in combination with 
lenalidomide and dexamethasone 
(KRd 56 mg/m2) to 
27 mg/m2 carfilzomib administered 
twice-weekly in combination with 
lenalidomide and dexamethasone 
(KRd 27 mg/m2) in subjects with 
relapsed or refractory multiple 
myeloma (RRMM) with 1 to 3 prior 
lines of therapy 
 
overall response, defined as the best 
overall response of stringent complete 
response [sCR], complete response 
[CR], very good partial response 
[VGPR], and partial response [PR] per 
International Myeloma Working Group 
Uniform Response Criteria 
[IMWG-URC] over the duration of the 
study 
Key Secondary 
 
compare progression-free survival 
(PFS) between treatment arms 
 
PFS over the duration of the study 
 
compare patient-reported 
convenience with carfilzomib-dosing 
schedule between treatment arms 
 
convenience as measured by the 
Patient-reported Convenience With 
Carfilzomib-dosing Schedule Question 
after cycle 4 of treatment 
Secondary 
 
describe safety and tolerability in 
treatment arms  
 
incidence of treatment-emergent 
adverse events  
 
compare additional efficacy 
parameters between treatment arms  
 
time to response (TTR)  
 
duration of response (DOR)  
 
time to progression (TTP)  


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Objectives 
Endpoints 
 
compare overall survival (OS) 
between treatment arms 
 
OS over the duration of the study 
 
compare rate of minimal residual 
disease negative (MRD[-]) in bone 
marrow aspirates between treatment 
arms  
 
MRD[-]CR, defined as achievement of 
CR or better by Independent Review 
Committee (IRC) per IMWG-URC and 
achievement of MRD negativity as 
assessed by next-generation 
sequencing method at a 10-5 
threshold over the duration of the 
study 
 
MRD[-] status at 12 months, defined 
as achievement of MRD negativity at 
12 months (± 4 weeks) from 
randomization, as assessed by 
next-generation sequencing method 
at a 10-5 threshold  
Secondary (continued) 
 
compare patient-reported physical 
functioning and role functioning 
between treatment arms 
 
physical functioning and role 
functioning over time as measured by 
the Physical Functioning and Role 
Functioning scales of the European 
Organization for Research and 
Treatment of Cancer Quality-of-life 
Questionnaire Core 30 
(EORTC QLQ-C30) over the duration 
of the study 
 
compare patient-reported treatment 
satisfaction between treatment arms 
 
treatment satisfaction as measured by 
the Satisfaction With Therapy (SWT) 
scale of the Cancer Therapy 
Satisfaction Questionnaire (CTSQ) 
after cycle 4 of treatment 
  


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Exploratory 
Objectives 
Endpoints 


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Exploratory 
Objectives 
Endpoints 
4.2 
Hypotheses 
Once-weekly KRd 56 mg/m2 is non-inferior in terms of efficacy when compared with 
twice-weekly KRd 27 mg/m2.   
5. 
Study Design 
5.1 
Overall Design 
This is a phase 3, multicenter, open-label, randomized study in subjects with RRMM who 
have received 1 to 3 prior therapies.  The study will consist of a screening period of up to 
28 days, a treatment duration of up to 12 cycles of 28 days, and a 30-day safety 
follow-up period.    
Subjects will receive the study drug(s) determined by randomization for a maximum of 
12 cycles.  No crossover between the treatment arms is allowed.  After discontinuation 
of study drug(s) subjects will have a safety follow-up visit 30 (+3) days after the last dose 
of all study drug(s).  After end of study, subjects may continue treatment per local 
standard of care at the discretion of the investigator.   
All subjects will be assessed for multiple myeloma disease response according to the 
IMWG-URC (Section 12.11) every 28 ± 7 days from cycle 1 day 1 through the end of 
cycle 12 or disease progression until death, loss to follow-up, withdrawal of full , or until 
first subsequent antimyeloma treatment consent (whichever occurs first), regardless of 
cycle duration, dose delays or treatment discontinuation. 
Subjects who end study drug(s) before completing 12 cycles without confirmed 
progressive disease (PD) are required to complete disease response assessments and 
report new antimyeloma treatment every 28 ± 7 days until 12 months after 
randomization, first subsequent antimyeloma treatment, death, loss to follow-up, 
withdrawal of full consent, or confirmed PD, whichever comes first.  All subjects with 


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confirmed disease progression within 12 months of randomization will be followed for 
survival every 28  7 days until 12 months after randomization, death, loss to follow-up, 
or withdrawal of full consent, whichever occurs first. 
The disease assessment schedule is independent of treatment schedules.   
Subjects will be randomized in a 1:1 ratio to 1 of 2 arms: 
 
Arm 1:  KRd using once-weekly carfilzomib 56 mg/m2  
 
Arm 2:  KRd using twice-weekly carfilzomib 27 mg/m2  
Randomization will be performed using an interactive voice/web response system 
(IxRS).  Subjects will be stratified based on the following criteria:  original (not revised) 
International Staging System (ISS) stage at the time of study entry (stage 1 or 2 vs stage 
3), prior lenalidomide treatment (yes vs no), prior PI treatment (yes vs no), prior 
anti-CD38 exposure (yes vs no).   
All subjects enrolled will have pharmacokinetic samples assessed.  Approximately 
15 subjects in each arm will be invited to participate in the intensive pharmacokinetics 
(PK)/pharmacodynamics (PDn) substudy at selected sites.  Sparse PK samples will be 
collected from the rest of the subjects, eg, subjects who do not consent to participate in 
the intensive PK/PDn substudy.  See Sections 9.2.5 and 9.2.6 for more details. 
An independent data monitoring committee (DMC) will be convened for this study and 
will act in an advisory capacity to the sponsor with respect to safeguarding the interests 
of study subjects, assessing interim data, monitoring the overall conduct of the study, 
and providing with recommendations relating to continuing, modifying, or stopping the 
study based on these findings (International Council for Harmonisation Good Clinical 
Practice [ICH GCP 5.5.2]).  Details of the DMC will be described in the DMC Charter.  
The initial assessment from this committee will be planned after 30 subjects 
(approximately 15 for the experimental arm and 15 for the control arm) have been 
enrolled and have finished the first cycle of treatment to ensure safety of all arms.  
A provision will be made allowing an early follow-up DMC meeting to be decided at the 
time of the initial assessment.  The DMC will meet approximately every 6 months to 
review safety data on a regular basis, and once to review the efficacy data for futility.  
The interim analysis for futility is planned to occur when the first 230 subjects have been 
randomized and had a best overall response (BOR) assessed by the date when 
treatment was completed, confirmed PD or death occurred, subject was lost to follow-up, 
withdrew full consent, or started new therapy, whichever occurred first.   


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The individual subject disease response and disease progression for this study will be 
independently assessed by an Independent Review Committee (IRC) in accordance with 
the IMWG-URC (Section 12.11).  The membership criteria and operational details of the 
IRC will be described in the IRC Charter.  The IRC will centrally review the  
disease-related tests and assessments (Section 9.2.2) to evaluate disease progressions 
and responses without the knowledge of randomization assignments or Investigator’s 
disease assessments.  The IRC assessment will be used for the primary analysis of 
efficacy endpoints except for MRD rate and COA endpoints.    
The overall study design is outlined in the study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
Approximately 460 subjects will be enrolled in the study, with approximately 230 subjects 
per arm. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 10.1. 
5.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
5.2.2 
Number of Sites 
Approximately 100 investigative sites in North America, Europe, and Asia, including 
Japan are planned for inclusion in the study.  Sites that do not enroll subjects within 
3 months of site initiation may be closed.  
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 across all sites 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. 
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). 


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End of Study:  The end of study 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, long-term follow-up), as 
applicable.     
5.3.2 
Study Duration for Subjects 
The duration of screening is up to 28 days, and the duration of treatment for an 
individual subject is anticipated to be 12 cycles (or approximately 12 months from 
randomization), followed by safety follow-up visit that occurs 30 (+3) days after the last 
dose of all study drug(s).  Following 12 cycles and the safety follow-up visit the study is 
completed for that subject. 
The total study duration for an individual subject is estimated to be approximately 
14 months.  If a subject experiences treatment delays requiring in excess of 14 months 
to complete all 12 cycles the investigator must contact the medical monitor to discuss in 
order to approve treatment continuation. 
5.4 
Justification for Investigational Product Dose 
The carfilzomib dose (56 mg/m2) in the once-weekly KRd arm is based on the objective 
to evaluate the benefit-risk profile of a weekly KRd dose regimen that will address the 
patient need for more convenient dosing schedule and to establish non-inferiority with 
the on-label twice-weekly KRd 27 mg/m2 dose regimen.  
Once-weekly carfilzomib has been evaluated in clinical studies at doses as high as 
88 mg/m2 and data have shown that weekly carfilzomib in combination with 
dexamethasone (Kd) can be used safely and effectively in patients with RRMM 
(Berenson et al, 2016).  
In the phase 1/2 CHAMPION1 study, the maximum tolerated dose of carfilzomib 
administered once-weekly with dexamethasone was 70 mg/m2 and an overall response 
rate of 77% was observed at this dose (Berenson et al, 2016).  The randomized phase 3 
A.R.R.O.W. study demonstrated that treatment with carfilzomib (70 mg/m2) administered 
once-weekly with dexamethasone led to an improvement in PFS compared with 
carfilzomib (27 mg/m2) administered twice-weekly with dexamethasone (11.2 vs 
7.6 months; HR = 0.69; 95% CI, 0.54, 0.88) (Mateos et al, 2018).  
The safety experience from 56 subjects with RRMM with weekly KRd 56 mg/m2 (n = 10) 
or 70 mg/m2 (n= 46) in Study CFZ013 (NCT02335983) has not identified any safety 
concerns which would preclude the investigation of KRd 56 mg/m2 weekly in this study.  


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The subject incidence of grade ≥ 3 treatment-emergent adverse events was 70.0% in 
the KRd 56 mg/m2 group and 69.6% in the KRd 70 mg/m2 group.  Grade ≥ 3 adverse 
events reported in more than 2 patients were thrombocytopenia (56 mg/m2, n = 2; 
70 mg/m2, n = 4), neutropenia (56 mg/m2, n = 1; 70 mg/m2, n = 4), anemia (56 mg/m2, 
n = 2; 70 mg/m2, n = 3), pneumonia (70 mg/m2, n = 4), decreased platelet count 
(56 mg/m2, n = 1; 70 mg/m2, n = 3), decreased neutrophil count (56 mg/m2, n = 2; 
70 mg/m2, n = 2), hypertension (56 mg/m2, n = 1; 70 mg/m2, n = 3), and 
hypophosphatemia (70 mg/m2, n = 4).  There were 3 deaths in the KRd 70 mg/m2 group 
(1 each due to cardiac arrest, cardiac disorder, and disease progression).  No deaths 
occurred in the KRd 56 mg/m2 group (Biran et al, 2018).  The median weekly dose of 
carfilzomib was 53.2 mg/m2 for subjects administered 20/56 mg/m2 and 62.4 mg/m2 for 
subjects administered 20/70 mg/m2.  The median relative dose intensity of carfilzomib 
was 90.7 for subjects administered 20/56 mg/m2 and 88.2 for subjects administered 
20/70 mg/m2.  The median weekly dose and the relative dose intensity suggest that 
20/56 mg/m2 weekly dose was tolerable.     
Available efficacy results indicated similar efficacy (as determined by ORR) with either 
KRd 56 mg/m2 or KRd 70 mg/m2 (90.0% versus 89.1%, respectively) to the effect 
previously reported for twice-weekly KRd (27 mg/m2) in the randomized phase 3 
ASPIRE study (Biran et al, 2018).  In ASPIRE, KRd 27 mg/m2 was compared with Rd 
alone in a similar patient population proposed in this phase 3 study (Study 20180015).  
The carfilzomib arm proved superior at the first interim analysis for efficacy reducing the 
risk of progression or death by 31% (median PFS [KRd vs Rd]:  26.3 months vs 
17.6 months).  The ORR was 87.1% in the KRd versus 66.7% in the Rd arm.  The OS 
benefit seen at the final analysis was 8 months (median OS was 48.3 months for KRd 
arm vs 40.4 months for Rd arm; Siegel et al, 2018; Stewart et al, 2015). 
Given these data, this phase 3 study will evaluate the 56 mg/m2 once-weekly dose 
schedule for carfilzomib in combination with lenalidomide and dexamethasone to 
establish non-inferiority to KRd 27 mg/m2 twice-weekly.   
5.5 
Patient Input on Study Design 
No patient input was obtained for this study design.   
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).   


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Eligibility criteria will be evaluated during screening.  Eligibility labs are to be confirmed 
by central laboratory prior to enrollment. 
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  
All screening laboratory assessments must done in accordance with Table 12-1.  Local 
laboratory assessments may not be used in place of central laboratory assessments 
where required. 
Subjects are eligible to be included in the study only if all the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities or procedures or subject’s legally acceptable representative has 
provided informed consent prior to any study-specific activities/procedures being 
initiated when the subject has any kind of condition that, in the opinion of the 
Investigator, may compromise the ability of the subject to give written informed 
consent. 
102 
Males or females ≥ 18 years of age. 
103 
Subject has multiple myeloma with documented relapse or progression after 
most recent myeloma treatment.  Subjects refractory to the most recent line of 
therapy are eligible, unless last treatment contained PI or lenalidomide and 
dexamethasone. 
 
Refractory is defined as disease that is nonresponsive or progresses within 
60 days of last therapy 
104 
Subjects must have at least PR to at least 1 line of prior therapy.  
105 
Subjects must have received at least 1 but not more than 3 prior lines of therapy 
for multiple myeloma (induction therapy followed by stem cell transplant and 
consolidation maintenance therapy will be considered as 1 line of therapy).  See 
Section 12.8 for guidelines for documenting prior treatment.  
106 
Prior therapy with a PI is allowed if the patient achieved at least a PR to most 
recent treatment with a PI, did not relapse within 60 days of discontinuation of the 
PI and the PI was not removed due to toxicity.  A history of prior neuropathy is 
permitted if this was not grade 3, grade 4 or grade 2 with pain and if not resolved 
within the 14 days before enrollment, is less than or equal to grade 2 without 
pain. 
107 
Prior therapy with a lenalidomide and dexamethasone containing regimen is 
allowed if the patient achieved at least a PR to most recent treatment with 
lenalidomide and dexamethasone, did not progress within the first 3 months of 
initiating a lenalidomide and dexamethasone containing treatment or relapse 
within 60 days of discontinuation of lenalidomide and dexamethasone containing 
treatment and treatment was not discontinued due to toxicity.  A history of prior 


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neuropathy is permitted if this was not grade 3, grade 4 or grade 2 with pain and 
if not resolved within the 14 days before enrollment, is less than or equal to 
grade 2 without pain.  Patients are permitted to have received single agent 
lenalidomide as maintenance therapy within 60 days of enrollment. 
108 
Measurable disease with at least 1 of the following assessed within 28 days prior 
to randomization: 
 
IgG multiple myeloma: serum monoclonal protein (M-protein) level ≥ 1.0 g/dL 
 
IgA, IgD, IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL 
 
urine M-protein ≥ 200 mg per 24 hours 
 
in subjects without measurable serum or urine M-protein, serum-free light 
chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum 
kappa lambda ratio  
109 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of  2 
(see Section 12.9). 
6.2 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
Disease-related 
201 
Waldenström macroglobulinemia. 
202 
Multiple myeloma of IgM subtype. 
203 
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes). 
204 
Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard 
differential).  
205 
Primary amyloidosis (patients with multiple myeloma with asymptomatic 
deposition of amyloid plaques found on biopsy would be eligible if all other 
criteria are met). 
206 
Myelodysplastic syndrome.  
Other Medical Conditions 
207 
History of other malignancy within the past 5 years, with the following exceptions: 
 
Malignancy treated with curative intent and with no known active disease 
present for ≥ 3 years 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 
 
Adequately treated breast ductal carcinoma in situ without evidence of 
disease 
 
Prostatic intraepithelial neoplasia without evidence of prostate cancer 


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 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ 
 
Treated medullary or papillary thyroid cancer 
 
Similar neoplastic conditions with an expectation of > 95% 5-year 
disease-free survival 
208 
Known HIV infection, hepatitis C infection (subjects with hepatitis C that achieve 
a sustained virologic response after antiviral therapy are allowed), or hepatitis B 
infection (subjects with hepatitis B surface antigen or core antibody that achieve 
sustained virologic response with antiviral therapy are permitted with a 
requirement for regular monitoring for reactivation for the duration of treatment on 
the study).   
209 
Ongoing graft-vs-host disease. 
210 
Acute active infection requiring systemic antibiotics, antifungal, antiviral (except 
antiviral therapy directed at hepatitis B) agents within 14 days prior to 
randomization. 
211 
Known cirrhosis. 
212 
Significant neuropathy (grades 3 to 4, or grade 2 with pain) within 14 days prior 
to randomization. 
213 
Subjects with pleural effusions requiring thoracentesis or ascites requiring 
paracentesis within 14 days prior to randomization. 
Cardiopulmonary Conditions  
214 
Uncontrolled hypertension, defined as a subject whose blood pressure is greater 
than or equal to 160 mmHg systolic or greater than or equal to 100 mmHg 
diastolic when taken in accordance with the European Society of 
Hypertension/European Society of Cardiology 2018 guidelines (Section 12.10; 
Williams et al, 2018). 
215 
Active congestive heart failure (New York Heart Association Class III to IV), 
symptomatic ischemia, uncontrolled arrhythmias, screening ECG with corrected 
QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction 
within 4 months prior to randomization.   
216 
Intolerance to hydration due to pre-existing pulmonary or cardiac impairment. 
217 
History of interstitial lung disease or ongoing interstitial lung disease. 
Prior/Concomitant Therapy 
218 
Immunotherapy within 28 days prior to randomization. 
219 
Monoclonal antibody therapy within 28 days prior to randomization. 
220 
Chemotherapy with approved anticancer therapeutic within 28 days prior to 
randomization. 
221 
Glucocorticoid therapy within 14 days prior to randomization that exceeds a 
cumulative dose of 160 mg of dexamethasone or equivalent dose of other 
corticosteroids. 


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222 
Focal radiation therapy within 7 days prior to randomization.  Radiation therapy to 
an extended field involving a significant volume of bone marrow within 28 days 
prior to randomization (ie, prior radiation must have been to < 30% of the bone 
marrow). 
223 
Major surgery (except kyphoplasty) within 28 days prior to randomization. 
224 
Autologous or allogeneic stem cell transplant within 90 days prior to 
randomization. 
225 
Contraindication or intolerance to lenalidomide, dexamethasone, or carfilzomib. 
226 
Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize 
carfilzomib). 
227 
Subject has known hypersensitivity to any of the products or components to be 
administered during dosing, including hypersensitivity to antiviral drugs.  
Prior/Concurrent Clinical Study Experience 
228 
Currently receiving treatment in another investigational device or drug study, or 
< 28 days since ending treatment on another investigational device or drug 
study(ies).   
Organ Function Assessments  
229 
Hepatic dysfunction within 28 days prior to randomization:  
 
direct bilirubin  1.5x the upper limit of normal (ULN) 
 
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
 2.5 x ULN  
230 
Left ventricular ejection fraction < 40% assessed by transthoracic 
echocardiogram (ECHO).  
231 
Absolute neutrophil count (ANC) < 1 x 109/L within 28 days prior to 
randomization.  Screening ANC should be independent of growth factor support 
for ≥ 1 week. 
232 
Hemoglobin < 80 g/L within 28 days prior to randomization.  Use of erythropoietic 
stimulating factors and red blood cell (RBC) transfusions per institutional 
guidelines is allowed; however, most recent RBC transfusion must not have been 
performed within 7 days prior to obtaining screening hemoglobin. 
233 
Platelet count < 50 x 109/L (≤ 30 x 109/L if myeloma involvement in the bone 
marrow is > 50%) within 28 days prior to randomization.  Subjects should not 
have received platelet transfusions for at least 1 week prior to obtaining the 
screening platelet count. 
244 
Calculated or measured creatinine clearance < 30 mL/min (calculation must be 
based on the Cockcroft and Gault formula) within 28 days prior to randomization. 
Other Exclusions 
235 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 30 days after the last dose of 
all study drug(s).  (Females of childbearing potential should only be included in 


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the study after a confirmed menstrual period and a negative highly sensitive urine 
or serum pregnancy test).     
236 
Female subjects of childbearing potential unwilling to use 2 methods of 
contraception (1 highly effective form of contraception and 1 additional effective 
contraceptive method) for at least 28 days before starting study drug(s), during 
treatment, during treatment interruptions, and for an additional 30 days after the 
last dose of all study drug(s).  Refer to Section 12.5 for additional contraceptive 
information. 
237 
Female subjects of childbearing potential with a positive pregnancy test 
assessed at screening (by a highly sensitive serum pregnancy test 10 to 14 days 
prior to first dose of study drugs).    
238 
Male subjects with a female partner of childbearing potential who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or use a 
condom with spermicide during treatment and for an additional 90 days after the 
last dose of all study drug(s), even if they have undergone a successful 
vasectomy.  Refer to Section 12.5 for additional contraceptive information. 
239 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom with spermicide during treatment and for an additional 90 days 
after the last dose of all study drug(s). 
240 
Male subjects unwilling to abstain from donating blood, semen, or sperm during 
treatment and for an additional 90 days after the last dose of all study drug(s). 
241 
Females subjects unwilling to abstain from donating blood during treatment and 
for an additional 90 days after the last dose of all study drug(s). 
242 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study assessments (including 
COA) to the best of the subject and investigator’s knowledge. 
243 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, 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). 
The subject or the subject’s legally acceptable representative 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). 


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Each subject who enters into the screening period for the study (defined as the point 
when 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 via Interactive Voice/Web Response System 
(IxRS).  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 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.  This number will not necessarily be the same as the randomization number 
assigned for the study.   
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 demographics, screen failure details, eligibility 
criteria, and any serious adverse events.  If a serious adverse event is observed from 
the time informed consent is signed up to the point of screen failure, then serious 
adverse events, medical history, and concomitant medications will also be collected.   
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened once.  Refer to Section 9.1.1.  
Subjects who experience a technical failure of central laboratory samples at screening 
(for example sample is lost or damaged in transit, or otherwise cannot be analyzed) will 
not be considered a screen failure. Central lab samples may be retested during 
screening in such cases, subject to the screening window not being exceeded.   
7. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, combination products, 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. 


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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 below. 
7.1 
Treatment Procedures 
7.1.1 
Investigational Product: Carfilzomib 
7.1.1.1 
Dosage Formulation 
Carfilzomib will be manufactured and packaged by Amgen and distributed using Amgen 
clinical study drug distribution procedures. 
Carfilzomib is supplied as a sterile, lyophilized, white to off-white powder ready for 
reconstitution.  It is supplied for single use in 50 mL Type 1 glass vials containing 60 mg 
of carfilzomib drug product with an elastomeric stopper and flip-off lid.    
7.1.1.2 
Dosage, Administration, and Schedule 
Hematology and chemistry samples will be repeated within 3 days prior to cycle 1 day 1 
and reviewed by the investigator before first dose. 
Baseline laboratories for SPEP/UPEP/SIFE/UIFE/SFLC, will also be collected and 
checked by the investigator or treating physician before treatment is administered on 
cycle 1 day 1 if the screening laboratory assessments were not performed within 14 
days of randomization. 
Both arms: 
Each subject’s first dose of carfilzomib will be calculated based upon baseline body 
surface area (BSA) using the Mosteller formula.  In subjects with BSA > 2.2 m2, the dose 
should be capped based on a BSA of 2.2 m2.  The dose for each subject should not be 
revised unless the subject has a change in body weight of > 20% (gain or loss) in which 
case the BSA should be recalculated.  Carfilzomib dose is to be recalculated using the 
updated BSA and applied until such time that any future weight change requires further 
BSA recalculation.   The dose can also be modified in response to toxicity following the 
dose modification guideline tables using the most current BSA if this has been 
recalculated since the first cycle due to weight change.  
Carfilzomib will be administered as an IV infusion.  Mechanical infusion pumps are 
recommended, but gravity-dependent infusions are permitted if the infusion duration can 
be reliably maintained.   


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The planned dose (mg/m2), quantity administered (mg), start date/time, stop date/time, 
reason for change in planned dose, reason for dose change/withheld, reason for dose 
delay, reason for dose interruption and package lot number of carfilzomib are to be 
recorded on each subject's eCRF. 
Arm 1 (once-weekly KRd 56 mg/m2): 
Carfilzomib will be administered once-weekly IV as a 30 ± 5 minute infusion using an 
infusion pump on days 1, 8, and 15 of each 28-day cycle.  The dose will be 20 mg/m2 on 
day 1 of the first cycle and 56 mg/m2 beginning with day 8 of cycle 1 and thereafter.  All 
carfilzomib doses should be administered on the scheduled day  2 days, and the day 8 
and 15 doses should have at least a 5-day treatment-free interval.  Dose delays > 2 
days are only permitted during the start of a new cycle. 
Arm 2 (twice-weekly KRd 27 mg/m2): 
Carfilzomib will be administered twice-weekly IV as a 10 minute ± 5 minute infusion 
using an infusion pump on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle.  The dose 
will be 20 mg/m2 on days 1 and 2 of the first cycle and 27 mg/m2 beginning with day 8 of 
cycle 1 and thereafter.   
Every effort should be made to maintain the days 1, 2, 8, 9, 15, and 16 of 28-day 
schedule.  If this is not possible, then priority should be to maintain consecutive 
dosing days.  For example, if day 1 of a new cycle is started 2 days later than originally 
scheduled, the entire cycle should shift by 2 days, such that the new days 1, 2, 8, 9, 15, 
and 16 of the next cycle are maintained.  There must always be at least 5 days between 
the second dose of 1 week and the first dose of the following week (ie, between days 2 
and 8, and days 9 and 15).  Mid-cycle doses that are missed should not be made up 
unless these parameters are maintained. 
7.1.1.3 
Intravenous Prehydration 
Subjects may receive IV prehydration (normal saline or other appropriate IV fluid) prior to 
each carfilzomib infusion during cycle 1.  Investigators must consider IV prehydration in 
subjects at high-risk for tumor lysis or renal toxicity.  All subjects must be monitored for 
fluid overload and hydration should be tailored to individual needs  
Thereafter, carfilzomib prehydration may only be administered if the subject’s condition 
and/or risk factors require it.  The total volume of prehydration and the indication will be 
recorded on the Concomitant Medications eCRF.  


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Carfilzomib infusion must occur at a facility capable of managing hypersensitivity 
reactions.   
7.1.1.4 
Starting Dose in Hepatic Insufficiency 
For subjects with baseline chronic hepatic impairment (mild, moderate), reduce the 
starting and subsequent doses of carfilzomib by 25% (Brown et al, 2017): 
 
for once-weekly arm: 15 mg/m2 day 1 of cycle 1 and 42 mg/m2 day 8 of cycle 1 and 
thereafter; 
 
for twice-weekly arm: 15 mg/m2 day 1 and 2 of cycle 1 and 20 mg/m2 day 8 of cycle 1 
and thereafter.  
If hepatic function returns to normal, the dose may be re-escalated to 56 mg/m2 (for 
once-weekly arm) and 27 mg/m2 (for twice-weekly arm) after the first cycle.  For dose 
modification due to subsequent changes in hepatic function, refer to Section 7.4.1.1.2. 
Mild and moderate hepatic dysfunction is defined as: 
 
Mild:  
1.0 x ULN < bilirubin ≤ 1.5 x ULN; or AST > ULN with bilirubin ≤ ULN 
 
Moderate: 1.5 x ULN < bilirubin < 3 x ULN with any AST     
7.1.2 
Non-investigational Products 
7.1.2.1 
Dexamethasone:  Dosage, Administration, and Schedule 
Dexamethasone, a non-Amgen non-investigational product, will also be used in this 
study.  Dexamethasone should be taken weekly orally or by IV infusion at a dose of 
40 mg.  When dexamethasone is administered on the same day as carfilzomib, it should 
be started and completed within 4 hours of the start of carfilzomib infusion.  A 30 minute 
interval between the end of the dexamethasone infusion and the start of the carfilzomib 
infusion is recommended.  All doses should be administered on the scheduled days 
 2 days. 
The planned dose, quantity administered, start date/time, stop date/time, route, reason 
for dose change/withheld, reason for dose delay, reason for dose interruption are to be 
recorded on each subject’s eCRF.   
7.1.2.2 
Lenalidomide 
7.1.2.2.1 
Prescribing Requirements 
Lenalidomide, a non-Amgen non-investigational product, will also be used in this study.   
Within the United States, lenalidomide should be administered in accordance with the 
REVLIMID REMS program of Celgene Corporation (http://www.revlimidrems.com/.)  All 
physicians who prescribe lenalidomide for research subjects enrolled into this study, and 


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all research subjects enrolled on this study, must be registered in and comply with all 
requirements of the REVLIMID REMS program.   
Females of childbearing potential (FCBP) must agree to monitoring for pregnancy.  In 
addition, males and FCBP are subject to certain restrictions as detailed in Section 12.5 
while receiving lenalidomide. 
Outside the United States, all investigators and subjects must adhere to the 
requirements of the lenalidomide restricted distribution program in effect in their local 
country.   
7.1.2.2.2 
Dosage, Administration, and Schedule 
In subjects with normal renal function, lenalidomide will be taken once-daily orally on 
days 1 to 21 of each cycle at a dose of 25 mg.  In subjects with renal impairment (mild to 
moderate or severe), please refer to the regional product label.  Lenalidomide should be 
taken at home by the subject at about the same time each day.  Lenalidomide capsules 
should be swallowed whole with water.  The capsules should not be opened, broken, or 
chewed.  If a planned dose is missed, it should be taken as soon as possible within the 
same calendar day and with a return to the regular schedule the following day.  If a 
planned dose is missed for more than a calendar day, subjects should not make up 
doses, but should resume the dosing regimen as per schedule.  Dose modifications are 
permitted in response to toxicity following the dose modification guideline tables. 
The planned dose, quantity administered, start date, and reason for dose change are to 
be recorded on each subject’s eCRF.   
7.1.3 
Medical Devices 
No investigational medical devices will be used.   
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
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, antiviral prophylaxis, thromboprophylaxis, 
tumor lysis prophylaxis, proton pump inhibitor, bisphosphonate therapy, and prophylaxis 


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for Pneumocystis jirovenci pneumonia, 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 
Antiviral Prophylaxis 
An antiviral is a required concomitant medication for the duration of treatment with 
carfilzomib.  Acyclovir (eg, 400 mg orally 3 times a day, or 800 mg orally 2 times a day or 
per institutional standards), famcyclovir (eg, 125 mg orally given 3 days, twice a day or 
per institutional standards), or valacyclovir (eg, 500 mg orally, twice a day or per 
institutional standards), dose adjustments for renal function where appropriate, initiated 
within 1 week of the first dose of carfilzomib and should continue for the duration of 
treatment with carfilzomib.  
7.1.4.2 
Prophylaxis for Hepatitis B Reactivation 
Hepatitis B virus (HBV) reactivation prophylaxis should be considered for patients at risk 
(ie, patients tested positive on serology or had a prior history of HBV infection) as per 
institutional standards. 
7.1.4.3 
Thromboprophylaxis 
It is strongly recommended that all subjects receive an anticoagulant (eg, low molecular 
weight heparin, direct oral anti-coagulant, warfarin, enteric-coated aspirin at standard 
prophylactic dose or other anticoagulant or antiplatelet medication).  Additional or 
secondary thromboprophylaxis medication is strongly recommended in subjects with 
elevated risk of thrombosis, based on an individual benefit/risk assessment (Li et al, 
2017). 
7.1.4.4 
Tumor Lysis Syndrome Prophylaxis 
An approved uric acid-lowering agent (eg, allopurinol) in subjects at high-risk for tumor 
lysis syndrome (TLS) due to high tumor burden may be prescribed at the investigator’s 
discretion, according to the package insert. 
Subjects should be well hydrated to reduce the risk of TLS and decline in renal function; 
refer to the current Carfilzomib IB for safety guidance regarding TLS. 
7.1.4.5 
Proton-pump Inhibitor 
Proton-pump inhibitor (omeprazole or equivalent) is required while on dexamethasone. 
7.1.4.6 
Bisphosphonate or Monoclonal Antibody Therapy 
Concomitant therapy should be administered to all subjects with evidence of lytic 
destruction of bone or with osteopenia (Gralow et al; 2013; Terpos et al, 2013) unless 


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contraindicated.  Commercially available therapies are preferred when available and 
should be used for subjects with osteolytic or osteopenic myelomatous bone disease 
according to the manufacturer’s recommendations, as described in the prescribing 
information.    
Subjects who are using bisphosphonate or monoclonal antibody therapy when they 
enter the study should continue the same treatment.  Subjects with evidence of lytic 
destruction of bone or with osteopenia who are not using a bisphosphonate or 
monoclonal antibody therapy at the time of randomization should start therapy as soon 
as possible during cycle 1 or 2 of treatment.  Investigators should not start 
bisphosphonate or monoclonal antibody therapy during the study, unless it has been 
agreed with the sponsor that there is no sign of disease progression. 
7.1.4.7 
Prophylaxis for Pneumocystis Jirovenci  
Pneumocystis jirovenci pneumonia prophylaxis should be considered, as per institutional 
guidelines while on dexamethasone.   
7.1.5 
Other Treatment Procedures 
No other treatment procedures are required.     
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, combination product, or device after it is released for distribution 
to market or clinic by either (1) Amgen or (2) distributors or partners for whom Amgen 
manufactures the material.  This includes all components distributed with the drug, such 
as packaging drug containers, delivery systems, labeling, and inserts. 
This includes any investigational products provisioned and/or repackaged/modified by 
Amgen: carfilzomib.   
Any product complaint(s) associated with an investigational product(s) or  
non-investigational products(s) 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 
7.1.7.1 
Anticancer Therapeutic or Radiation 
Concurrent therapy with a marketed or investigational anticancer therapeutic or radiation 
to large marrow reserves for either a palliative or therapeutic intent is excluded.  


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7.1.7.2 
Corticosteroids 
Long-term corticosteroids for nonmalignant conditions (eg, asthma, inflammatory bowel 
disease) equivalent to a dexamethasone dose > 4.0 mg/day or prednisone > 20 mg/day 
are not permitted.  Corticosteroids given short-term (up to 2 weeks) for non-malignant 
conditions are permitted provided that the cumulative dose is less than 40 mg per week 
dexamethasone equivalent.  Medical monitor should be contacted if short-term 
corticosteroid use is required > 2 weeks or at cumulative dose of more than 40 mg 
dexamethasone equivalent. 
7.1.7.3 
Plasmapheresis 
Plasmapheresis is not permitted at any time while the subject is receiving study 
treatment.  For subjects requiring plasmapheresis while on study treatment, every 
attempt should be made to document disease status by IMWG criteria first.  Study 
treatment must be discontinued.   
7.1.7.4 
Myeloid Growth Factors 
The prophylactic use of myeloid growth factors is prohibited, but they may be used for 
management of neutropenia in accordance with American Society of Clinical Oncology 
Guidelines (Smith et al, 2015). 
7.2 
Method of Treatment Assignment 
Subjects will be randomized in 1:1 allocation ratio to 1 of the 2 treatment arms in an 
open-label manner: 
 
Arm 1:  KRd using once-weekly carfilzomib 56 mg/m2 (days 1, 8, 15; 30 minutes 
[ 5 minutes] IV) 
 
Arm 2:  KRd using twice-weekly carfilzomib 27 mg/m2 (days 1, 2, 8, 9, 15, 16; 
10 minutes [ 5 minutes] IV) 
The randomization will be performed using an IxRS.  The randomization number will be 
provided on the IxRS randomization confirmation document and the randomization date 
is to be documented in the subject’s medical record and on the enrollment eCRF. 
The randomization will be stratified based on the following criteria: 
 
original ISS stage at study entry (stage 1 or 2 vs stage 3)  
 
prior lenalidomide treatment (yes vs no)  
 
prior PI treatment (yes vs no) 
 
prior anti-CD38 exposure (yes vs no)   


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Subjects will receive the treatment determined by randomization for the duration of 
12 cycles or until treatment discontinuation for reasons outlined in Section 8.1.  No 
crossover between the treatment arms will be allowed. 
7.3 
Blinding 
This is an open-label study; blinding procedures are not applicable.   
7.4 
Dose Modification 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.1.1 
Amgen Investigational Product:  Carfilzomib 
Carfilzomib will be discontinued, temporarily delayed, or dosage temporarily reduced, in 
the event of a treatment-related toxicity that, in the opinion of the investigator, warrants 
the discontinuation, temporary delay or dose reduction as indicated in Table 7-2 and 
Table 7-3. Dose reduction levels of carfilzomib for toxicity management of individual 
subjects are provided in Table 7-1.  Subjects that require a dose level reduction and 
tolerate the reduced dose for 1 full cycle may at the discretion of the treating physician 
increase the dose to a prior dose starting with the next cycle except when the dose 
reduction is due to:  pulmonary hypertension, pulmonary toxicity, grade 3 or worse 
cardiac failure, and drug-induced hepatotoxicity.   
Table 7-1.  Dose Decrements for Carfilzomib  
Nominal Dose 
(mg/m2) 
Reduced Carfilzomib Doses (mg/m2) 
Dose -1 
Dose -2 
Dose -3 
Dose -4 
20a, b 
15 
11 
Discontinue 
- 
27 
20 
15 
11 
Discontinue 
56  
45  
36  
27 
20 
 a If dose reduction of carfilzomib is required on cycle 1 day 1 or cycle 1 day 2, the investigator should 
contact the medical monitor to discuss the situation before any additional doses of carfilzomib are 
administered. 
b For subjects with baseline chronic hepatic impairment (mild, moderate), reduce the starting and 
subsequent doses of carfilzomib by 25% (ie, for once-weekly arm: 15 mg/m2 day 1 of cycle 1 and 
42 mg/m2 day 8 of cycle 1 and thereafter; for twice-weekly arm: 15 mg/m2 day 1 and 2 of cycle 1 and 
20 mg/m2 day 8 of cycle 1 and thereafter). 
The subject will be considered on protocol treatment while receiving carfilzomib or 
lenalidomide.  
If day 1 of a cycle is delayed, all subsequent doses within the cycle and also day 1 of 
subsequent cycles should be adjusted accordingly to maintain the 28-day cycle duration.  
However, if a within-cycle dose is delayed, then the dates of the subsequent within-cycle 
doses should not be adjusted.  For within-cycle doses, if administration does not 


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commence within the allowable window of the scheduled administration date, then the 
dose will be considered a missed dose and this missed dose will not be made up.  
Administration may resume at the next planned dosing date.   
If a subject requires interruption of carfilzomib for more than 6 consecutive weeks due to 
unresolved toxicities, the subject must be discontinued permanently from study 
treatment. 
If a subject requires interruption of carfilzomib for more than 6 weeks for reasons other 
than toxicity, medical monitor approval is required prior to resuming treatment.  The 
reason for dose change of carfilzomib is to be recorded on each subject’s eCRF. 
7.4.1.1.1 
Carfilzomib:  Guidelines for Hematologic Toxicity 
Guidelines for carfilzomib dose modification in the event of thrombocytopenia and 
neutropenia are summarized in Table 7-2. 
Table 7-2.  Dose Modification Guidelines for Thrombocytopenia and Neutropenia 
Hematologic toxicity 
Recommended Action 
Thrombocytopenia 
When platelets fall to 
< 30 x 109/L and for each 
subsequent drop to 
< 30 x 109/L 
If platelets 10 to 30 x 109/L 
without evidence of 
bleeding 
 hold 
 restart at previous dose 
when platelets > 30 x 109/L 
If evidence of bleeding or 
platelets < 10 x 109/L 
 hold 
 restart at 1 dose decrement 
when platelets > 30 x 109/L 
Neutropenia 
When ANC falls to 
< 0.75 x 109/L and for each 
subsequent drop to 
< 0.75 x 109/L  
If ANC 0.5 to 0.75 x 109/L 
 continue at full dose 
If ANC < 0.5 x 109/L 
 hold dose 
 resume at 1 dose 
decrement when  
ANC ≥ 0.5 x 109/L 
ANC = absolute neutrophil count. 
7.4.1.1.2 
Carfilzomib:  Guidelines for Nonhematologic Toxicity 
Guidelines for dose modification in the event of nonhematologic toxicities are 
summarized in Table 7-3. 


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Table 7-3.  Dose Modification Guidelines for Nonhematologic Toxicities 
Symptom/Sign/Investigation 
Recommended Action 
Renal Dysfunctiona: 
CrCl ≥ 15 mL/min 
Full dose 
CrCl < 15 mL/min (NCI-CTCAE 
grade 4) 
Hold dose and monitor renal function.  If attributable to 
carfilzomib, resume when renal function has recovered 
to within 25% of baseline; restart at 1 dose level 
reduction.  If not attributable to carfilzomib, dosing may 
be resumed at the discretion of the physician.  If dialysis 
required use the maximal dose of 20 mg/m2 and 
administer carfilzomib after dialysis. 
Chronic dialysis stable for 
≥ 30 days 
Dose may be re-escalated up to full dose as clinically 
tolerated 
Hepatic Dysfunction and Related Investigations 
Mild to moderate liver dysfunction: 
defined as 2 consecutive values, 
at least 28 days apart, of: 
 (1) total bilirubin (> 33% direct) 
> 1x ULN to < 3x ULN 
 OR 
 (2) an elevation of AST and/or 
ALT with normal bilirubin 
25% dose reduction. 
Dose may be re-escalated if liver function tests return to 
normal and drug-induced hepatotoxicity is excluded. 
Grade 3 elevation in ALT and/or 
AST (> 5x ULN) 
Hold carfilzomib until resolution to baseline. 
Monitor any abnormality weekly.  Resume carfilzomib 
with a 25% dose reduction if drug-induced hepatotoxicity 
is excluded. 
Grade 3 elevation in total bilirubin 
Hold carfilzomib until resolution to baseline.  Monitor 
total bilirubin and direct bilirubin weekly. 
Upon resolution of total bilirubin to normal, resume 
carfilzomib dosing with a 25% dose reduction if 
drug-induced hepatotoxicity is excluded. 
Drug-induced hepatotoxicity 
(attributable to carfilzomib) 
Discontinue carfilzomib 
Other Nonhematologic Toxicities 
Tumor lysis syndrome:  3 or more 
of the following: 
 increase in creatinine of ≥ 50% 
 increase in uric acid, of ≥ 50% 
 increase in phosphate of ≥ 50% 
 increase in potassium of ≥ 30% 
 decrease in calcium OR 
 increase in LDH of ≥ 2-fold from 
baseline 
Hold carfilzomib until all abnormalities in serum 
chemistries have resolved; resume at full dose. 
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Table 7-3.  Dose Modification Guidelines for Nonhematologic Toxicities 
Symptom/Sign/Investigation 
Recommended Action 
Congestive heart failure 
Any subject with congestive heart failure, whether or 
not drug-related, must have the dose held until 
resolution or return to baseline.  Appropriate medical 
management should be initiated and continued as 
clinically indicated.  If no resolution after 4 weeks, 
carfilzomib will be permanently discontinued. 
< Grade 3 
Once congestive heart failure resolves or returns to 
baseline, resume at full dose. 
 Grade 3 
Once congestive heart failure resolves or returns to 
baseline, treatment may continue at 1 dose level 
reduction.   
Infection (grade 3 or 4) 
Hold carfilzomib.  Once infection is controlled and 
the subject is without infection-related symptoms, 
and if ANC > 1.0 × 109/L, resume at full dose.  If 
ANC < 1.0 × 109/L, follow hematologic toxicities 
dose reduction guidelines.  
Hepatitis B reactivation 
Hold carfilzomib until infection is adequately 
controlled (see Section 9.2.3.4.3). 
Neuropathy (grade 2 with emergent 
pain, or grade 3) 
Hold carfilzomib until resolved to ≤ grade 2 without 
pain; then resume at 1 dose decrement. 
Neuropathy (grade 4) 
Permanently discontinue carfilzomib. 
Dyspnea (grade ≥ 2) 
Hold carfilzomib until resolution to grade 1 or 
baseline, then resume at 1 dose decrement.  
Investigate cause and record findings.  If caused by 
another adverse event listed in this table, follow 
recommendations for that adverse event. 
Hypertension (SBP > 140 and/or DBP > 90, measured per Appendix 10 in Section 12.10) 
< grade 3 
Continue at same dose and initiate appropriate 
treatment to control hypertension (see Section 12.10 
for guidance) 
Grade ≥ 3 
Hold carfilzomib until resolution to normal or 
baseline.  Initiate appropriate antihypertensive 
therapy prior to resuming carfilzomib at 1 dose 
decrement. 
Pulmonary toxicity: 
Non-infectious interstitial lung 
disease, acute respiratory failure, 
ARDS (≥ grade 3) 
Hold carfilzomib until resolution to grade 1 or 
baseline and restart at 1 dose decrement. 
Pulmonary hypertension (grade ≥ 3) 
Hold carfilzomib until resolution to grade 1 or 
baseline and restart at 1 dose decrement 
Posterior reversible encephalopathy 
syndrome: 
Headaches, altered mental status, 
seizures, visual loss, and hypertension 
If PRES is suspected, hold carfilzomib.  Consider 
evaluation with neuroradiological imaging, 
specifically MRI, for onset of visual or neurological 
symptoms suggestive of PRES.  If PRES is 
confirmed, permanently discontinue carfilzomib.  If 
the diagnosis of PRES is excluded, carfilzomib 
administration may resume at same dose, if clinically 
appropriate.   
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Table 7-3.  Dose Modification Guidelines for Nonhematologic Toxicities 
Symptom/Sign/Investigation 
Recommended Action 
Thrombotic microangiopathy: 
Fever, microangiopathic hemolytic 
anemia, renal failure, 
thrombocytopenia, neurological 
manifestations 
If the diagnosis is suspected, hold carfilzomib and 
manage per standard of care including plasma 
exchange as clinically appropriate.  If TMA is 
confirmed, permanently discontinue carfilzomib.  If 
the diagnosis is excluded, carfilzomib can be 
restarted 
Venous thrombosis (≥ grade 3) 
Hold carfilzomib and adjust anticoagulation regimen; 
resume at full dose once anticoagulation has been 
optimized per treating investigator’s discretion. 
Any other drug-related nonhematologic 
toxicity ≥ grade 3b 
For carfilzomib attribution, hold dose.  Resume at 
1 dose decrement when toxicity has resolved to 
grade 1 or less or to baseline grade.  
Page 3 of 3 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; ARDS = acute respiratory distress 
syndrome; AST = aspartate aminotransferase; CrCl = creatinine clearance; DBP = diastolic blood 
pressure; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; NCI-CTCAE = National 
Cancer Institute-Common Terminology Criteria for Adverse Events; PRES = Posterior Reversible 
Encephalopathy Syndrome; SBP = systolic blood pressure; TMA = thrombotic microangiopathy; 
ULN = upper limit of normal. 
a For a rapid fall from baseline in CrCl or an absolute fall of ≥ 60 mL/min, contact the medical monitor. 
b In the event of a possible drug-related nonhematologic toxicity, the investigator should, to the best of 
his/her ability, assess its relationship to lenalidomide (R), carfilzomib (K), dexamethasone (d), or the 
combination of KRd to the extent possible.  If both carfilzomib and lenalidomide are considered likely to be 
involved, then recommended actions for both should be instituted.   
7.4.1.1.3 
Conditions Not Requiring Carfilzomib Dose Reduction 
Carfilzomib do not need to be held in the following cases: 
 
grade 3 nausea, vomiting, or diarrhea (that responds within 7 days to adequate 
treatment of antiemetics and/or antidiarrheal agents) 
 
grade 3 dexamethasone-related hyperglycemia 
 
isolated grade 3 -glutamyl transferase elevation 
 
grade 3 fatigue (unless persisting for > 7 days) 
 
alopecia 
7.4.1.2 
Non-Amgen Non-Investigational Product:  Lenalidomide 
Lenalidomide may be discontinued, temporarily delayed, or dosage temporarily reduced, 
in the event of a treatment-related toxicity that, in the opinion of the investigator, 
warrants the discontinuation, temporary delay or dose reduction.   
Investigators are advised to consult the approved regional labeling for lenalidomide for 
additional details.   
The reason for dose change of lenalidomide is to be recorded on each subject’s eCRF. 


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7.4.1.3 
Non-Amgen Non-Investigational Product:  Dexamethasone 
Dexamethasone may be discontinued, temporarily delayed, or dosage temporarily 
reduced, in the event of a treatment-related toxicity that, in the opinion of the 
investigator, warrants the discontinuation, temporary delay or dose reduction.   
Investigators are advised to consult the approved regional labeling for dexamethasone 
for additional details.   
The reason for dose change of dexamethasone is to be recorded on each subject’s 
eCRF.   
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product and/or other protocol-required therapies during 
the study are provided in the IPIM. 
7.6 
Treatment Compliance 
Administration of IV medicinal products will occur at the study center.  Oral medication 
may be dispensed for self-administration at home.  Subjects are to document all 
administered doses and missed doses in a medication diary for all study-required 
medication taken at home.   
7.7 
Treatment of Overdose 
None of the investigational products in this study have specific antidotes.  Therapy for 
overdose involves monitoring and management of acute side effects until the subject is 
stable. 
7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
Prior therapies for non-multiple myeloma conditions that were being taken/used from 
30 days prior to signing of the informed consent form (ICF) will be collected on the 
Concomitant Medications eCRF.   
Collect therapy name, indication, dose, unit, frequency, start date and stop date. 
Prior therapies for multiple myeloma must date back to the original diagnosis and will be 
collected on the Prior Multiple Myeloma Therapy eCRF.  For subjects who are being 
referred to the research site, critical referral information will constitute multiple myeloma 
information from source notes.  Prior lines of multiple myeloma treatment are defined as 
a planned course of therapy.  Therefore, during initial treatment, the induction ± 


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autologous stem cell transplant ± consolidation and maintenance would be considered 
1 line of therapy (see Section 12.8 for additional guidance on lines of therapy). 
For prior antimyeloma therapies, collect transplant, best response, did subject 
relapse/progress on or after this regimen, date of relapse/progression, drug name, 
reason for therapy, start date, stop date, reason medication was stopped.  
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 informed consent through the 30 days 
after the last dose of all study drug(s). 
For all concomitant therapies, collect therapy name, indication, dose, unit, frequency, 
start date and stop date and record on Concomitant Medications eCRF.      
It is recommended to follow the Eighth Joint National Committee 2014 evidence-based 
guideline for the management of high blood pressure in adults (James et al, 
2014Section).  For elderly subjects, it is recommended to implement the 2018 ESH and 
ESC guidelines Section (Williams et al, 2018).   
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. 
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 


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the subject the possibilities for continuation of the Schedule of Activities (see Table 2-1) 
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 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 study drugs 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 
 
Pregnancy 
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.   


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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 (Table 2-1) 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.   
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 center.  
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. 


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9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1).  
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 ICF, the site will register the subject in the IxRS and screen the subject to 
assess eligibility for participation.  The screening window is up to 28 days from date of 
consent until randomization. 
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. 
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 
rescreening 1 time.  
Rescreen subjects must first be registered as screen failures in IxRS and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 28-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 28 days 
after the original signing of the ICF, all screening procedures, including informed 
consent, must be repeated. 
9.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 2-1).  Subjects assessed as eligible 
for the study will be randomized to a treatment arm and must start study treatment within 
3 days of randomization.  The date of the first dose of protocol-required therapies is 


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defined as day 1.  All subsequent doses and study visits will be scheduled based on the 
day 1 date (see Section 7.1.1.2 for additional details).  Protocol-required therapies are to 
be administered last during each visit in which they are required, except for the ECGs 
required on cycle 1 day 8 and cycle 2 day 1 which should be performed at the end of 
carfilzomib infusion.   
9.1.3 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason (including 
subjects who complete 12 cycles of treatment), a safety follow-up visit will be performed 
approximately 30 (+3) days after the last dose of all study drug(s) unless the subject is 
lost to follow-up, has withdrawn full consent, or has died.  Subjects who discontinue 
treatment due to confirmed PD are also to complete the safety follow-up visit. 
9.1.4 
Long-term Follow-up 
After discontinuation from study treatment, subjects who do not have confirmed PD are 
required to continue follow-up every 28 ± 7 days for survival, disease response 
assessments and reporting of new antimyeloma treatment until 12 months after 
randomization, first subsequent antimyeloma treatment, death, loss to follow-up, 
withdrawal of full consent, or confirmed PD, whichever comes first.  For applicable study 
subjects, long-term follow-up will commence 28 days after the Safety Follow-up visit. 
All subjects with confirmed PD before 12 months from randomization will be followed for 
survival every 28  7 days until 12 months after randomization, death, loss to follow-up, 
or withdrawal of full consent, whichever comes first.  For applicable study subjects, long 
term follow-up will commence 28 days after the Safety Follow-up visit. 
Disease response assessments and survival information will be collected as indicated in 
the Schedule of Activities (Table 2-1). 
9.1.5 
End of Study 
The end of study for each subject is the date they withdraw full consent from the study, 
completes the final safety follow-up visit (following 12 cycles of treatment) or final 
long-term follow-up visit (whichever is later), or death.  This could be a safety follow-up 
visit 30 (+3) days after last dose of all study drug(s) or a final long-term follow-up 
response or survival assessment.   


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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 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved ICF before any study-specific procedures are performed. 
9.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected to 
study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on biomarker variability 
and PK of the protocol-required therapies.  
9.2.1.3 
Medical History 
The Investigator or designee will collect a complete medical and surgical history that 
started within 30 days prior to signing of the ICF.  In addition, medical history will include 
collecting information on the subject's significant medical conditions, prior surgeries, and 
neuropathy history, dating back to the original diagnosis.  Record all findings on the 
medical history eCRF.  The current toxicity grade will be collected for each condition that 
has not resolved.   Cardiovascular risk factors, which include family history of 
cardiovascular disease and smoking history, will also be collected.   
In addition to the medical history above, multiple myeloma history must date back to the 
original diagnosis.  For subjects who are being referred to the research site, critical 
referral information will constitute multiple myeloma information from source notes.  Prior 
lines of multiple myeloma treatment are defined as a planned course of therapy.  
Therefore, during initial treatment, the induction ± autologous stem cell 
transplant ± consolidation and maintenance would be considered 1 line of therapy (see 
Section 12.8 for additional guidance on lines of therapy).   
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). 


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9.2.1.5 
Physical Measurements 
Height (in centimeters) should be measured without shoes.  Weight (in kilograms) should 
be measured without shoes.  
Body Surface Area should be calculated using the Mosteller Formula (Mosteller, 1987):   
BSA (m²) = ([Height(cm) × Weight(kg)]/3600) ½.  
9.2.1.6 
Substance Abuse History 
Obtain a detailed history of prior and/or concurrent use of tobacco. 
9.2.1.7 
Performance Status 
The subject’s performance status will be assessed using the ECOG PS (Section 12.9).   
9.2.2 
Efficacy Assessments 
Disease assessments will be based on central laboratory data and local imaging 
obtained every 28 ± 7 days until confirmed PD (Section 9.2.2.5) irrespective of cycle 
duration including dose delays and treatment discontinuation.   
Disease response and progression assessments include: serum protein electrophoresis 
(SPEP), urine protein electrophoresis (UPEP), serum-free light chain (SFLC), serum and 
urine immunofixation (SIFE, UIFE, respectively) (Section 9.2.2.1), bone marrow sample 
evaluation (Section 9.2.2.2), serum calcium, bone lesion evaluation (Section 9.2.2.3) and 
plasmacytoma evaluation (Section 9.2.2.4). 
9.2.2.1 
SPEP, UPEP, SFLC, SIFE, and UIFE 
Serum protein electrophoresis, UPEP, SIFE, UIFE, and SFLC will all be conducted at 
the central laboratory.  Samples will be collected every 28 ± 7 days (starting from cycle 1 
day 1) irrespective of cycle duration including dose delays and treatment discontinuation.  
Blood will be obtained for SFLC, SPEP, and SIFE.  Twenty-four-hour urine samples will 
be obtained for UPEP and UIFE.  A 24-hour urine sample obtained as standard of care 
may be used as the screening assessment, if obtained within 24-hours prior to signing 
consent and sent to central lab for analysis.  Results for SPEP, UPEP, or SFLC must be 
available at screening and before randomization.  Serum protein electrophoresis, UPEP, 
and SFLC will be repeated on cycle 1 day 1 (unless screening values are within 14 days 
of cycle 1 day 1).   
Post cycle 1 day 1, UPEP and UIFE will be collected every 28 days as part of every 
myeloma disease assessment, along with SPEP, SIFE, and SFLC, and submitted to the 
central laboratory for processing.    


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Subjects will be evaluated for disease response and progression according to the IMWG 
response criteria in Section 12.11.  Disease status categories include sCR, CR, VGPR, 
PR, SD, and PD.  Investigator evaluation of disease response is to be based solely on 
the central laboratory results, not on local laboratory results for laboratory-based 
parameters. 
The following confirmation assessments are required for all response categories (sCR, 
CR, VGPR, and PR; refer to definitions in Section 12.11): 
 
all response categories require 2 consecutive assessments before initiation of any 
new therapy 
 
all categories also require no known evidence of progression including new bone 
lesions if radiographic studies were performed   
 
confirmation of CR or better requires bone marrow assessment (aspirate or biopsy 
per IMWG-URC guidelines; sCR determination in this study requires a bone marrow 
biopsy or aspirate clot for immunohistochemistry) 
 
extramedullary plasmacytoma evaluation (if present at screening) 
9.2.2.2 
Bone Marrow Sample Evaluation Including FISH and MRD[-]CR 
Assessment 
A baseline bone marrow aspirate sample will be collected during the 28-day screening 
period, or prior to dosing at cycle 1 day 1 and used to confirm the diagnosis and quantify 
the percent (%) of myeloma cell involvement.  Where the screening platelet count is 
< 50 x 109/L, the site must allow sufficient time for the bone marrow sample to be 
processed and the percent (%) myeloma cell involvement reported before 
randomization.   
The priority order of testing of the baseline bone marrow aspirate sample by the central 
laboratory, based on the volume and quality of sample obtained, will be  
 
for tumor specific sequence identification for MRD measurement by next-generation 
sequencing (NGS) 
 
cytomorphology analysis to confirm multiple myeloma diagnosis and to quantify the 
percent of myeloma cells in bone marrow 
 
fluorescent in situ hybridization (FISH). 
Sites should also follow this guidance when collecting sample from the subject:  if the 
bone marrow aspirate sample taken at baseline and received by the central lab are 
found to be of insufficient quantity or quality for testing at least 1 measure above, the site 
may be contacted to request provision of a suitable archival bone marrow aspirate or 
core sample to send to the central laboratory for analysis. 


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After screening, bone marrow samples are required at 2 subsequent time points: 
 
to confirm a response of CR or better, bone marrow samples should be collected 
within 35 days of the second consecutive laboratory disease assessment which 
shows CR.  Samples to be collected at CR confirmation are: 
 
Cytomorphology to assess percent (%) plasma cells:  from a bone marrow 
aspirate 
 
MRD:  from a bone marrow aspirate, which should be frozen 
 
Immunochemistry to confirm sCR:  a bone marrow biopsy (trephine) or an 
aspirate clot  
 
At 12 months (± 4 weeks) from randomization (fixed landmark analysis), a sample is 
required for MRD assessment unless MRD analysis was done within the past 
4 months, or if the subject has started new anti-myeloma therapy prior to 12-month 
landmark, or disease progression is recorded.   
9.2.2.3 
Bone Lesion Assessment (Skeletal Survey, CT, or PET/CT) 
Skeletal survey will include lateral radiograph of the skull, anteroposterior and lateral 
views of the spine, and anteroposterior views of the pelvis, ribs, femora, and humeri.  
Low-dose whole body computed tomography or fluorodeoxyglucose-positron emission 
tomography/computed tomography (FDG-PET/CT) may be used in place of skeletal 
survey.  A standard of care bone lesion radiographic assessment performed within 
45 days of Cycle 1 Day 1 may be used as the Screening assessment, and does not 
need to be repeated, unless standard of care method of assessment is different from as 
specified above, ie, MRI bone lesion assessment would not be allowed to substitute for 
the Screening bone lesion assessment. 
It should be repeated if worsening clinical symptoms suggest PD or as clinically 
indicated.  The same method of assessment used at baseline will be used throughout 
the study.  These imaging studies will be read locally.   
9.2.2.4 
Extramedullary Plasmacytoma 
Extramedullary plasmacytoma evaluation will be conducted at screening only if a lesion 
is suspected clinically.  The evaluation may be done within 28 day screening window, if 
performed as a part of standard of care.  If a measurable extramedullary plasmacytoma 
is detected during screening, evaluation will be repeated during treatment to confirm a 
response of PR or better, or to confirm PD or as clinically indicated.  Clinical assessment 
of measurable sites of extramedullary disease will be performed and evaluated locally 
every 28 ( 7) days for subjects with a history of plasmacytoma or as clinically indicated 
during treatment for other subjects.  If assessment can only be performed radiologically, 
then evaluation of extramedullary plasmacytomas may be done every 12 weeks.  The 


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same technique, which may include clinical evaluation by palpation, ultrasound, CT 
scan, magnetic resonance imaging (MRI), or PET/CT should be employed for each 
measurement of plasmacytoma dimensions as clinically appropriate (refer to Section 
12.11).  Bidimensional lesion measurements must be performed and recorded in the 
designated eCRF.   
9.2.2.5 
Progressive Disease Assessment 
Confirmation of PD requires 2 consecutive assessments made before the institution of 
any new therapy, as well as no known evidence of progressive or new bone lesions if 
radiographic studies were performed.  Radiographic studies are not required to satisfy 
these response requirements.  Bone marrow, plasmacytoma, and skeletal survey 
assessments are not required to be confirmed by repeat testing. 
Local laboratory evaluation will not be accepted.  The assessments outlined in 
Section 12.11 are required for PD.  Subjects will be considered to have PD if they meet 
the criteria for progression by a variable that was not considered measurable at 
baseline; however, for subjects who had a measurable serum or urine M-spike at 
baseline, progression cannot be defined by increases in SFLC alone  
(Kumar et al, 2016). 
9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Table 2-1). 
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 Common 
Terminology Criteria for Adverse Events (CTCAE) and is described in Section 12.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after signing of the ICF through the 
30 (+3) days after the last dose of all study drug(s) 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 ICF through 
30 (+3) days after the last dose of all study drug(s) are reported using the Event eCRF. 


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All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours, 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. 
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 or fatal serious adverse events (regardless of causality) after completion of the 
protocol-required reporting period (as defined in Section 9.2.3.1.1.2), 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.   
After End of Study, there is no requirement to actively monitor study subjects after the 
study has ended with regards to study subjects treated by the investigator.  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 after the subject ends the study. 
The method of recording, evaluating, and assessing causality of adverse events, and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 12.4. 
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. 


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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 
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 IB and will notify the IRB/IEC, if 
appropriate according to local requirements. 
9.2.3.1.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management process.   


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9.2.3.1.6 
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 30 days (for 
female subjects) and 90 days (for female partners of male subjects) after the last dose of 
all study drug(s).   
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. 
Further details regarding pregnancy and lactation are provided in Section 12.5. 
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 signs eCRF.  Take 3 blood pressure measurements spaced 1 to 
2 minutes apart and additional measurements if the first 2 are more than 10 mmHg apart 
for either systolic or diastolic blood pressure (see Section 12.10).   
The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the vital signs eCRF.   
Additional Vital Sign Measurements 
In cycles 1 and 6, an additional blood pressure measurement post-carfilzomib infusion 
will be collected (within 30 minutes of the end of infusion). 
Record all measurements on the vital signs eCRF.  For blood pressure, record the 
average blood pressure.   
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 


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position, the subject should be in most recumbent position as possible.  The ECG must 
include the following measurements: heart rate, QRS, QT, QTc, and PR intervals.  The 
principal investigator or (eg, designated site physician, central reader) will review all 
ECGs.  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.   
Electrocardiograms will be required in all subjects at screening.  Electrocardiogram 
monitoring is required on cycle 1 day 8 and cycle 2 day 1 at the end of the carfilzomib 
infusion, and as clinically indicated. 
9.2.3.4 
Other Safety 
9.2.3.4.1 
Echocardiogram 
All subjects will have a baseline ECHO, including assessments of systolic and diastolic 
left ventricular function and right ventricular function.  Screening ECHO may be done 
within 30 days prior to randomization, if performed as a part of standard of care.  
Echocardiogram is to be repeated approximately every 6 months (± 2 weeks) from cycle 
1 day 1 until safety follow-up visit, and additionally, if clinically indicated.  An ECHO must 
be performed within 72 hours of the onset of a cardiac failure event.  
9.2.3.4.2 
Pulmonary Function Tests (PFTs) 
Baseline and surveillance pulmonary function tests are may be performed if clinically 
indicated at the discretion of the investigator. 
9.2.3.4.3 
Hepatitis B 
All hepatitis testing will be performed locally.  All subjects will be tested at screening for 
hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and 
hepatitis B core antibody (anti-HBc), unless performed within 6 months of screening and 
there was no change in the subject’s risk factors within these 6 months. 
Subjects with no history of HBV infection that are negative for hepatitis serologies at 
screening should be followed as clinically indicated. 
Subjects with positive testing or who have a prior history of HBV infection should have 
consultation with a specialist in HBV and have HBV DNA testing and monitoring of HBV 
DNA every 12 weeks ( 2 weeks) or more frequently, if clinically indicated, through 
safety follow-up.  Subjects that have received hepatitis B vaccination with only anti-HBs 
positivity and no clinical signs of hepatitis do not require HBV DNA monitoring. 


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Any subject who becomes HBV DNA positive or develops reactivation of HBV will have 
study treatment interrupted and receive appropriate antiviral treatment as per a specialist 
in hepatitis B.  Resumption of clinical study therapy may be considered in subjects 
whose HBV reactivation is controlled and where the benefits of clinical study therapy 
outweigh the risks.  After cessation of study therapy for any reason, any ongoing 
monitoring and antiviral treatment should be under the guidance of a specialist in HBV. 
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 (Table 2-1) 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 
(Table 2-1).   
9.2.4.1 
Pregnancy Testing 
A serum pregnancy test must be completed at screening (10 to 14 days prior to cycle 1 
day 1).  A serum or urine pregnancy test must be completed within 24 hours of initiation 
of lenalidomide for FCBP.  Additional pregnancy testing must also be performed during 
treatment, as per Schedule of Activities (Table 2-1) and at the safety follow-up visit.  
Note:  Females who have undergone a bilateral tubal ligation/occlusion do not require 
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 
Form, see Figure 12-2).  Refer to Section 12.5 for contraceptive requirements.  
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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9.2.4.2 
Prespecified Biomarker Assessments 
Minimal residual disease in bone marrow is a mandatory measurement in this study.  
Minimal residual disease will be measured by a NGS-based assay.  Bone marrow 
aspirate sample will be collected as per Schedule of Activities (Table 2-1).  The bone 
marrow aspirate sample will be processed and stored according to a protocol that is 
provided by the central lab.  The samples will be analyzed centrally by the NGS-based 
MRD assay.  See Section 9.2.2.2 for details on priority of samples for bone marrow 
aspirate testing.   
9.2.5 
Pharmacokinetic Assessments 
All subjects enrolled will have pharmacokinetic (PK) samples assessed.  Approximately 
15 subjects in each arm will be invited to participate in the intensive PK/PDn substudy at 
select sites (see Section 9.2.9).  Sparse PK samples will be collected from the rest of the 
subjects, eg, subjects who do not consent to participate in the optional intensive PK/PDn 
substudy.   
Venous samples of approximately 2.5 mL will be collected for measurement of plasma 
concentrations of carfilzomib as specified in the Schedule of Activities (Table 2-1).  
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.   
Samples will be collected within ± 5-minute time windows around the nominal time points 
(except for the time point immediately prior to the end of infusion, for which the PK 
collection needs to occur prior to the end of infusion).   
9.2.6 
Pharmacodynamic Assessments (Only for Subjects Participating in 
the Optional Intensive PK/PDn Substudy) 
Venous blood samples of approximately 2 mL will be collected for measurement of 
carfilzomib PDn as per Schedule of Activities (Table 2-1).  Blood samples will only be 
collected from approximately 15 subjects in each arm who consent to participate in 
optional intensive PK/PDn substudy (see Section 9.2.9).   
9.2.7 
Clinical Outcome Assessments 
All COAs will be completed via electronic tablet at the site prior to any other 
assessments or procedures. 
9.2.7.1 
EORTC QLQ-C30  
The EORTC QLQ-C30 is a self-reported 30-item generic instrument for use in cancer 
subjects across tumor types.  It assesses 15 domains consisting of 5 functional domains 


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(physical, role, emotional, cognitive, social), 9 symptom domains (fatigue, nausea and 
vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial 
difficulties), and a GHS or QOL scale (Aaronson et al, 1993).   
9.2.7.3 
Patient-reported Convenience With Carfilzomib-dosing Schedule 
Question 
This is a carfilzomib-specific convenience single-item/question.  This item was modified 
from a question used in the A.R.R.O.W. study (“neutral” option was removed).  This item 
is not psychometrically validated (see Section 12.12 for more details).   
9.2.7.5 
Cancer Therapy Satisfaction Questionnaire (CTSQ) 
The CTSQ measures treatment satisfaction in individuals with cancer (Trask et al, 2008). 
The CTSQ contains 3 domains covering 16 items (Cheung et al, 2016):  
 
Expectations of Therapy 
 
Feelings about side effects 
 
Satisfaction with therapy   


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9.2.9 
Optional Substudies 
9.2.9.1 
Intensive Pharmacokinetic/Pharmacodynamic Substudy 
Approximately 15 subjects in each arm will be invited to participate in the intensive 
PK/PDn substudy at select sites.  See Sections 9.2.5 and 9.2.6 for more details on the 
assessments.   
Documentation of informed consent for the optional intensive PK/PDn substudy must be 
confirmed prior to performing intensive PK/PDn procedures. 
9.2.10 
Other Assessments  
Not applicable.   
10. 
Statistical Considerations 
10.1 
Sample Size Determination 
The sample size was determined so that the primary objective could be tested via 
synthesis method at 1-sided 2.5% significance level with 80% power, including an 
interim analysis for futility when the first 230 subjects have been randomized and had 
the best overall response assessed by the date when treatment was completed, disease 
progression/death occurred, patient dropped out or started new therapy, whichever 
occurred first. 
A sample size of 460 subjects is needed to achieve 80% power for demonstrating that 
once-weekly KRd 56 mg/m2 preserves at least 60% of twice-weekly KRd 27 mg/m2 
effect in terms of ORR at a 1-sided 2.5% significance level by the synthesis method.  
The stratified relative risk (RR) of ORR during the first 12 cycles of treatment in ASPIRE 
study (twice-weekly Rd vs KRd 27 mg/m2 RR and 95% CI: 0.755 [0.696, 0.818]) will be 
used as the historical reference for the test of non-inferiority.  This calculation assumes a 
true RR of 1 with ORR = 86.6% for both arms (once-weekly KRd 56 mg/m2 vs 
twice-weekly KRd 27 mg/m2), and an interim analysis for futility at 50% information 
fraction using O’Brien-Fleming beta-spending function.  The reference ORR = 86.6% 
was determined based on the BOR observed by the end of 12 cycles of treatment in 
ASPIRE study (Amgen data on file).  


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10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
The analysis and reporting of the data from this study will be performed using the 
following analysis populations: 
10.2.1.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population constitutes all randomized subjects and will be the 
basis for the analyses of efficacy in this study.  Subjects in the analyses based on the 
ITT population will be analyzed according to the treatment group to which they were 
randomized. 
10.2.1.2 
Safety Population 
The safety population includes all randomized subjects who receive at least 1 dose of 
any study treatment (carfilzomib, lenalidomide, or dexamethasone), and will be the basis 
for the analyses of safety.  Subjects in the analyses based on the safety population will 
be analyzed according to the treatment group corresponding to the actual treatment 
received.  Any subject who received at least 1 weekly dose of carfilzomib 56 mg/m2 will 
be included in arm 1 (once-weekly KRd 56 mg/m2).  Otherwise, subjects will be included 
in arm 2 (twice-weekly KRd 27 mg/m2).  
10.2.1.3 
Per-Protocol Population 
The per-protocol population will include all randomized subjects who do not have any 
major protocol deviations that might affect the interpretation of the analyses of the 
efficacy endpoints.  The major protocol deviations include: 
 
Major inclusion criteria not met 
 
Major exclusion criteria not met 
 
Major treatment non-compliance 
 
Treatment received different from treatment randomized  
 
Concomitant use of protocol prohibited medications.  
10.2.2 
Covariates 
In addition to the stratification factors for randomization (original ISS stage at study 
entry, prior lenalidomide treatment, prior PI treatment, prior anti-CD38 exposure), other 
baseline covariates may be considered to examine primary and selected secondary 
endpoints in subgroups or in sensitivity analyses, as appropriate. More details will be 
described in the statistical analysis plan (SAP).   


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10.2.3 
Subgroups 
The ORR will be estimated for selected subgroups if appropriate: 
 
original ISS stage at baseline (stage 1 or 2 vs stage 3) 
 
prior lenalidomide treatment (yes vs no) 
 
prior PI treatment (yes vs no) 
 
prior anti-CD38 exposure (yes vs no) 
 
prior bortezomib treatment (yes, no) 
 
age (< 65,  65; 18 to  65, 65 to  75,  75) 
 
number of prior therapies (1 vs > 1; 1 vs 2 vs > 2) 
 
cytogenetic risk measured by FISH (high-risk vs standard risk) 
 
bortezomib refractory status (yes vs no) 
 
lenalidomide refractory status (yes vs no) 
 
prior transplant (yes vs no) 
10.2.4 
Handling of Missing and Incomplete Data 
Subjects may have missing data points for various reasons and the impact on the 
analysis might differ from 1 endpoint to another.  The general rules for accommodating 
the missing or incomplete data may be refined during the blind review of the data, and 
they will be described in detail in SAP.  Sensitivity analyses might be needed to evaluate 
the robustness of the primary analysis and/ or key secondary analyses results in case of 
significant missing data. 
Incomplete dates for the start of adverse event, concomitant medications, and death will 
be imputed and the detailed rules will be specified in SAP.   
The calculation of scores and methods to deal with missing data will be handled 
according to the EORTC QLQ-C30 questionnaire's standard scoring guidelines. 
No imputation will be done for the analysis of the primary and key secondary endpoints.  
The frequency of missing disease assessments and deviation of the actual disease 
assessment times from the scheduled assessment times will be summarized by 
treatment arms.  Sensitivity analyses will be performed to assess the impact of missing 
any disease or response assessment on the analysis of ORR and PFS.  Similar analysis 
will be performed for QOL endpoints.   
Details of missing data analysis and imputation rules will be described in SAP.   


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10.3 
Statistical Analyses 
The SAP 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. 
10.3.1 
Planned Analyses 
10.3.1.1 
Interim Analysis and Early Stopping Guidelines 
An interim futility analysis will be performed to limit the number of patients exposed to 
treatment in case of low activity.   
The primary purpose of this interim analysis is to assess the likelihood that the treatment 
effect of the once-weekly KRd 56 mg/m2 will preserve at least 60% of twice-weekly 
KRd 27 mg/m2 effect in terms of ORR.  The date of the analysis will be set up by Amgen 
based on the date when the first 230 subjects have been randomized and had a BOR 
assessed by the date when treatment was completed, confirmed PD or death occurred, 
subject was lost to follow-up, withdrew consent, or started new therapy, whichever 
occurred first. 
This interim data analysis will address the primary and key secondary study objectives 
for the selected subjects.  This analysis will be performed by an independent contract 
research organization, and the sponsor will be blinded to the results.  An independent 
DMC will review the unblinded results and may suggest early termination of the trial.  
Using an O’Brien-Fleming beta-spending function, the stopping boundary for futility in  
p-value scale is 0.289.  This stopping boundary corresponds to an approximate RR of 
0.930, meaning that the study is futile if the observed ORR in the once-weekly KRd 
56 mg/m2 arm is < 80.8%, when the observed ORR in the twice-weekly KRd 27 mg/m2 
arm is 86.6%.  With such a stopping boundary, the trial has over 70% probability to stop 
for futility when the null hypothesis of inferiority is true.   
Based on this stopping criteria and clinical evaluation of the benefit/risk ratio, the DMC 
may recommend the continuation of study for the final analysis including all subjects 
enrolled in the study. 
Data will be subject to ongoing checks for integrity, completeness, and accuracy in 
accordance with the Data Management Plan with the expectation that all outstanding 
data issues are resolved ahead of the snapshot.  The data will be locked to prevent 
further changes, and a snapshot of the locked database will be used in the analysis. 


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10.3.1.2 
Primary Analysis 
The primary analysis corresponds to the final analysis. 
10.3.1.3 
Final Analysis 
Amgen will set a final analysis data cut-off date for efficacy and safety analysis in 
anticipation of the date when all subjects have completed the study.  Final analysis will 
address all the study objectives.  Data will be subject to ongoing checks for integrity, 
completeness, and accuracy in accordance with the Data Management Plan with the 
expectation that all outstanding data issues are resolved ahead of the snapshot.  The 
data will be locked to prevent further changes, and a snapshot of the locked database 
will be used in the analysis. 
The hypotheses for the primary and key secondary objectives (ORR, PFS, and 
convenience after cycle 4 of treatment) will be tested using a fixed sequence hierarchical 
testing procedure to control the family-wise type I error rate at 1-sided 0.025 level.  The 
testing is ordered as follows: non-inferiority of ORR, non-inferiority of PFS, and 
superiority of patient-reported convenience after cycle 4 of treatment.  
Starting with the hypothesis of ORR, if any hypothesis in the sequence is rejected at a 
1-sided significance level of 0.025, then the subsequent hypothesis will be tested.  
Otherwise, if any hypothesis failed to be rejected, then the subsequent hypotheses will 
not be tested.   
For the primary endpoint, the stopping boundary (0.025 in p-value scale) corresponds to 
an approximate RR = 0.975, meaning that the study meets the primary objective if the 
observed ORR for the once-weekly KRd 56 mg/m2 arm is at least 84.3%, when the 
observed ORR in the twice-weekly KRd 27 mg/m2 arm is 86.6%.   
The final analysis of efficacy endpoints will be based on the ITT population, while the 
final analysis of safety endpoints will be based on the safety population.   
10.3.2 
Methods of Analyses 
10.3.2.1 
General Considerations 
The analyses of efficacy and safety endpoints will be based on the analysis sets defined 
in Section 10.2.1.  The primary and final analyses of the efficacy endpoints will use the 
ITT population, while the per-protocol population will be used for sensitivity analyses, if 
applicable.  The final analysis of the safety endpoint will use the safety population.   


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10.3.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Overall response over the duration of the study:  Clopper-Pearson 
method for by treatment overall response rate (ORR) estimate and CI.  
Mantel-Haenszel stratified RR for the inference of treatment effect.  
The synthesis approach will be used to show that once-weekly 
KRd 56 mg/m2 preserves at least 60% of twice-weekly KRd 27 mg/m2 
effect vs Rd. 
Secondary 
PFS over the duration of the study: Kaplan-Meier (KM) estimates for 
PFS distribution by treatment and PFS rates and CI at 6 and 12 
months, stratified Cox proportional hazards (PH) model for HR and CI 
estimate, and the synthesis approach will be used to show that once-
weekly KRd 56 mg/m2 preserves at least 50% of twice-weekly KRd 
27 mg/m2 effect vs Rd.  
The stratified HR of PFS observed during the first 12 months of 
treatment in ASPIRE study (twice-weekly Rd vs KRd 27 mg/m2 
RR 1.81; 95% CI: 1.39, 2.38) will be used as the historical reference 
for the test of non-inferiority. 
Patient-reported convenience after cycle 4 of treatment: 
Cochran-Mantel-Haenszel method will be used to evaluate the 
treatment effect (OR) for whether carfilzomib dosing is reported as 
convenient or inconvenient; a logistic regression model including the 
randomization stratification factors and treatment group will be 
considered for sensitivity analysis.   
TTR: mean, SD, median, minimum and maximum among responders.  
DOR: KM method among responders. 
TTP: KM method and stratified Cox PH model  
OS over the duration of the study: KM estimates for OS distribution by 
treatment and OS rates and CI at 6 and 12 months, stratified Cox PH 
model for HR and CI estimate. 
MRD[-]CR: proportion of MRD[-]CR will be reported with CI calculated 
using Clopper-Pearson method. 
MRD[-] status at 12 months from randomization: proportion of MRD[-] 
will be reported with CI calculated using Clopper-Pearson method. 
Physical functioning and role functioning (EORTC QLQ-C30) over 
time: a repeated measures analysis of covariance adjusting for the 
baseline covariates.  A restricted maximum likelihood-based mixed 
model for repeated measures (MMRM) will be considered as 
sensitivity analysis. 
Patient-reported treatment satisfaction (CTSQ) after cycle 4 of 
treatment: analysis of covariance at the corresponding fixed time point. 
Exploratory 
Will be described in the statistical analysis plan finalized before 
database lock 
 


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10.3.2.3 
Safety Analyses 
10.3.2.3.1 
Adverse Events 
Incidence of all treatment-emergent adverse events will be tabulated by system organ 
class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product or other 
protocol-required therapies, and adverse events of interest will also be provided.  More 
details will be included in the SAP.   
10.3.2.3.2 
Laboratory Test Results 
The laboratory test results and their change from baseline will be summarized by cycle.   
10.3.2.3.3 
Vital Signs 
The vital signs and their change from baseline will be summarized by cycle.  
10.3.2.3.4 
Physical Measurements 
The physical measurements and their change from baseline will be summarized by 
cycle.   
10.3.2.3.5 
Electrocardiogram 
The ECG measurements from this clinical study were performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.  Since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data; summaries and 
statistical analyses of ECG measurements are not planned, and these data would not be 
expected to be useful for meta-analysis with data from other studies.   
10.3.2.3.6 
Exposure to Investigational Product 
The extent of exposure to all study treatments (carfilzomib, lenalidomide, and 
dexamethasone) will be evaluated for each arm with respect to treatment duration 
number of cycles started, total dose received, number of doses administered, dose 
intensity.  The reasons for dose modifications, or discontinuation from any study 
treatment will be summarized separately.  More details will be included in the SAP.   
10.3.2.3.7 
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.   


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11. 
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Dimopoulos M, Wang M, Maisnar V, et al.  Response and progression-free survival 
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and dexamethasone (Rd) in the phase III ASPIRE study.  J Hematol Oncol.  2018;11:49.  
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recommendations for the diagnosis and management of myeloma-related renal 
impairment.  J Clin Oncol.  2016;34:1544-1557.  
Durie BG, Harousseau JL, Miguel JS, et al.  International uniform response criteria for 
multiple myeloma.  Leukemia.  2006;20:1467-1473.   
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Gralow JR, Biermann JS, Farooki A, et al.  NCCN Task Force Report: Bone Health In 
Cancer Care.  J Natl Compr Canc Netw.  2013;11(Suppl 3):S1-S50. 
He W, Goodkind D, Kowal P.  US Census Bureau, International Population Reports, 
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Hoy SM.  Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple 
Myeloma.  Target Oncol.  2016;11:2552-2562.  
James PA, Oparil S, Carter BL, et al.  2014 Evidence-Based Guideline for the 
Management of High Blood Pressure in Adults.  Report from the panel members 
appointed to the eighth Joint National Committee (JNC 8).  JAMA.  2014;311:507-520. 
Kistler K, Murphy B, Kalman J, et al.  A comparison of cardiac event rates in patients 
with or without multiple myeloma in the US. ASCO Annual Meeting Abstract.  2014. 
Knauf WU, Otremba B, Overkamp F, Kornacker M.  Bortezomib in Relapsed Multiple 
Myeloma – Results of a Non-Interventional Study by Office-Based Haematologists.  
Onkologie.  2009;32:175-180. 
Kortuem KM, Stewart AK.  Carfilzomib.  Blood.  2013;121:893–897. 


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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;26:149-157.   
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;17:328-346.  
Laubach J, Garderet L, Mahindra A, et al.  Management of relapsed multiple myeloma: 
recommendations of the International Myeloma Working Group.  Leukemia.  
2016;30:1005-1017.  
Li W, Garcia D, Cornell RF, et al.  Cardiovascular and Thrombotic Complications of 
Novel Multiple Myeloma Therapies: A Review.  JAMA Oncol.  2017;3(7):980-988.  
 Mateos MV, Moreau P, Berenson JR.  Once-weekly vs twice-weekly carfilzomib (K) 
dosing plus dexamethasone (d) in patients with relapsed and refractory multiple 
myeloma (RRMM): Results of the randomized phase 3 study A.R.R.O.W.  J Clin Oncol.  
2018;36.  Abstract 8000.   
Moreau P, Pylypenko H, Grosicki S, et al.  Subcutaneous versus intravenous 
administration of bortezomib in patients with relapsed multiple myeloma: a randomised, 
phase 3, non-inferiority study.  Lancet Oncol.  2011;12:431-440. 
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Noone AM, Howlader N, Krapcho M, et al.  SEER Cancer Statistics Review, 1975-2015, 
National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2015/, based 
on November 2017 SEER data submission, posted to the SEER web site, April 2018.  
Accessed 04 October 2018.   
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Cooperative Oncology Group.  Am J Clin Oncol.  1982;5(6):649–655. 
Papadas A, Asimakopoulos F.  Mechanisms of Resistance in Multiple Myeloma.  Handb 
Exp Pharmacol.  2017. 
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a single‐item measure of patient‐reported bother from side effects of cancer therapy. 
Cancer. 2018;124:991-997. 
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. 
Reeder CB, Reece DE, Kukreti V, et al.  Once- versus twice-weekly bortezomib 
induction therapy with CyBorD in newly diagnosed multiple myeloma.  Blood.  
2010;115(16):3416-3417. 
REVLIMID® (lenalidomide) United States Prescribing Information.  Summit NJ: Celgene 
Corporation; December 2017.  http://www.revlimid.com/wp-content/uploads/full-
prescribing-information.pdf.  Accessed 5 June 2018. 
REVLIMID® (lenalidomide) Summary of Product Characteristics.  Uxbridge, UK: Celgene 
Ltd; 18 September 2017.  http://www.revlimid.com/wp-content/uploads/full-prescribing-
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Richardson P, Mitsiades C, Schlossman R, et al.  The treatment of relapsed and 
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Siegel DS, Dimopoulos MA, Ludwig H, et al.  Improvement in Overall Survival With 
Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory 
Multiple Myeloma.  J Clin Oncol.  2018;36:728-734.  
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Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone in 
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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 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
AST 
aspartate aminotransferase 
BOR 
best overall response 
BSA 
body surface area 
CFR 
US Code of Federal Regulations 
COA 
Clinical Outcome Assessment 
CR 
complete response 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT 
computed tomography 
CTSQ 
Cancer Therapy Satisfaction Questionnaire 
DMC 
data monitoring committee 
DOR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EORTC 
European Organization for Research and Treatment of Cancer 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer 
Quality-of-life Questionnaire Core 30 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FCBP 
females of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
GHS 
global health status 
HBsAg 
hepatitis B surface antigen 


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Abbreviation or Term 
Definition/Explanation 
HBV 
hepatitis B virus 
HR 
hazard ratio 
HRQOL 
health-related quality-of-life 
HRT 
hormone-replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IMiD 
immunomodulatory drug 
IMWG-URC 
International Myeloma Working Group Uniform Response 
Criteria 
Interactive Voice/Web 
Response System (IxRS) 
telecommunication/web-based technology that is linked to a 
central computer in real time as an interface to collect and 
process information   
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Boards 
IRC  
Independent Review Committee 
ISS 
International Staging System 
IV 
intravenous 
KM 
Kaplan-Meier 
KRd 
carfilzomib in combination with lenalidomide and 
dexamethasone  
MM 
multiple myeloma 
MMRM 
mixed model for repeated measures 
MRD 
minimal residual disease 
MRD[-] 
minimal residual disease negative  
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NDMM 
newly diagnosed multiple myeloma 
NGS 
next-generation sequencing 
OR 
odds ratio 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PDn 
pharmacodynamics 
PET/CT 
positron emission tomography/computed tomography 
PFS 
progression-free survival 


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Abbreviation or Term 
Definition/Explanation 
PH 
proportional hazard 
PI 
proteasome inhibitor 
PK 
pharmacokinetics 
PR 
partial response 
RBC 
red blood cell 
Rd 
lenalidomide with dexamethasone 
REMS 
Risk Evaluation and Mitigation Strategy 
RR 
relative risk 
RRMM 
relapsed or refractory multiple myeloma 
SAP 
Statistical Analysis Plan 
sCR 
stringent complete response 
SFLC 
serum-free light chain 
SIFE 
serum immunofixation 
SmPC 
Summary of Product Characteristics 
Source Data 
Information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical 
study necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
SPD 
maximal perpendicular diameter 
SPEP 
serum protein electrophoresis 
SWT 
Satisfaction With Therapy 
TLS 
tumor lysis syndrome 
TTP 
time to progression 
TTR 
time to response 
UIFE 
urine immunofixation 
UPEP 
urine protein electrophoresis 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
VGPR 
very good partial response 
 


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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 by the 
local laboratory.  
Local laboratory results may be used in the event that the central laboratory results are 
not available for the purpose of a time sensitive study treatment decision, including 
laboratories for efficacy assessment.  A sample for central analysis is to be obtained at 
the same time for each laboratory assessment in Table 12-1.  Any local laboratory result 
used to make a study treatment decision must be entered into the electronic case report 
form (eCRF) with the exception of the myeloma response assessment where only the 
central laboratory results are to be entered. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 6.1 to 6.2 of the protocol. 
Subjects must fast for at least 9 hours before screening hematology and serum 
chemistries.  If central laboratory results for lactate dehydrogenase, bilirubin, aspartate 
aminotransferase, and potassium are not reported/available at screening, local 
laboratory results may be utilized if completed within the screening window and must be 
reported on the eCRF.  Screening coagulation, pregnancy, and hepatitis B serology tests 
will be done at local laboratories.  Post-enrollment, laboratory samples may be collected 
and analyzed by local laboratories if immediate results are necessary for management of 
treatment-emergent adverse events or dosing determination.  Evaluation of lab results 
for dose determination as required per Schedule of Assessments must be documented 
prior to dosing in each cycle.  Any local lab values that lead to dose modification 
decisions must be recorded in the eCRF.  Any local lab results that fulfill ≥ grade 3 
values per Common Terminology Criteria for Adverse Events (CTCAE) must be 
recorded in the eCRF. 
For cycle 1 day 1, hematology and serum chemistry panel from screening may be used 
if within 3 days of day 1 and within 48 hours of D1 of a cycle from C2 onwards.     
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
 


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Table 12-1.  Analyte Listing 
Central Laboratory 
Chemistry 
Hematology 
Disease Assessments 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Albumin 
Calcium 
Corrected calcium 
Glucose 
BUN or Urea 
Creatinine 
Total bilirubin 
Direct bilirubin 
Alk phosphatase 
AST (SGOT) 
ALT (SGPT) 
Phosphate 
Magnesium 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC 
Differential 
Neutrophils 
Bands/stabs 
Segs 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Plasma cell count: 
 
plasma cell percent 
MRD assessment by 
NGS (bone marrow 
aspirate) 
FISH (bone marrow 
aspirate) 
SPEP 
Serum Immunofixation 
UPEP 
Urine immunofixation 
SFLC 
Pharmacokinetics 
Pharmacodynamics 
Central Laboratory Screening Only 
Screening only: 
LDH 
Uric acid 
Amylase 
Lipase 
Fasting lipid panel: 
 
Total cholesterol 
 
HDL 
 
LDL 
 
Triglycerides 
Screening only: 
HbA1c 
 
Screening only: 
NT-proBNP 
Screening only unless 
clinically indicated: 
Quantitative 
immunoglobulins 
(serum): IgA, IgD, IgE, 
IgG, IgM 
beta2-microglobulin 
(serum) 
Local Laboratory 
 
Screening only - 
Coagulation: 
PT/INR 
PTT 
 
Screening and as 
required by protocol: 
Other: 
Serum pregnancy 
Urine pregnancy 
HBV serologies 
 Hepatitis B surface 
antigen (HBsAg) 
 Hepatitis B surface 
antibody (anti-HBs) 
 Hepatitis B core 
antibody (anti-HBc) 
HBV DNA testing 


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ALT = alanine aminotransferase; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface 
antibody; AST = aspartate aminotransferase; BUN = blood urea nitrogen; FISH = fluorescent in situ 
hybridization; HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HDL = high density lipoprotein; Ig = immunoglobulin; INR = international normalized ratio; LDH = lactate 
dehydrogenase; LDL = low density lipoprotein; MRD = minimal residual disease; NGS = next-generation 
sequencing; NT-proBNP = N terminal of the prohormone brain natriuretic peptide; PT = prothrombin time; 
PTT = partial thromboplastin time;  RBC = red blood cell count; 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 cell count. 
 


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12.3 
Appendix 3.  Study Governance Considerations 
Data Monitoring Committees and Independent Review Committee 
Data Monitoring Committee 
An independent data monitoring committee (DMC) will be convened for this study and 
will act in an advisory capacity to the sponsor with respect to safeguarding the interests 
of study subjects, assessing interim data, monitoring the overall conduct of the study, 
and providing with recommendations relating to continuing, modifying, or stopping the 
study based on these findings (International Council for Harmonisation Good Clinical 
Practice [ICH GCP 5.5.2]).  Details of the DMC will be described in the DMC Charter.  
The initial assessment from this committee will be planned after 30 subjects 
(approximately 15 for the experimental arm and 15 for the control arm) have been 
enrolled and have finished the first cycle of treatment to ensure safety of all arms.  A 
provision will be made allowing an early follow-up DMC meeting to be decided at the 
time of the initial assessment.  The DMC will meet approximately every 6 months to 
review safety data on a regular basis, and once to review the efficacy data for futility.  
The interim analysis for futility is planned to occur when the first 230 subjects have been 
randomized and had a best overall response (BOR) assessed by the date when 
treatment was completed, confirmed progressive disease or death occurred, subject was 
lost to follow-up, withdrew full consent, or started new therapy, whichever occurred first.  
Records of all meetings will be maintained by the DMC for the duration of the study.  
Records of all meetings will be transferred and stored in the trial master folder at the 
conclusion of the study.  Further details are provided in the DMC charter. 
Independent Review Committee 
The individual subject disease response and disease progression for this study will be 
independently assessed by an Independent Review Committee (IRC) in accordance with 
the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) 
(Section 12.11).  The membership criteria and operational details of the IRC will be 
described in the IRC Charter.  The IRC will centrally review the disease-related tests and 
assessments (Section 9.2.2) to evaluate disease progressions and responses without 
the knowledge of randomization assignments or Investigator’s disease assessments.  
The IRC assessment will be used for the primary analysis of efficacy endpoints except 
for minimal residual disease (MRD) rate and clinical outcome assessments (COA) 
endpoints.   


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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 ICH 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.  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 US Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Recruitment Procedures 
Site staff will identify potential subjects from their existing patient population or may seek 
referral patients through existing professional networks or other community sources such 
as patient advocacy groups.  All patient-facing materials must be reviewed/approved by 
the sponsor and the local IRB/IEC.   
 


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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 center.  
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. 
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 


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subject or a legally acceptable representative 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 28 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. 


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Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
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 the Case Report Form (CRF) 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. 


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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:  
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 electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 


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adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
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 must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 


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All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
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 Voice Response System/Interactive Web Response System (IxRS) 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 COA). 
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. 
 
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 


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 
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 
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 center 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. 
 
Note:  Treatment-emergent adverse events will be defined in the statistical analysis 
plan (SAP) 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram [ECG], 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 disease-related event or 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 inpatient 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. 
Is a congenital anomaly/birth defect 


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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: 
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 case report form (CRF). 
o Additionally, the investigator is required to report a fatal disease-related event 
on the Event CRF. 
 
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 Severity (or toxicity defined below); 
o Assessment of relatedness to investigational product, other protocol-required 
therapies, and/or study-mandated activity and/or 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 as a single event with the worst severity on the Event CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to Amgen 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 record the adverse event by the diagnostic term for that 
adverse event (not the individual signs/symptoms).  Only in the event that no 
diagnosis can be made should the individual signs/symptoms be documented as 
an 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 5.0 which is available 
at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product, protocol-required therapies, and/or study-mandated activity and/or 
procedure(s) 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 and/or Product 
Information, for marketed products, 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 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 


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Assessment of Causality 
 
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, 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 Events form.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using a paper-based Serious Adverse Event 
Contingency Report Form (also referred to as the electronic Serious Adverse 
Event [eSAE] 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 the 
paper-based Serious Adverse Event Contingency Report Form (see Figure 12-1). 
 
Once the study has ended, serious adverse event(s) suspected to be related to 
investigational product will be reported to Amgen if the investigator becomes aware 


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of a serious adverse event.  The investigator should use the paper-based Serious 
Adverse Event Contingency Report Form to report the event. 
 
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 
For the region-specific guidance regarding the use of lenalidomide, please refer to the 
regional label. 
Study-specific contraception requirements for males and females of childbearing 
potential are outlined in Section 6.2. 
12.5.1 
Risks Associated With Pregnancy 
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 30 days (for female subjects) and 90 days (for male 
subjects) after the last dose of protocol-required therapies. 
12.5.2 
Counseling  
12.5.2.1 
Female Subjects of Childbearing Potential 
For a female of childbearing potential, lenalidomide is contraindicated unless all of the 
following are met (ie, all females of childbearing potential [FCBP] must be counseled 
concerning the following risks and requirements prior to the start of lenalidomide study 
therapy): 
 
She understands the potential teratogenic risk to the unborn child.  
 
She understands the need for effective contraception, without interruption, 28 days 
before starting study treatment, throughout the entire duration of study treatment,  
during treatment interruptions, and for an additional 30 days after the last dose of all 
study drug(s) 
 
She should be capable of complying with effective contraceptive measures.  
 
She is informed and understands the potential consequences of pregnancy and the 
need to notify her study doctor immediately if there is a risk of pregnancy.  
 
She understands the need to commence the study treatment as soon as study drug 
is dispensed after a negative pregnancy test.  
 
She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol. 
 
She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide. 
The investigator must ensure that for FCBP:   
 
Complies with the conditions for pregnancy risk minimization, including confirmation 
that she has an adequate level of understanding.  
 
Acknowledge the aforementioned requirements.  


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12.5.2.2 
Female Subjects Not of Childbearing Potential 
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of 
the following are met (ie, all females NOT of childbearing potential must be counseled 
concerning the following risks and requirements prior to the start of lenalidomide study 
therapy):  
 
She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide  
12.5.2.3 
Male Subjects: 
 
Traces of lenalidomide have been found in blood, sperm, and semen.  Male subjects 
taking lenalidomide must meet the following conditions (ie, all males must be 
counseled concerning the following risks and requirements prior to the start of 
lenalidomide study therapy):  
 
Understand the potential teratogenic risk if engaged in sexual activity with a 
pregnant female or a female of childbearing potential  
 
Understand the need for the use of a condom with spermicide even if he has had 
a vasectomy, if engaged in sexual activity with a pregnant female or a female of 
childbearing potential. 
 
Counseling about the requirement for latex condom with spermicide use during 
sexual contact with FCBP and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days and at the time that lenalidomide 
treatment is discontinued.  During counseling, subjects must be reminded to not 
share study drug and to not donate blood, sperm, or semen. 
12.5.3 
Definition of Females of Childbearing Potential 
A female is considered fertile after menarche and until becoming postmenopausal 
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: 
 
Documented hysterectomy; 
 
Documented bilateral salpingectomy; or 
 
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 


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 
Postmenopausal female 
 
A postmenopausal state is defined as no menses for 12 consecutive 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. 
 
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 
12.5.4 
Contraception Methods  
12.5.4.1 
Contraception Methods for Female Subjects 
Females of childbearing potential should be advised to avoid becoming pregnant while 
being treated with carfilzomib or lenalidomide.  Lenalidomide is structurally related to 
thalidomide.  Thalidomide is a known human teratogenic active substance that causes 
severe life-threatening birth defects. An embryo-fetal development study in animals 
indicates that lenalidomide produced malformations in the offspring of female monkeys 
who received the drug during pregnancy.  The teratogenic effect of lenalidomide in 
humans cannot be ruled out.  Therefore, a risk minimization plan to prevent pregnancy 
must be observed.  
Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral 
blood lymphocytes.   
Therefore, as a precaution, FCBP and/or their male partners must agree to use 
2 methods of contraception as described below or abstain from sexual activity 28 days 
before treatment, during treatment, during treatment interruptions, and for an additional 
30 days after the last dose of all study drug(s). 
Female subjects of childbearing potential must agree to use 2 methods of contraception 
simultaneously (1 highly effective form of contraception as described below, and 
1 additional effective contraceptive method [male latex or synthetic condom with 
spermicide for male partners of FCBP, or a diaphragm or cervical cap]).  


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Highly Effective Contraceptive Methods 
Note: Failure rate of < 1% per year when used consistently and correctly. 
 
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 study and the 
preferred and usual lifestyle of the subject) 
12.5.4.2 
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 study and the 
preferred and usual lifestyle of the subject).  
 
Use a condom with spermicide during treatment and for an additional 90 days after 
the last dose of protocol-required therapies even if he has undergone a successful 
vasectomy. 
The female partner should consider using an acceptable method of effective 
contraception such as: hormonal, intrauterine device, intrauterine hormonal-releasing 
system, 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]). 
Male subjects with a pregnant partner must practice sexual abstinence or wear a 
condom with spermicide to prevent exposure of the unborn child to carfilzomib or 
lenalidomide through semen. 
Male subjects will be warned that sharing study drug is prohibited and will be counseled 
about pregnancy precautions and potential risks of fetal exposure. 
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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12.5.4.3 
Unacceptable Methods of Birth Control for Male and Female 
Subjects 
Birth control methods that are considered unacceptable in clinical studies include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
12.5.5 
Pregnancy Testing  
12.5.5.1 
Female Subjects 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for FCBP, including FCBP who commit to complete abstinence, as outlined 
below. 
Before starting lenalidomide: 
Female Subjects: 
 
FCBP must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior 
to starting lenalidomide.  The first pregnancy test must be performed within 10 to 
14 days prior to the first dose of study drugs and the second pregnancy test must be 
performed within 24 hours prior to the start of lenalidomide.  The subject may not 
receive lenalidomide until the Investigator has verified that the results of these 
pregnancy tests are negative. 
 
Will be warned that sharing study drug is prohibited and will be counseled about 
pregnancy precautions and potential risks of fetal exposure. 
 
Must agree to abstain from donating blood during study participation and for at least 
90 days after the last dose of all study drug(s). 
During study participation and for 30 days after discontinuation from the study: 
Female Subjects: 
 
FCBP with regular menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, and 
30 [+3] days after the last dose of all study drug(s).  If menstrual cycles are irregular, 
the pregnancy testing must occur weekly for the first 28 days and then every 14 days 
while on study, 30 [+3] days after the last dose of all study drug(s). 
 
In addition to the required pregnancy testing, the Investigator must confirm with 
FCBP that she is continuing to use 2 reliable methods of birth control at each visit. 
 
Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted at a minimum of every 28 days and at the time that lenalidomide 
treatment is discontinued.  During counseling, subjects must be reminded to not 
share study drug and to not donate blood. 


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 
Pregnancy testing and counseling must be performed if a subject misses her period 
or if her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide 
treatment must be discontinued during this evaluation. 
 
Females must agree to abstain from breastfeeding during study participation and for 
at least 30 days after the last dose of all study drug(s). 
 
If pregnancy or a positive pregnancy test does occur in a study patient, study drug 
must be immediately discontinued.  
12.5.5.2 
Male Subjects: 
If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately.  
12.5.6 
Additional Precautions  
 
Subjects should be instructed never to give lenalidomide to another person and to 
return any unused lenalidomide to the study doctor at the end of treatment.  
 
Only enough lenalidomide for 1 cycle of therapy may be dispensed with each cycle 
of therapy. 
 
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding.  
Prophylactic antibiotics should be considered particularly in subjects with 
neutropenia.  
 
Carfilzomib could decrease the effectiveness of oral contraceptives.  The investigator 
should notify subjects of this risk when choosing the methods of birth control. 
Additional medications given during the study may alter the contraceptive.  The 
investigator must discuss these contraceptive changes with the subject. 
 
Female subjects should not donate blood during therapy and for at least 90 days 
after the last dose of all study drug(s).  
 
Male subjects should not donate blood, semen, or sperm during therapy and for at 
least 90 days after the last dose of all study drug(s).  
 
Additional medications given during the study may alter the contraceptive 
requirements.  These additional medications may require female subjects to use 
different method of highly effective methods of contraception and/or for an increased 
length of time.  The investigator must discuss these contraceptive changes with the 
subject.   
12.5.7 
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 30-days after the last 
dose of protocol-required therapies.  
 
Information will be recorded on the Pregnancy Notification Form (see 
Figure 12-2).  The form 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 Form that violates the 
country or regions local privacy laws). 


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 
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 30 days 
after the last dose of all study drugs.  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 elective termination of a pregnancy for 
medical reasons will be reported as an adverse event or serious adverse event.  
Abnormal pregnancy outcomes (eg, spontaneous abortions, stillbirth, fetal death, 
congenital anomalies) 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 has 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 poststudy 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.  
 
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 
90 days after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Form.  The form (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 Form 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. 


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 
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. 
12.5.8 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 30 days after the last dose of 
protocol-required therapies. 
 
Information will be recorded on the Lactation Notification Form (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 235.   
 
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 30 days after discontinuing protocol-
required therapies. 


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Figure 12-2.  Pregnancy and Lactation Notification Forms 
 
 
Amgen Proprietary - Confidential 
Pregnancy Notification Form 
 
Report to Amgen at: USTO fax: +1-888-814-8653, Non-US fax: +44 (0)207-136-1046 or email (worldwide): svc-ags-in-us@amgen.com 
 
1. Case Administrative Information 
Protocol/Study Number:  20180015 
 
 
Study Design:  X Interventional 
Observational (If Observational: 
Prospective 
Retrospective) 
 
2. Contact Information 
Investigator Name   
_ 
Site #   
 
 
Phone (  
)  
_ 
Fax (_     _)  
 
 
Email   
 
Institution   
 
Address    
 
 
3.  Subject Information 
Subject ID #   
_ 
Subject Gender: 
Female 
Male 
Subject age (at onset):       (in years) 
 
4.  Amgen Product Exposure 
 
Amgen Product 
Dose at time of 
conception 
Frequency 
Route 
Start Date 
mm  
/dd  
/yyyy  
 
 
Was the Amgen product (or study drug) discontinued? 
Yes 
No 
If yes, provide product (or study drug) stop date: mm    
/dd   
/yyyy  
 
Did the subject withdraw from the study? 
Yes 
No 
 
 
5.  Pregnancy Information 
Pregnant female’s last menstrual period (LMP) 
mm   
/ dd______/ yyyy  
  
Unknown 
N/A 
 Estimated date of delivery   mm  
/ dd  
_/ yyyy  
 
If N/A, date of termination (actual or planned) mm   
 
/ dd   _/ yyyy  
 
 
Has the pregnant female already delivered? 
Yes 
No  
Unknown 
N/A 
If yes, provide date of delivery:  mm    
 
/ dd   
 
/ yyyy  
 
Was the infant healthy? 
Yes 
No 
Unknown 
N/A 
If any Adverse Event was experienced by the infant, provide brief details:  
 
 
 
 
 
 
Form Completed by: 
 
Print Name:    
 
 
 
 
 
Title:    
 
 
Signature:    
 
 
Date:    
 
 
 
 
FORM-115199                                                                                       Version 1.0                                                                         Effective Date: 24-Sept-2018 


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g
y
 
Lactation Notification Form 
 
 
Report to Amgen at: USTO fax: +1-888-814-8653, Non-US fax: +44 (0)207-136-1046 or email (worldwide): svc-ags-in-us@amgen.com 
1. Case Administrative Information 
Protocol/Study Number:  20180015 
 
 
Study Design:  X Interventional 
Observational (If Observational: 
Prospective 
Retrospective) 
 
2.  Contact Information 
Investigator Name   
 
 
 
Site #   
 
 
Phone (  
)  
 
 
Fax (  
)  
 
 
Email   
 
Institution   
 
Address    
 
 
 3.  Subject Information 
Subject ID #   
 
 
 
 
 
Subject age (at onset):       (in years)
 
4.  Amgen Product Exposure 
 
 
Amgen Product 
Dose at time of 
breast feeding 
Frequency 
Route 
Start Date 
mm  
/dd  
/yyyy  
 
 
Was the Amgen product (or study drug) discontinued? 
Yes 
No 
If yes, provide product (or study drug) stop date: mm    
/dd   
/yyyy  
 
Did the subject withdraw from the study? 
Yes 
No 
 
5.  Breast Feeding Information 
 
Did the mother breastfeed or provide the infant with pumped breast milk while actively taking an Amgen product? 
Yes 
No 
 
If No, provide stop date:  mm   
 /dd   
/yyyy  
 
Infant date of birth: mm  
/dd  
/yyyy  
  
Infant gender: 
Female 
Male 
 
Is the infant healthy? 
Yes 
No 
Unknown 
N/A 
 
 
If any Adverse Event was experienced by the mother or the infant, provide brief details:  
 
 
 
 
 
 
 
  Form Completed by: 
 
Print Name:    
 
 
 
Title:    
 
 
Signature:    
 
 
Date:    
 
 
FORM-115201                                                                                      Version 1.0                                                                           Effective Date: 24-Sept-2018 


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12.6 
Appendix 6.  Sample Storage and Destruction 
Any blood or bone marrow sample collected according to the Schedule of Activities 
(Table 2-1) 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 
multiple myeloma, the dose response and/or prediction of response to carfilzomib, 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 results of pharmacogenetic, biomarker development, 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.  After the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood or bone marrow 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 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 


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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 
Hepatotoxicity stopping rules are described in Section 7.4.1.1.2. 
 


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12.8 
Appendix 8.  Guidelines for Documenting Prior Treatment 
Subjects must have documented relapse after at least 1, but no more than 3 prior 
treatment regimens or lines of therapy for multiple myeloma including relapse after the 
last line of therapy prior to enrollment.  When documenting prior treatments for multiple 
myeloma, the following guidelines should be used: 
 
A new line of therapy is considered to start when a planned course of therapy is 
modified to include other treatment agents (alone or in combination) as a result of 
lack of adequate response, progressive disease (PD) (even if the level of 
progression has not yet met International Myeloma Working Group-Uniform 
Response Criteria [IMWG-URC] for PD), relapse, or toxicity. 
 
An increase in dose of therapy, with the intention of recapturing response in a 
subject who has evidence of progression on that therapy, is considered a new 
therapy. 
 
A new line of therapy is also considered to start when a planned period of 
observation of therapy is interrupted by a need for additional treatment for the 
disease. 
 
Examples of 1 line of therapy include: 
 
Induction therapy and stem cell transplant followed by planned maintenance 
therapy (provided there is no intervening PD) 
 
Induction therapy followed by maintenance therapy (provided there is no 
intervening PD) 
 
Documentation of at least partial response (PR) to at least 1 prior therapy 
 
For patients with prior carfilzomib therapy, documentation of response (≥ PR) must 
be available for the most recent previous carfilzomib therapy as well as stop date.  
Documentation that the subject was not removed from carfilzomib therapy due to 
toxicity must also be available.  For patients with prior therapy with either carfilzomib, 
the start of the 6-month treatment-free interval is when either carfilzomib is 
discontinued even if other portions of the regimen are continued. 
 
 
 


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12.9 
Appendix 9.  ECOG Performance Status 
Grade 
Description 
0 
Normal activity, fully active, able to carry on all predisease performance 
without restriction. 
1 
Symptoms, but fully ambulatory, restricted in physically strenuous 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 
ECOG = Eastern Cooperative Oncology Group. 
Source:  Oken et al, 1982. 
 


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12.10 
Appendix 10.  2018 ESH/ESC Office Blood Pressure Measurement 
  
For more information, please see American Medical Association, 2019 (https://www.ama-
assn.org/delivering-care/hypertension/one-graphic-you-need-accurate-blood-pressure-reading). 
 
 
  
 
 


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12.11 
Appendix 11.  Summary of International Myeloma Working Group - 
Uniform Response Criteria  
Response 
Subcategory 
Multiple Myeloma Response Criteria 
sCR 
 
Negative immunofixation on the serum and urine and  
 
Disappearance of any soft tissue plasmacytomas and 
 
< 5% plasma cells in bone marrow aspirate and  
 
Normal SFLC ratio and  
 
Absence of clonal cells in bone marrow biopsy by immunohistochemistry or 
2- to 4-color flow cytometrya  
CR 
 
Negative immunofixation on the serum and urine and  
 
Disappearance of any soft tissue plasmacytomas and 
 
< 5% plasma cells in bone marrow  
 
In subjects with baseline measurable disease only by SFLC, normal SFLC 
ratio 
VGPR 
 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or  
 
 90% reduction in serum M-protein with urine M-protein < 100 mg per 
24 hours 
 
In subjects with baseline measurable disease only by SFLC, a decrease 
 90% in the difference between involved and uninvolved FLC levels 
 
In subjects 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 per 24 hours   
 
In subjects with measurable disease only by SFLC, a decrease  50% in 
the difference between involved and uninvolved FLC levels is required in 
place of the M-protein criteria. 
 
In addition to these criteria, if present at baseline, a  50% reduction in the 
size (SPD) of soft tissue plasmacytomas is also required 
SD 
 
Not meeting criteria for CR, VGPR, PR, or PD 
PD 
 
Increase of 25% from lowest confirmed response value in 1 or more of the 
following: 
 
Serum M-component (absolute increase must be  0.5 g/dL if the 
lowest M-component was < 5 g/dL  
 
Urine M-component (absolute increase must be  200 mg per 24 hours)  
 
Only in subjects without measurable serum and urine M protein levels:  
the difference between involved and uninvolved FLC levels (absolute 
increase must be > 10 mg/dL) 
 
Increase of serum M-component of ≥ 1 g/dL if the lowest M-component was 
≥ 5 g/dL) 
 
Appearance of new lesion(s),  50% increase from nadir in SPD of > 
1 lesion, or  50% increase in 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 
CR = complete response; FC = flow cytometry; FLC = free light chain; PD = progressive disease; 
PR = partial response; sCR = stringent complete response; SFLC = serum-free light chain; SPD = maximal 
perpendicular diameter; VGPR = very good partial response 
a In this study, only immunohistochemistry is used for response assessment. 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
Page 138 of 145 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
All response categories (complete response [CR], stringent complete response [sCR], 
very good partial response [VGPR], partial response [PR]) require 2 consecutive 
assessments before the initiation of any new therapy, as well as no known evidence of 
progressive or new bone lesions if radiographic studies were performed.  Radiographic 
studies are not required to satisfy these response requirements.  Bone marrow, 
plasmacytoma, and skeletal survey assessments are not required to be confirmed by 
repeat testing.   
Subjects will continue in the last confirmed response category until there is confirmation 
of progression or improvement to a higher response status; subjects cannot move to a 
lower response category. 
For sCR:  presence/absence of clonal cells is based upon the kappa/lambda (κ/λ) ratio. 
An abnormal kappa lambda ratio by immunohistochemistry and/or immunofluorescence 
requires a minimum of 100 plasma cells for analysis. 
Response criteria for all categories and subcategories of response, except CR, sCR, 
and PD are applicable only to patients that have measurable disease, defined by at least 
1 of:   
 
Immunoglobulin (Ig) G multiple myeloma:  serum monoclonal paraprotein (M-protein) 
level ≥ 1.0 g/dL, 
 
IgA, IgD, IgE multiple myeloma:  serum M-protein level ≥ 0.5 g/dL, 
 
urine M-protein ≥ 200 mg/24 hours,  
 
in subjects without measurable serum or urine M-protein, serum-free light chain 
(SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio 
Determination of PD while on study requires 2 consecutive assessments (to confirm 
response or PD, 2 discrete samples are required; samples may be drawn on the same 
day) before classification of PD and/or the institution of new therapy.  Confirmative 
samples for PD after new therapy can be used.  Serum M-component increases of 
≥ 1 g/dL from nadir are sufficient to define progression if nadir M-component is ≥ 5 g/dL. 
Plasmacytomas:  A plasmacytoma is considered measurable if the longest diameter is at 
least 1 cm and the product of the cross diameters is at least 1 cm2.  Progression is 
defined as appearance of a new lesion(s), ≥ 50% increase from nadir of the sum of the 
products of the maximal perpendicular diameter (SPD) of the measurable lesion as 
measured serially, or a ≥ 50% increase in the longest diameter of a previous lesion 
> 1 cm short axis; ≥ 50% increase in plasma cells if this is the only measure of disease.    


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
Page 139 of 145 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
For defining nadir, in the case where a value is felt to be a spurious result per 
physician/Independent Review Committee (IRC) discretion (eg, a possible laboratory 
error), that value will not be considered when determining the lowest value. 
Sources:  Kumar et al, 2016; Rajkumar et al, 2011; Durie et al, 2006.  
 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
Page 140 of 145 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
12.12 
Appendix 12.  Patient-reported Convenience With 
Carfilzomib-dosing Schedule Question 
Instructions: We want to ask you a question about the convenience of the 
carfilzomib-dosing schedule you are receiving in this clinical study.  Please provide 
1 response.  
I find the carfilzomib-dosing schedule   
1 Very Inconvenient 2 Inconvenient  3 Convenient 4 Very Convenient  


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
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Date:  02 September 2021 
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Date:  02 September 2021 
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FORM-001520, v.22, 05 February 2018 
 


Product:  Carfilzomib 
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Product:  Carfilzomib 
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Date:  02 September 2021 
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Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  02 September 2021 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
 Superseding Amendment 3 
Protocol Title:  A Randomized, Open-label, Phase 3 Study Comparing Once-
weekly vs Twice-weekly Carfilzomib in Combination With Lenalidomide and 
Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma 
(A.R.R.O.W.2) 
 
Amgen Protocol Number Carfilzomib 20180015 
EudraCT Number:  2018‐000665‐36 
NCT Number:  03859427 
 
Amendment Date: 
02 September 2021 
 
Rationale:   
The protocol amendment dated 02 September 2021 is being amended to:   
 
revise exclusion criterion 214 from ‘exceeds’ to ‘greater than or equal to’ in order to 
retain consistency with Protocol Amendment 2 on the exact cutoff blood pressure for 
exclusion.   
 
correct an error in Section 9.2.2.2 to clarify that the percent myeloma cell 
involvement must be reported before randomization for subjects with a screening 
platelet count  50 x 109/L.   
 
update the protocol on typographical, formatting, and editorial changes.   
 
 
 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  12 August 2021 
Page 1 of 27 
Amgen Proprietary - Confidential 
FORM-492529, Effective Date: 02 Mar 2020, Version:  6.0 
Amendment 3 
Protocol Title:  A Randomized, Open-label, Phase 3 Study Comparing Once-
weekly vs Twice-weekly Carfilzomib in Combination With Lenalidomide and 
Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma 
(A.R.R.O.W.2) 
 
Amgen Protocol Number Carfilzomib 20180015 
EudraCT Number:  2018‐000665‐36 
NCT Number:  03859427 
 
Amendment Date: 
12 August 2021 
Rationale: 
The protocol amendment dated 12 August 2021 is being amended to: 
 
to remove the word “rate” from overall response rate of the primary endpoint 
 
update the Schedule of Activities to align with language updates 
 
clarify study duration for subjects (Section 5.3.2) 
 
clarify inclusion criterion 103 
 
replace inclusion criteria 106 and 107 with 110 and 111, respectively 
 
clarify exclusion criterion 214 and replace exclusion criterion 234 with 244 
 
clarify administration of Dexamethasone (Section 7.1.2.1) 
 
update the section 7.1.2.2.2. Dosage, Administration, and Schedule to clarify the 
dosage of Lenalidomide that investigator should refer to the regional product label for 
dose adjustments in patients with renal impairment 
 
update other protocol-required therapies include thromboprophylaxis 
(Section 7.1.4.3) and bisphosphonate or monoclonal antibody therapy 
(Section 7.1.4.6) 
 
clarify that the study treatment with lenalidomide and dexamethasone will be 
discontinued upon confirmation of disease progression (Section 7.4.1.2 and 7.4.1.3) 
 
update Section 9.1.4 to clarify long-term follow-up will commence 28-days after the 
safety follow-up visit 
 
update SPEP, UPEP, SFLC, SIFE, and UIFE (Section 9.2.2.1) 
 
update bone marrow sample assessment at baseline (remove permission to use 
archival material) (Section 9.2.2.2) 
 
update Bone Lesion Assessment (Section 9.2.2.3) 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  12 August 2021 
Page 2 of 27 
Amgen Proprietary - Confidential 
FORM-492529, Effective Date: 02 Mar 2020, Version:  6.0 
 
update language in the SAE safety reporting sections to align with the alternative 
protocol language provided in the Memorandum sent out on 16Jul2021 
 
update Pulmonary Function Tests (Section 9.2.3.4.2) to clarify that the Baseline and 
surveillance pulmonary function tests are optional; may be performed if clinically 
indicated at the discretion of the investigator.   
 
update Planned Analysis (Section 10.3.1) and Methods of Analysis (Section 10.3.2) 
 
update Appendix 4 to align to eSAE Timed Transmission process 
 
update Appendix 11 to align with IMWG guidance 
 
aligned the protocol with current Amgen protocol template and safety reporting 
language 
 
typographical, formatting, and editorial changes were done throughout the protocol 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  24 August 2020  
Page 1 of 57 
Confidential 
 
Amendment 2 
Protocol Title:  A Randomized, Open-label, Phase 3 Study Comparing 
Once-weekly vs Twice-weekly Carfilzomib in Combination With 
Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory 
Multiple Myeloma (A.R.R.O.W.2) 
 
Amgen Protocol Number (Carfilzomib) 20180015 
EudraCT number 2018‐000665‐36 
Amendment Date: 
24 August 2020 
 
Rationale: 
 
To amend the secondary objective to collect progression free survival and overall 
survival over the duration of the study 
 
Overall study design language amended to assess subjects with multiple 
myeloma disease response until first subsequent antimyeloma treatment  
 
Updated language for randomization with regard to the staging system to be 
used 
 
Updated language for data monitoring committee to meet approximately every 
6 months to review safety and efficacy data for futility planned to occur when the 
first 230 subjects are randomized 
 
Added information of dose infusion using an infusion pumps 
 
Study procedures section amended to remove conduct of interviews with 
subjects to validate questionnaires for multiple myeloma module 
 
Deleted early success for efficacy from interim analysis 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  10 October 2019 
Page 1 of 45 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Randomized, Open-label, Phase 3 Study Comparing 
Once-weekly vs Twice-weekly Carfilzomib in Combination with Lenalidomide and 
Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma 
(A.R.R.O.W.2) 
 
Amgen Protocol Number (carfilzomib) 20180015 
 
 
Amendment Date: 
10 October 2019 
 
Rationale: 
This protocol is amended to: 
 
Hepatitis B testing (hepatitis B surface antigen, hepatitis B surface antibody, and 
hepatitis B core antibody) has been added at screening for all subjects who have not 
had testing within 6 months of screening.  In addition, guidance has been provided 
regarding hepatitis B virus (HBV) DNA testing and monitoring for subjects with 
positive hepatitis B serology or a prior history of HBV. 
 
Overall survival at 1 year has been added as a secondary endpoint to satisfy 
requests to collect information on overall survival.   
 
A long-term follow-up (LTFU) period with a duration of 12 months after randomization 
was added to separate this period from the safety follow-up period after cessation of 
treatment.  The LTFU period outlines the collection of overall survival data for all 
subjects up to 12 months from randomization.  In addition, clarifications were made 
regarding the collection of disease response assessments and subsequent 
antimyeloma therapy every 28  7 days until end of study for subjects who 
discontinued study treatment and do not have confirmed progressive disease.  End 
of study for each subject was clarified to account for the long-term follow-up period. 
 
Dexamethasone is to be administered 40 mg weekly.  Clarifications were made to 
the treatment descriptions and the study schema to specify the weekly dose regimen 
for dexamethasone. 
 
For disease response assessments, a bone marrow sample is to be collected and for 
confirmation of stringent complete response (sCR) a bone biopsy or aspirate clot is 
required for immunohistochemistry.  Clarifications were made to the notes of the 
Schedule of Activities to specify the type of bone marrow sample required for specific 
assessments.  Additionally, clarifications on sample requirements, timing of 
assessments, and response categories/subcategories were made to descriptions of 
the efficacy assessments and the IMWG summary in the protocol appendix. 
 
Dose modification guidelines for non-hematological toxicities were revised for renal 
dysfunction to align with the product labeling.  The guidelines for congestive heart 
failure were clarified for events < grade 3 and  grade 3.  Guidelines were added for 
hepatitis B reactivation. 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  10 October 2019 
Page 2 of 45 
CONFIDENTIAL 
 
 
 
The planned interim analysis will be for futility and early success for efficacy.  
Additionally, clarifications were made on the disposition of the database for the 
respective planned analyses. 
 
 
The analyte listing was formatted to better clarify which assessments should be 
performed by central laboratory and those which could be handled by a local 
laboratory.  New analytes were listed and clarifications were made to which analytes 
were required at screening only. 
 
Recording the severity of an adverse event was clarified for when the severity 
changes from the date of onset to the date of resolution. 
 
Inclusion criteria for prior therapy was clarified with the addition of bullets.  No 
changes were made to the requirements. 
 
Administration, typographical and formatting changes were made throughout the 
protocol.  Updates have been implemented to align with the current template. 

SAP_001.pdf: 
Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  22 May 2023 
Page 1 of 66 
CONFIDENTIAL  
 
 
 
Internal Use Only Compliance 
Statistical Analysis Plan 
 
Protocol Title: 
A Randomized, Open-label, Phase 3 Study 
Comparing Once-weekly vs Twice-weekly 
Carfilzomib in Combination with Lenalidomide 
and Dexamethasone in Subjects with Relapsed or 
Refractory Multiple Myeloma (A.R.R.O.W.2) 
Short Protocol Title: 
A Study Comparing Once-weekly vs 
Twice-weekly Carfilzomib in Combination with 
Lenalidomide and Dexamethasone in Subjects with 
Relapsed or Refractory Multiple Myeloma 
Protocol Number: 
20180015 
NCT Number: 
03859427 
Authors: 
, Ph.D., MS 
Biostatistics Senior Manager, GBS, Amgen Inc.  
, Ph.D.  
Biostatistics Director, GBS, Amgen Inc.  
Sponsor: 
Amgen Inc. 
One Amgen Center Drive, Thousand Oaks, CA 
91320, United States 
SAP Date: 
Document Version 
Original (v 1.0) 
Amendment 1 (v 2.0)  
Date 
21 December 2018 
09 December 2021 
Amendment 2 (v 3.0)  
22 May 2023 
 
 
 
 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  22 May 2023 
Page 2 of 66 
CONFIDENTIAL  
 
 
 
Internal Use Only Compliance 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
21 December 2018 
 
Amendment 1 (v2.0) 
09 December 2021 
1. Section 2.1 Objectives and Endpoints: 
 changed the wording for some endpoints: 
‘overall response rate’ to ‘overall 
response’, “1-year PFS” to “PFS over the 
duration of the study”, ‘subject incidence’ 
to ‘incidence’, ‘MRD[-]CR rate’ to            
‘MRD[-]CR’, ‘MRD[-] rate’ to ‘MRD[-] 
status’, changed the time window for 
MRD[-] status from ± 2 weeks to ± 4 
weeks per protocol amendment 
 added OS as the secondary endpoint per 
protocol amendment  
 
2. Section 2.2 Hypotheses and/or Estimations: 
 updated the language to distinguish the 
hypothesis for overall response/PFS and 
patient-reported convenience  
3. Section 3.1 Study Design: 
 added follow-up for survival 
 added “Following the safety follow up 
visit, all subjects with confirmed PD 
before 12 months from randomization will 
be followed for survival every 28  7 days 
until 12 months after randomization, 
death, loss to follow-up, or withdrawal of 
full consent, whichever comes first.” 
 Changed “the first 50% of the subjects 
have been randomized and had a best 
overall response (BOR) assessed” to 
“the first 230 subjects (50% of the 
planned total 460 subjects) have been 
randomized and had the opportunity to 
be followed for a best overall response 
(BOR) assessment” for interim analysis 
plan. This update is also applied to 
Section 3.2, 6.5, and 7.1 
 added DMC review for Japan patients 
 updated Figure 3-1. Study Schema 
(adding long-term follow-up) per protocol 
4. Section 3.2 Sample Size: 
 added the software used in calculation 
5. Section 4.1 Planned Covariates: 
 added “in the stratified analyses” for the 
stratification factors for randomization 
6. Section 4.2 Subgroups: 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  22 May 2023 
Page 3 of 66 
CONFIDENTIAL  
 
 
 
Internal Use Only Compliance 
 specified that the subgroups will be 
defined based on the data reported on 
CRF 
 added subgroup “prior bortezomib 
treatment (yes vs no)” 
 added subgroup “baseline creatinine 
clearance (<50, ≥50 mL/min)” 
7. Section 5 Definitions: 
 added definition for baseline bone lesion 
and plasmacytoma assessment 
 moved actual cumulative dose of study 
treatment to relative dose intensity 
section 
 updated description of BSA calculation in 
carfilzomib dose calculation 
 removed End of Study Treatment Date 
 updated the EOS date for the individual 
subject to clarify the context 
 removed the list of CRFs for deriving last 
known alive date, which will be 
documented in a separate document 
 defined MRD[-]CR rate instead of  
MRD[-]CR;  
 changed the time window for MRD[-] 
status from ± 2 weeks to ± 4 weeks 
 added definition for OS 
 added the censoring situation: (5) lost to 
follow-up or withdrawn consent 
 updated the calculation for number of 
weeks of actual treatment for 
dexamethasone and lenalidomide 
 updated Table 5-3 Planned 
Dexamethasone Dose Schedule 
 updated the planned dose intensity 
calculation for dexamethasone 
 updated the calculation for the number of 
weeks of actual treatment in lenalidomide 
actual dose intensity 
 updated the description for Study Day 
 updated the wording for censoring in TTP 
 updated the description for TEAE to align 
with DES 
8. Section 6.3 Per Protocol Set:  
 updated wording for the inclusion criteria 
103, 106, 107 and exclusion criteria 214, 
221 and 222 per protocol; added 
exclusion criteria 206, 215 and 244 
 added corresponding IPD numbers to 
Major treatment non-compliance  
9. Section 6.4 PK/PDn Analyses Set(s):  


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  22 May 2023 
Page 4 of 66 
CONFIDENTIAL  
 
 
 
Internal Use Only Compliance 
 updated the description 
10. Section 6.5 Interim Analysis Set:  
 removed the description for independent 
safety data review 
11. Add Section 6.6 Modified Full Analysis 
Set(mFAS)  
12. Section 7.1 Interim Analysis and Early  
Stopping Guidelines & Section 7.3 Final 
Analysis: 
 added the description for database 
snapshot 
 removed the corresponding RR stopping 
boundary 
 removed the corresponding RR stopping 
boundary 
13. Section 9.2 Subject Accountability: 
 added the summary for COVID-19 
impact 
 added the summary for subjects who 
completed the 12 cycles treatment for 
each study drug 
14. Section 9.3 Important Protocol Deviations:  
 added the summary for COVID-19 
impact 
15. Section 9.4 Demographic and Baseline 
Characteristics:  
 added albumin (g/dL) 
 added the summary for analysis 
population and listing of randomization 
16. Section 9.5 Efficacy Analyses Table 9-1 
and Table 9-2: 
 changed the wording for some endpoints: 
‘overall response rate’ to ‘overall 
response’, “1-year PFS” to “PFS over the 
duration of the study”, ‘MRD[-]CR rate’ to   
‘MRD[-]CR’, ‘MRD[-] rate’ to ‘MRD[-] 
status’    
 added OS 
 added mFAS in sensitivity analysis for 
ORR, PFS and Patient-reported 
convenience 
 added a sensitivity analysis based on Per 
Protocol Set for Physical functioning and 
role functioning 
 added “The testing is done once at the 
primary (final) analysis on ITT analysis 
set” to key secondary endpoints 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  22 May 2023 
Page 5 of 66 
CONFIDENTIAL  
 
 
 
Internal Use Only Compliance 
 removed reporting P-value for MRD[-]CR 
and MRD[-] status 
17. Section 9.5.1 Analyses of Primary Efficacy  
    Endpoint(s) for ORR:  
 changed Uh from “KRd 27mg/m2 BIW vs 
Rd” to “Rd vs KRd 27mg/m2 BIW” and 
log (1.325) to log (0.755) to align with 
sample size section 
 updated the expression for H0 and Ha to 
align with the Uh change. 
 added SAS code for calculating 1-sided 
p-value  
 updated the description for constancy 
assumption check 
 added sensitivity analysis based on 
mFAS 
18. Section 9.5.2 Analyses of Secondary 
Efficacy Endpoint(s):  
For PFS: 
 added H0 and Ha for PFS endpoint. 
 changed Uh from “KRd 27mg/m2 BIW vs 
Rd” to “Rd vs KRd 27mg/m2 BIW” and 
log (0.552) to log (1.812) 
 added SAS code for calculating 1-sided 
p-value  
 added “The subcategory of death with 
the primary reason of COVID-19 infection 
or COVID-19 pneumonia will be included 
in the PFS events” to the PFS summary 
 added sensitivity analysis based on 
mFAS 
 
For Patient-reported convenience: 
 specified that the descriptive summary 
will be based on all randomized subjects 
as well as all expected subjects at the 
scheduled visit 
 changed the Safety Analysis Set to ITT 
Analysis Set 
 added sensitivity analysis based on 
mFAS 
 
For Physical functioning and role functioning 
(EORTC QLQ-C30) over time: 
 changed Health-related Quality-of-Life 
Analysis Set to ITT Analysis Set 
 added descriptive summary for the scale 
scores, change from baseline, and the 
completion rate  
 added the multiple imputation for missing 
data for Physical functioning and role 
functioning scale scores 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  22 May 2023 
Page 6 of 66 
CONFIDENTIAL  
 
 
 
Internal Use Only Compliance 
 added a sensitivity analysis based on Per 
Protocol Set 
 removed reporting p-value 
 
For MRD[-]CR, MRD[-] status:  
 added sensitivity analysis based on 
ORCA assessed response 
 removed reporting p-value 
Added analysis for OS 
19. Section 9.6.2 Adverse Events:  
 removed the listings for AE and death 
 
20. Section 9.6.3 Laboratory Test Results:  
 added the summary for ALT/AST/Total 
Bilirubin and potential Hy’s law cases 
 
21. Section 9.6.8 Exposure to Investigational 
Product and Non-Investigational Products:  
 separated the summary of Dose 
Change/Withheld to Dose missed and 
Dose reduction 
 added the number (%) with COVID-19 
control measures for reason of dose 
modification 
 
22. Appendix A. Handling of Incomplete Dates 
and Missing Dates:  
 
added imputation rules for new anti-
myeloma therapy start date 
 
added imputation rules for prior multiple 
myeloma therapy and 
relapse/progression to prior multiple 
myeloma therapy  
 
updated the imputation rules for death 
date per AMGEN GBS Oncology 
Endpoint Guide v1.0 
Amendment 2 (v3.0) 
22 May 2023 
1. Section 5. Definitions: 
 
modified the language for 
Cytogenetic risk group  
 
added definition for patient-reported 
convenience 
 
2. Section 9.2. Subject Accountability 
 
for key study dates, added last 
subject last dose of IP, last subject 
end of study 
 
3. Section 9.3. Important Protocol 
Deviations 
 
added subject listing for 
inclusion/exclusion criteria 
deviations 
 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  22 May 2023 
Page 7 of 66 
CONFIDENTIAL  
 
 
 
Internal Use Only Compliance 
4. Section 9.4. demographic and baseline 
disease characteristics:  
 
added PI refractory status, Anti-
CD38 refractory status, Refractory 
to the last prior line of therapy, 
Immunoglobulin heavy and light 
chain types  
 
5. Section 9.5.1. Analyses of Primary 
Efficacy Endpoint(s):  
 
added the non-inferiority margin for 
ORR 
 
6. Section 9.5.2. Analyses of Secondary 
Efficacy Endpoint(s):  
 
added additional sensitivity 
analyses  
 
added the analysis of restricted 
mean survival time (RMST) for PFS 
 
added “the observed treatment 
effect retention rate will be 
reported” for PFS analysis 
 
added subgroup analysis for PFS 
and OS 
 
added assessments for the 
adequacy of proportional hazard 
assumption and piecewise Cox 
models for OS 
 
specified that the p-value of the 
hypothesis test for patient-reported 
convenience will be reported after 
Cycle 4 
 
added safety follow-up visit in the 
comparison analysis for patient-
reported convenience, and QLQ-C30 
 
for the model of CTSQ analysis, 
changed the independent variable 
“baseline score” to “scale score 
measured at Cycle 2 Day 1 visit” 
 
7. Section 10. Changes from Protocol-
specified Analysis:  
 
specified that the RMST and 
observed treatment effect retention 
rate are included as additional 
analyses for PFS; the non-inferiority 
margin for ORR is specified in 
Section 9.5 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  22 May 2023 
Page 8 of 66 
CONFIDENTIAL  
 
 
 
Internal Use Only Compliance 
Table of Contents 
Table of Contents ................................................................................................... 8 
1. 
Introduction ........................................................................................................... 14 
2. 
Objectives, Endpoints and Hypotheses ................................................................. 14 
2.1 
Objectives and Endpoints .......................................................................... 14 
2.2 
Hypotheses and/or Estimations ................................................................. 16 
3. 
Study Overview .................................................................................................... 17 
3.1 
Study Design ............................................................................................. 17 
3.2 
Sample Size .............................................................................................. 19 
4. 
Covariates and Subgroups ................................................................................... 20 
4.1 
Planned Covariates ................................................................................... 20 
4.2 
Subgroups ................................................................................................. 20 
5. 
Definitions ............................................................................................................. 20 
6. 
Analysis Sets ........................................................................................................ 31 
6.1 
Intent-to-Treat (ITT) Analysis Set (Full Analysis Set) ................................. 31 
6.2 
Safety Analysis Set ................................................................................... 31 
6.3 
Per Protocol Set ........................................................................................ 31 
6.4 
Pharmacokinetic/Pharmacodynamic (PK/PDn) Analyses Set(s) ................ 33 
6.5 
Interim Analyses Set ................................................................................. 34 
6.6 
Modified Full Analysis Set ......................................................................... 34 
7. 
Planned Analyses ................................................................................................. 34 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 34 
7.2 
Primary Analysis ....................................................................................... 35 
7.3 
Final Analysis ............................................................................................ 35 
8. 
Data Screening and Acceptance ........................................................................... 36 
8.1 
General Principles ..................................................................................... 36 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 36 
8.3 
Handling of Missing and Incomplete Data ................................................. 36 
8.4 
Detection of Bias ....................................................................................... 37 
8.5 
Outliers ..................................................................................................... 37 
8.6 
Distributional Characteristics ..................................................................... 37 
8.7 
Validation of Statistical Analyses ............................................................... 37 
9. 
Statistical Methods of Analysis.............................................................................. 38 
9.1 
General Considerations ............................................................................. 38 
9.2 
Subject Accountability ............................................................................... 39 
9.3 
Important Protocol Deviations ................................................................... 40 


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9.4 
Demographic and Baseline Characteristics ............................................... 40 
9.5 
Efficacy Analyses ...................................................................................... 42 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 46 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 48 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 55 
9.6 
Safety Analyses ........................................................................................ 55 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 55 
9.6.2 
Adverse Events ......................................................................... 55 
9.6.3 
Laboratory Test Results ............................................................ 56 
9.6.4 
Vital Signs ................................................................................. 57 
9.6.5 
Physical Measurements ............................................................ 57 
9.6.6 
Electrocardiogram ..................................................................... 57 
9.6.7 
Left Ventricular Ejection Fraction (LVEF) ................................... 58 
9.6.8 
Exposure to Investigational Product and Non-
Investigational Products ............................................................ 58 
9.6.9 
Exposure to Concomitant Medication ........................................ 59 
9.7 
Other Analyses ......................................................................................... 59 
9.7.2 
Analyses of Clinical Outcome Assessments (COA) ................... 60 
9.7.3 
Analyses of Biomarker Endpoints .............................................. 60 
10. 
Changes from Protocol-specified Analyses ........................................................... 60 
11. 
Literature Citations / References ........................................................................... 60 
12. 
Appendices ........................................................................................................... 62 
Appendix A.  Handling of Incomplete Dates and Missing Dates  ........................... 62 
Appendix B.  Clinical Outcome Assessment Forms/Instruments ........................... 64 
 
List of Table 
 
Table 5-1. Censoring Rules for Primary PFS Analysis ................................................... 24 
Table 5-2. Planned Carfilzomib Dose Schedule ............................................................. 27 
Table 5-3.  Planned Dexamethasone Dose Schedule .................................................... 28 
Table 5-4. Planned Lenalidomide Dose Schedule ......................................................... 29 
Table 9-1. Primary Efficacy Endpoint Summary Table ................................................... 42 
Table 9-2. Secondary Efficacy Endpoint Summary Table .............................................. 43 
Table 9-3. Exploratory Efficacy Endpoint Summary Table ............................................. 46 


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Table 12-1. EORTC QLQ-C30 Functional Scales and Scoring Details .......................... 64 
Table 12-2. Scoring information for SWT Domain in CTSQ ........................................... 65 
  
List of Figures 
 
Figure 3-1.  Study Schema ............................................................................................ 18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BIW 
twice-weekly 
BOR 
best overall response 
BSA 
body surface area 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
COA 
clinical outcome assessment 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSQ 
Cancer Therapy Satisfaction Questionnaire 
DMC 
data monitoring committee 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EOI 
event of interest 
EORTC 
European Organization for Research and Treatment of 
Cancer 
EORTC QLQ-C30 
European Organization for Research and Treatment of 
Cancer Quality-of-life Questionnaire Core 30 


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Abbreviation or Term 
Definition/Explanation 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
HR 
hazard ratio 
HRQOL 
health-related quality-of-life 
IMWG-URC 
International Myeloma Working Group Uniform Response 
Criteria 
Interactive Voice/Web 
Response System (IxRS) 
telecommunication/web-based technology that is linked to 
a central computer in real time as an interface to collect 
and process information   
IPD 
important protocol deviation 
IRC  
Independent Review Committee 
ISS 
International Staging System 
ITT 
intent-to-treat 
IV 
intravenous 
KM 
Kaplan-Meier 
KRd 
carfilzomib in combination with lenalidomide and 
dexamethasone  
LFT 
liver function test 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
modified full analysis set 
MI 
multiple imputation 
MM 
multiple myeloma 
MMRM 
mixed model for repeated measures 
MRD 
minimal residual disease 
MRD[-] 
minimal residual disease negative  
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
OR 
odds ratio 
ORCA 
Onyx response computer algorithm 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PDn 
pharmacodynamics 
PFS 
progression-free survival 


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Abbreviation or Term 
Definition/Explanation 
PH 
proportional hazard 
PI 
proteasome inhibitor 
PK 
pharmacokinetics 
PR 
partial response 
PT 
preferred term 
QW 
once-weekly 
Rd 
lenalidomide with dexamethasone 
RMST 
restricted mean survival time 
RR 
relative risk 
RRMM 
relapsed or refractory multiple myeloma 
SAP 
statistical analysis plan 
sCR 
stringent complete response 
STD 
standard deviation 
SSAP 
supplemental statistical analysis plan 
SWT 
Satisfaction with Therapy 
TEAE(s) 
treatment-emergent adverse event(s) 
TTP 
time to progression 
TTR 
time to response 
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 superseding protocol amendment 3 for study 
20180015, Carfilzomib, dated 02 September 2021. The scope of this plan includes the 
interim futility analysis and the primary analysis (the 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 
Primary 
 
compare efficacy of 
56 mg/m2 carfilzomib administered 
once-weekly (QW) in combination with 
lenalidomide and dexamethasone 
(KRd 56 mg/m2) to 
27 mg/m2 carfilzomib administered 
twice-weekly (BIW) in combination 
with lenalidomide and dexamethasone 
(KRd 27 mg/m2) in subjects with 
RRMM with 1 to 3 prior lines of 
therapy 
 
overall response (defined as the best 
overall response of stringent complete 
response [sCR], complete response 
[CR], very good partial response 
[VGPR], and partial response [PR] per 
International Myeloma Working Group 
Uniform Response Criteria 
[IMWG-URC]) over the duration of the 
study 
Key Secondary 
 
compare progression-free survival 
(PFS) between treatment arms 
 
PFS over the duration of the study 
 
compare patient-reported 
convenience with carfilzomib-dosing 
schedule between treatment arms 
 
convenience as measured by the 
Patient-reported Convenience with 
Carfilzomib-dosing Schedule Question 
after cycle 4 of treatment 
Secondary 
 
describe safety and tolerability in 
treatment arms 
 
incidence of treatment-emergent 
adverse events 
 
compare additional efficacy 
parameters between treatment arms 
 
time to response (TTR)  
 
duration of response (DOR)  
 
time to progression (TTP) 
 
compare overall survival (OS) 
between treatment arms 
 
OS over the duration of the study 
 
compare rate of minimal residual 
disease negative (MRD[-]) in bone 
 
MRD[-]CR, defined as achievement of 
CR or better by Independent Review 
Committee (IRC) per IMWG-URC and 


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marrow aspirates between treatment 
arms 
achievement of MRD negativity as 
assessed by next-generation 
sequencing (NGS) method at a 10-5 
threshold over the duration of the 
study 
 
MRD[-] status at 12 months, defined 
as achievement of MRD negativity at 
12 months (± 4 weeks) from 
randomization, as assessed by NGS 
method at a 10-5 threshold 
 
compare patient-reported physical 
functioning and role functioning 
between treatment arms 
 
physical functioning and role 
functioning over time as measured by 
the Physical Functioning and Role 
Functioning scales of the European 
Organization for Research and 
Treatment of Cancer Quality-of-life 
Questionnaire Core 30 
(EORTC QLQ-C30) over the duration 
of the study 
 
compare patient-reported treatment 
satisfaction between treatment arms 
 
treatment satisfaction as measured by 
the Satisfaction with Therapy (SWT) 
scale of the Cancer Therapy 
Satisfaction Questionnaire (CTSQ) 
after cycle 4 of treatment 
 
 
Exploratory 


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2.2 
Hypotheses and/or Estimations 
KRd 56 mg/m2 QW is non-inferior in terms of overall response and PFS, and is superior 
in terms of patient-reported convenience when compared with KRd 27 mg/m2 BIW.  
The hypotheses for the primary and key secondary objectives (ORR, PFS, and 
convenience after cycle 4 of treatment) will be tested using a fixed sequence hierarchical 
testing procedure to control the family-wise type I error rate at 1-sided 0.025 level.   
 


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3. 
Study Overview 
3.1 
Study Design 
This is a phase 3, multicenter, open-label, randomized study in subjects with RRMM who 
have received 1 to 3 prior therapies.   
Subjects will be randomized in a 1:1 ratio to 1 of 2 arms: 
Arm 1:  KRd using carfilzomib 56 mg/m2 QW 
      Arm 2:  KRd using carfilzomib 27 mg/m2 BIW 
Randomization will be performed using an interactive voice/web response system (IxRS) 
and subjects will be stratified based on the following criteria: original International 
Staging System (ISS) stage at study entry (stage 1 or 2 vs stage 3); prior lenalidomide 
treatment (yes vs no), prior proteasome inhibitor (PI) treatment (yes vs no), prior 
anti-CD38 exposure (yes vs no).  
Subjects will receive the study drug(s) determined by randomization for a maximum of 
12 cycles.  No crossover between the treatment arms is allowed. After completion or 
discontinuation of all study drug(s), subjects will have a safety follow-up visit 30 (+3) 
days after the last dose of all study drug(s).  
All subjects will be assessed for multiple myeloma disease response and disease 
progression by investigator and a blinded Independent Review Committee (IRC) 
according to the International Myeloma Working Group-Uniform Response Criteria 
(IMWG-URC) (Kumar et al, 2016; Rajkumar et al, 2011; Durie et al, 2006) using central 
laboratory test results every 28 ± 7 days from cycle 1 day 1 through the end of cycle 12 
or disease progression until death, loss to follow-up, withdrawal of full consent, or first 
subsequent antimyeloma treatment (whichever occurs first), regardless of treatment 
cycle duration, dose delays or treatment discontinuation. The disease assessment 
schedule is independent of treatment schedules.   
Following the safety follow-up visit, subjects who do not have confirmed progressive 
disease (PD) before 12 months from randomization are required to continue follow-up 
every 28 ± 7 days for survival, disease response assessments and report new 
antimyeloma treatment until 12 months after randomization, first subsequent 
antimyeloma treatment, death, loss to follow-up, withdrawal of full consent, or confirmed 
PD, whichever occurs first.  
Following the safety follow up visit, all subjects with confirmed PD before 12 months 
from randomization will be followed for survival every 28  7 days until 12 months after 


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randomization, death, loss to follow-up, or withdrawal of full consent, whichever comes 
first.  
The response based on IRC assessment will be used for the primary analysis of efficacy 
endpoints. 
The independent data monitoring committee (DMC) will review safety data on a regular 
basis (approximately every 6 months) and review the efficacy data once for the interim 
futility analysis to provide recommendations relating to continuing, modifying, or stopping 
the study. The first planned DMC meeting for data review will take place when 
approximately 30 subjects (15 in each arm) have completed at least 1 cycle of treatment.  
The primary purpose of the interim futility analysis is to assess the futility in terms of 
ORR. The interim futility analysis is planned to occur when the first 230 subjects (50% of 
the planned total 460 subjects) have been randomized and had the opportunity to be 
followed for a best overall response (BOR) assessment by the date when treatment was 
completed, confirmed PD or death occurred, subject was lost to follow-up, withdrew 
consent, or started new antimyeloma therapy, whichever occurred first.  
The DMC will also perform a review per Japan-specific requirements to evaluate the 
tolerability of KRd 20/56 mg/m2 QW on the first 3 to 6 Japanese subjects randomized to 
the KRd 20/56 mg/m2 QW arm and received at least 1 cycle of study treatment. Details 
of the DMC’s responsibilities will be described in the DMC Charter.   
The overall study design is outlined in the study schema in Figure 3-1. The endpoints 
are defined in Section 2.1. 
 
 
 
 
 
 
 
 
 


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Figure 3-1.  Study Schema 
 
3.2 
Sample Size 
The sample size was determined so that the primary objective could be tested via 
synthesis method at 1-sided 2.5% significance level with 80% power, including an 
interim futility analysis when the first 230 subjects (50% of the planned total 460 
subjects) have been randomized and had the opportunity to be followed for the best 
overall response assessment by the date when treatment was completed, confirmed 
disease progression/death occurred, subject was lost to follow-up, withdrew consent, or 
started new antimyeloma therapy, whichever occurred first. 
A sample size of approximately 460 subjects is needed to achieve 80% power for 
demonstrating that KRd 56 mg/m2 QW preserves at least 60% of KRd 27 mg/m2 BIW 
effect in terms of ORR at a 1-sided 2.5% significance level by the synthesis method.  
The stratified relative risk (RR) of ORR during the first 12 cycles of treatment in ASPIRE 
study (BIW Rd vs KRd 27 mg/m2 RR and 95% CI: 0.755 [0.696, 0.818]) will be used as 
the historical reference for the test of non-inferiority. This calculation assumes a true RR 
of 1 with ORR = 86.6% for both arms (KRd 56 mg/m2 QW vs KRd 27 mg/m2 BIW), and 
an interim analysis for futility at 50% information fraction using an O’Brien-Fleming type 
beta-spending function.  The reference ORR = 86.6% was determined based on the 
BOR observed by the end of 12 cycles of treatment in ASPIRE study (Amgen data on 
file). 


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The statistical software EAST 6 (version 6.4.1) and R (version 3.6.1) were used in the 
calculation for sample size determination. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
The planned covariates to be used for the primary analysis of the primary endpoint and 
the selected secondary endpoints in the stratified analyses are the stratification factors 
for randomization per IxRS: original ISS stage at study entry (stage 1 or 2 vs stage 3), 
prior lenalidomide treatment (yes vs no), prior PI treatment (yes vs no), prior anti-CD38 
exposure (yes vs no). 
4.2 
Subgroups 
The ORR, PFS and OS will be estimated for the following selected subgroups defined 
by the baseline data reported on CRF or from the central lab, as appropriate. When 
there is not a sufficient number of subjects in the subgroup, i.e., less than 5% of the 
whole population, relevant subgroups may be combined.  
 
original ISS stage at baseline (stage 1 or 2 vs stage 3)  
 
prior lenalidomide treatment (yes vs no)  
 
prior PI treatment (yes vs no) 
 
prior anti-CD38 exposure (yes vs no)   
 
prior bortezomib treatment (yes vs no) 
 
age (years) (<65, ≥65; 18 - <65, 65 - <75, ≥75) 
 
region (Europe vs Non-Europe) 
 
baseline creatinine clearance (CrCl, mL/min) (<50, ≥50) 
 
number of prior therapies (1 vs >1; 1 vs 2 vs >2) 
 
cytogenetic risk measured by FISH (high-risk (t(4;14), t(14;16), deletion 17p) vs 
standard risk) 
 
bortezomib refractory status (yes vs no) 
 
lenalidomide refractory status (yes vs no) 
 
prior transplant (yes vs no)  
 
5. 
Definitions 
Baseline 
The baseline value is the latest value measured on/before day 1 of the first dose of any 
protocol-specified therapy. If a subject doesn’t receive any protocol-specified therapy, 
then the latest value prior to or on randomization date will be used. 


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For bone lesion and plasmacytoma assessment, the baseline is defined as the most 
recent assessment within 45 days (bone lesion) or 28 days (plasmacytoma) prior to or 
on the randomization date, or up to 7 days (inclusive) after initiation of the study 
treatment if the patient has been dosed. 
 
Best overall response by investigator assessment 
Best overall response for a subject by investigator assessment is the best post baseline 
confirmed response by the analysis trigger date based on the responses by visit 
collected on myeloma response assessment CRF. The response assessments done 
after confirmed disease progression or initiation of new anti-myeloma therapy will be 
excluded from the analysis of primary endpoint. 
 
Best overall response by IRC assessment 
Best overall response for a subject by IRC as collected on IRC Evaluation CRF. Details 
of the IRC will be described in the IRC charter. 
 
Cytogenetic Risk group as determined by Fluorescent in Situ Hybridization (FISH) 
Cytogenetic risk group is defined based on the central laboratory FISH analytes 
t(4;14), t(14;16) and deletion 17p regardless of any other FISH analyte test results.      
High risk group: Subjects who have abnormal results in the tests of analytes t(4;14) 
or t(14;16), and/or deletion 17p. 
Standard risk group: Subjects who have normal results in the tests of all the three 
analytes t(4;14), t(14;16) and deletion 17p. 
Missing: Subjects who cannot be identified as high or standard risk. 
 
Death Date  
Death date for a subject is defined as the date recorded on the End of Study CRF 
page where the primary reason for ending the study is Death or the date on the 
Survival Status CRF page where the subject status is Dead. Incomplete death dates 
will be imputed using the imputation rules as presented in Appendix A. The imputed 
death date will be used in calculation of duration of response, progression-free survival 
and overall survival.  
 
Duration of Response (DOR) 


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For subjects with a PR or better, i.e., sCR, CR, VGPR, or PR, the DOR is defined as the 
time (months) from the earliest date when a PR or better is first achieved, and 
subsequently confirmed, to the earliest date of confirmed PD or death due to any cause. 
For those who are alive and have not experienced PD by analysis time, DOR will be 
censored based on the same censoring rules for PFS as listed in Table 5-1 if applicable.  
DOR (month) = (PD/death date or censoring date - response start date + 1) / 30.4 
 
Duration of Study Treatment  
Duration of treatment with carfilzomib, lenalidomide and dexamethasone will be defined 
as the time from the first start date of each drug to the last stop date of each drug. 
Duration of the whole study treatment will be from the earliest start date among the three 
study drugs to the latest stop date among the three study drugs. 
Duration (week) = (last dose date of the drug – first dose date of the drug + 1) / 7 
 
End of Study Date  
For an individual subject, the end of study date is the date of withdrawal of full consent 
from the study, lost to follow-up, completeness of the final safety follow-up visit, or 
completeness of final long-term follow-up visit (whichever is later), decision by sponsor, 
or death. The end of study date will be recorded on the End of Study CRF page. 
For the overall study, the end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (i.e., 
last subject last visit), following any additional parts in the study (e.g., long-term follow-
up), as applicable.     
 
First Dose Date of Study Treatment  
It is the date on which a subject is administered the first dose of any study drug. 
 
International Staging System (ISS) Stage at Baseline 
ISS stage at baseline will be calculated using serum beta-2 microglobulin and serum 
albumin values collected at baseline, according to the criteria published by the 
International Myeloma Working Group (Greipp 2005): 
Stage 1: Serum beta-2 microglobulin < 3.5 mg/L and serum albumin ≥ 3.5 g/dL 


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Stage 2: Serum beta-2 microglobulin < 3.5 mg/L and serum albumin < 3.5 g/dL or Serum 
beta-2 microglobulin 3.5 – < 5.5 mg/L irrespective of the serum albumin 
Stage 3: Serum beta-2 microglobulin ≥ 5.5 mg/L 
 
Investigational Product (IP)  
IP for this study refers to Kyprolis® (carfilzomib). 
 
Last Dose Date of Study Treatment  
The Last Dose Date of Study Treatment for a subject is the last date when a non-zero 
dose of any study drug was administered. 
 
Last Known Alive Date 
Last Known Alive Date is the latest date before the death date, according to the dates 
recorded on relevant CRFs and in the data collected by the vendors (which will be 
specified in a separate document). 
 
Minimal Residual Disease Negative-Complete Response (MRD[-]CR) Rate 
MRD[-]CR rate is defined as the proportion of subjects with achievement of CR or better 
by IRC per IMWG-URC and achievement of MRD negativity as assessed by 
next-generation sequencing (NGS) method at a 10-5 threshold over the duration of the 
study among all ITT subjects. 
 
MRD[-] Rate at 12 Months 
MRD[-] rate at 12 months is defined as the proportion of subjects with achievement of 
MRD negativity at 12 months (± 4 weeks) from randomization, as assessed by NGS 
method at a 10-5 threshold among all ITT subjects. Per protocol, the 12-month sample 
may be omitted if the MRD analysis with confirmed results was performed within 4 
months prior to the scheduled test at 12 months from randomization, or if subject has 
started new antimyeloma therapy prior to 12-month landmark, or if disease progression 
is recorded. So, MRD negativity results from bone marrow samples obtained at 8 to 13 
months from randomization and prior to new antimyeloma therapy or disease 
progression will be considered in the calculation.  


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Overall Response Rate (ORR) 
ORR is the proportion of ITT subjects whose best overall response is sCR, CR, VGPR, 
or PR per IMWG-URC over the duration of the study. 
 
Overall Survival (OS) 
OS is defined as the time (in months) from randomization to the date of death due to any 
cause. 
OS = (death date or censoring date - randomization date + 1) / 30.4 
Subjects still alive or lost to follow-up or withdrawn consent from study by the analysis 
time will be censored at the date on which the subject is last known to be alive. 
 
Progression-Free Survival (PFS)  
PFS will be calculated from the date of randomization until the first documentation of PD 
or death due to any cause, whichever occurs first. 
PFS (month) = (PD/death date or censoring date - randomization date + 1) / 30.4 
The duration of PFS will be right censored for subjects who meet any one of the 
following conditions: (1) no baseline/no post-baseline disease assessments; (2) starting 
a new anti-myeloma therapy before documentation of progressive disease or death; (3) 
progressive disease or death immediately after more than 1 consecutively missed 
disease assessment visit (that is, progressive disease or death immediately after more 
than 63 days without disease assessment visit); (4) alive without documentation of 
disease progression before the analysis trigger date; (5) lost to follow-up or withdrawn 
consent. These censoring rules for PFS primary analysis are following the derivations 
used for historical ASPIRE study.  
Table 5-1. Censoring Rules for Primary PFS Analysis 
Situation 
Date of Progression or Censoring Outcome 
No baseline/no post-baseline 
disease assessments 
Date of randomization 
Censored 
New anti-myeloma treatment 
started before documentation 
of PD or death 
Date of last disease assessment 
prior to start of a new anti-myeloma 
treatment 
Censored 
Death or PD immediately after 
more than 1 consecutively 
Date of last disease assessment 
visit before the first missed visit 
Censored 


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missed disease assessment 
visit* 
Alive and without PD 
documentation 
Date of last disease assessment 
Censored 
Lost to follow-up or withdrawn 
consent 
Date of last 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 PD 
assessment 
Date of death 
Progressed 
 
* If death or PD is more than 63 days after previous disease assessment (63 days corresponds 
to approximately 2 cycles plus a 7-day window), or randomization date if there is no previous 
disease assessment. 
 
 
Patient-reported Convenience 
Patient-reported convenience is measured by the Patient-reported Convenience 
with Carfilzomib-dosing Schedule Question. The questionnaire is a carfilzomib-
specific convenience single-item/question and will be collected on Day 1 of Cycle 
2, Cycle 5 and Cycle 12 before dosing, and safety follow-up. The items in the 
questionnaire will be collapsed into two categories for analysis purpose: 
Convenient, and Inconvenient, where 
 
Convenient = 4 (Very convenient), 3 (Convenient) 
 
Inconvenient = 2 (Inconvenient) or 1 (Very inconvenient) 
For the comparison analysis of key secondary endpoint (patient-reported 
convenience after Cycle 4 of treatment), subjects who reported at least one “Very 
convenient” or “Convenient” after Cycle 4 will be included in the Convenient 
category; subjects with missing response of patient-reported convenience at all 
visits after cycle 4 will be included in the Missing category; otherwise, subjects 
will be in the Inconvenient category. 
 
Relative Dose Intensity (RDI) 
RDI reflects whether the dose intensity of a therapy was implemented as planned. It will 
be calculated as the ratio of actual dose intensity relative to planned dose intensity.  
 
Relative Dose Intensity (%) = 100 × Actual Dose Intensity
Planned Dose Intensity 
 
Carfilzomib:  


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Actual dose intensity is defined as the actual amount of carfilzomib in mg/m2 delivered to 
a subject per week of treatment.  
Actual Dose Intensity (mg/𝑚2/week) = Actual Cumulative Dose of Carfilzomib (mg/m2)
Number of Weeks of Actual Treatment
 
Actual cumulative dose of carfilzomib (mg/m2) is the sum of received doses (mg) divided 
by body surface area (BSA) (m²) of the subject. BSA is to be determined by the 
Mosteller Formula (Mosteller 1987):   
BSA (m²) = ([Height (cm) × Weight (kg)] / 3600) ½ 
BSA should be calculated at baseline and utilized to calculate required carfilzomib 
doses.  BSA should be recalculated if weight changes by more than 20% (gain or loss 
from weight used in the previous BSA calculation), and the new recalculated BSA will be 
used for subsequent infusions until further weight changes by more than 20%. If BSA is 
> 2.2 m2, then BSA will be capped at 2.2 for carfilzomib dose calculation.  
Number of weeks of actual treatment will be calculated as (Last Dose Date of 
Carfilzomib – First Dose Date of Carfilzomib + i) / 7, where i = 7 if the last infusion is 
given on day 1 or 8 within the last cycle, i = 6 if the last infusion is given on day 2 or 9, i 
= 14 if the last infusion is given on day 15, i = 13 if the last infusion is given on day 16.   
Planned dose intensity is defined as the planned amount of carfilzomib in mg/m2 
delivered to a subject per week of treatment. It will be calculated as the planned 
cumulative dose of carfilzomib in mg/m2 divided by the planned number of weeks for the 
treatment per protocol based on the corresponding cycle and day of the last carfilzomib 
infusion. 
Planned Dose Intensity (mg/𝑚2/week)
= Planned Cumulative Dose of Carfilzomib (mg/m2)
Number of protocol specified treatment weeks   
Per protocol, one cycle is 28 days (4 weeks), so the planned number of treatment weeks 
will be calculated as 4 x (c-1) + j, where c is the cycle in which the last carfilzomib 
infusion is given, and j =1 if the last carfilzomib infusion is given on day 1 or 2 within the 
last cycle, j=2 if the last infusion is given on day 8 or 9, j=4 if the last infusion is given on 
cycle day 15 or 16.   
The planned cumulative dose of carfilzomib is the sum of planned carfilzomib dose 
(mg/m2) per week as specified in Table 5-2 across the planned treatment weeks. 


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Table 5-2. Planned Carfilzomib Dose Schedule 
Arm 
Cycle 
Week 
Protocol Specified Dose for 
Treatment Week (mg/m2) 
Carfilzomib 56 mg/m2 
QW with lenalidomide 
and dexamethasone 
1 
1st  
20 (on Day 1) 
2 or later 
1st 
56 (on Day 1) 
All cycles 
2nd  
56 (on Day 8) 
3rd 
56 (on Day 15) 
4th  
0 
Carfilzomib 27 mg/m2 
BIW with lenalidomide 
and dexamethasone 
1 
1st  
40 (20 on each day of Day 1 & 2) 
2 or later 
1st  
54 (27 on each day of Day 1 & 2) 
All cycles 
2nd   
54 (27 on each day of Day 8 & 9) 
3rd 
54 (27 on each day of Day 15 & 16) 
4th  
0 
 
Dexamethasone:  
The actual dose intensity is the actual amount of dexamethasone in mg delivered to a 
subject per week of treatment.  
Actual Dose Intensity (mg/week) = Actual Cumulative Dose of Dexamethasone (mg)
Number of Weeks of Actual Treatment
 
The actual cumulative dose of dexamethasone in mg is the sum of total quantity 
administered (mg) over the study.  
Number of weeks of actual treatment will be calculated as (Last Dose Date of 
dexamethasone – First Dose Date of dexamethasone + i) / 7, where i = 7 if the last 
dexamethasone dose is given on day 1, 8, 15, and 22 in cycle 1-9 or given on day 1, 8 in 
cycle 10 or later cycle, i = 6 if the last dose is given on day 2, 9, 16 in cycle 1-9, or on 
day 2, 9 in cycle 10 or later, i =14 if the last dose is given on day 15 in cycle 10 or later 
cycle, i = 13 if the last dose is given on day 16 in cycle 10 or later.   
Planned dose intensity (mg/week) is defined as the planned amount of dexamethasone 
in mg delivered to a subject per week of treatment. It will be calculated as follows. 
Planned Dose Intensity (mg/week) = Planned Cumulative Dose of dexamethasone (mg)
Number of protocol specified treatment weeks  
Per protocol, one cycle is 28 days (4 weeks), so the planned number of treatment weeks 
will be calculated as 4 x (c-1) + j, where c is the cycle in which the last dexamethasone 


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dose is taken, and j =1 if the last dexamethasone dose is taken on day 1 or 2, j=2 if the 
last dose is taken on day 8 or 9, j=3 if the last dose is taken on day 15 or 16 in cycle 1-9, 
j=4 if the last dose is taken on day 22, j=4 if the last dose is taken day 15 or 16 in cycle 
10-12.   
The planned cumulative dose of dexamethasone is the sum of planned dexamethasone 
dose (mg) per week as specified in Table 5-3 (40 mg per week for week 1-4 in cycle 1-9, 
40 mg per week for week 1-3 and 0 for week 4 in cycle 10 or later) across the planned 
treatment weeks.  
Table 5-3.  Planned Dexamethasone Dose Schedule 
Cycle 
Week Day (Arm) 
Protocol Specified Dose 
(mg) 
All cycles 
1st  
Day 1 (KRd 56 mg/m2 QW)  
40 
Day 1 & 2 (KRd 27 mg/m2 BIW) 
40 on Day 1 (or 20 on 
each day of Day 1 & 2) 
All cycles 
2nd  
Day 8 (KRd 56 mg/m2 QW) 
40 
Day 8 & 9 (KRd 27 mg/m2 BIW) 
40 on Day 8 (or 20 on 
each day of Day 8 & 9) 
All cycles 
3rd  
Day 15 (KRd 56 mg/m2 QW) 
40 
Day 15 & 16 (KRd 27 mg/m2 BIW) 
40 on Day 15 (or 20 on 
each day of Day 15 & 16) 
Cycle 1 – 9 
4th  
Day 22  
40 
Cycle 10-12 
4th  
Day 22 
0 
 
Lenalidomide:  
The actual dose intensity is the actual amount of drug in mg delivered to a subject per 
week of treatment.  
Actual Dose Intensity (mg/week) = Actual Cumulative Dose of Lenalidomide (mg)
Number of Weeks of Actual Treatment
 
The actual cumulative dose of lenalidomide in mg is the sum of total quantity 
administered (mg) over the study.  
Number of weeks of actual treatment will be calculated as (Last Dose Date of 
lenalidomide – First Dose Date of lenalidomide + i) / 7, where the value of i depends on 
the last dose day in a cycle, which is shown in the table below.  
Day # of last lenalidomide dose in a cycle 
Value of i 
Day 1 or 8 
7 
Day 2 or 9 
6 


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Day 3 or 10 
5 
Day 4 or 11 
4 
Day 5 or 12 
3 
Day 6 or 13 
2 
Day 7 or 14 
1 
Day 15 to Day 21 
14 - (Day # - 15) 
 
Planned dose intensity (mg/week) is defined as the planned amount of lenalidomide in 
mg delivered to a subject per week of treatment. It will be calculated as follows. 
Planned Dose Intensity (mg/week) = Planned Cumulative Dose of lenalidomide (mg)
Number of protocol specified treatment weeks 
Per protocol, one cycle is 28 days (4 weeks), so the planned number of treatment weeks 
will be calculated as 4 x (c-1) + j, where c is the cycle in which the last lenalidomide dose 
is given, and j =1 if the last lenalidomide dose is given on day 1 - 7, j=2 if the last dose is 
given on day 8 -14, j=4 if the last dose is given on day 15 - 21.   
The planned cumulative dose of lenalidomide is the sum of planned lenalidomide dose 
(mg) per week as specified in Table 5-4 (175 mg per week for week 1-3) across the 
planned treatment weeks. 
Table 5-4. Planned Lenalidomide Dose Schedule 
Cycle 
Week 
Day 
Protocol Specified Dose (mg)  
All cycles 
1st  
Day 1 - 7 
175 (25 mg per day) 
 
2nd  
Day 8 - 14 
175 (25 mg per day) 
 
3rd  
Day 15 - 21 
175 (25 mg per day) 
 
4th  
Day 22 - 28 
0 
 
Refractory to Prior Multiple Myeloma Therapy  
Subject is refractory to a drug of interest received during prior regimens if the data 
collected on Prior Multiple Myeloma Therapy (CHEMOTHERAPY AND TRANSPLANT) 
CRF page indicates that any of the following criteria is met: 


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a. 
The best response reached during at least one regimen containing the drug of 
interest was stable disease or progressive disease 
b. 
The reason that the drug of interest was stopped was progression in at least one 
regimen  
c. 
The date of relapse/progression is after start date and within 60 days after stop 
date of the drug on interest in at least one regimen 
 
Study Day 1  
Study day 1 for a subject corresponds to the earliest date when any study drug 
(carfilzomib, lenalidomide, or dexamethasone) is administered. For subjects who were 
never treated, study day 1 corresponds to the randomization date. 
 
Study Day 
The number of days from the study day 1 to a date of interest, inclusive:  
Study day = (date of interest – date of study day 1) + 1, where the date of interest is on 
or after the date of study day 1.  
Study day = (date of interest – date of study day 1), where the date of interest is before 
the date of study day 1. The study day is negative 1 for the day before Study Day 1. 
 
Time to Progression (TTP)  
TTP is defined as the duration (in months) from randomization to the first documented 
disease progression. 
TTP (month) = (documented PD date or censoring date - randomization date + 1) / 30.4 
The same censoring rule as per PFS described in Table 5-1 will be used for TTP except 
that death will be treated as a censoring event.   
 
Time to Response (TTR) 
TTR will be calculated only for subjects who achieve a best overall response of PR or 
better, i.e., sCR, CR, VGPR, or PR, and it will be calculated in months from 
randomization date to the earliest date when a PR or better is first achieved and 
subsequently confirmed: 


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TTR (month) = (confirmed response start date - randomization date + 1) / 30.4 
 
Treatment-emergent Adverse Event (TEAE)  
Treatment-emergent adverse events are defined as adverse events starting on or after 
the first dose of any study drug, and up to 30 days (inclusive) of the last dose of any 
study drug, excluding adverse events reported after End of Study date. 
6. 
Analysis Sets 
The analysis and reporting of the data from this study will be performed using the 
following analysis populations: 
6.1 
Intent-to-Treat (ITT) Analysis Set (Full Analysis Set) 
The ITT population constitutes all randomized subjects and will be the basis for the 
analyses of efficacy in this study.  Subjects in the analyses based on the ITT population 
will be analyzed according to the treatment arm to which they were randomized. 
6.2 
Safety Analysis Set 
The safety population includes all randomized subjects who receive at least 1 dose of 
any study treatment (carfilzomib, lenalidomide, or dexamethasone), and will be the basis 
for the analyses of safety.  Subjects in the analyses based on the safety population will 
be analyzed according to the treatment arm corresponding to the actual treatment 
received.   
6.3 
Per Protocol Set 
The per-protocol population will include all randomized subjects who do not have any 
major protocol deviations that might affect the interpretation of the analyses of the 
efficacy endpoints. Subjects with the following important protocol deviation (IPD) will be 
excluded from the per protocol set.  
 
Major inclusion criteria not met (103 - 109 in protocol):  
o Documented relapse or progression after the most recent myeloma treatment. 
Subjects refractory to the most recent line of therapy are eligible, unless the last 
treatment contained PI or lenalidomide and dexamethasone) (103) 
o Subjects must have at least PR to at least 1 line of prior therapy (104) 
o Subjects must have received at least 1 but not more than 3 prior lines of therapy 
for multiple myeloma (induction therapy followed by stem cell transplant and 
consolidation maintenance therapy will be considered as 1 line of therapy) (105) 


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o Inclusion criteria of prior therapy with PI (106) 
o Inclusion criteria of prior therapy with a lenalidomide and dexamethasone 
containing therapy (107) 
o Inclusion criteria of measurable disease (108) 
o Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 2 
(109) 
 
Major exclusion criteria not met 
 
Disease related (201 - 206 in protocol): 
o Waldenström macroglobulinemia (201) 
o Multiple myeloma of IgM subtype (202) 
o POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes) (203) 
o Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard 
differential) (204) 
o Primary amyloidosis (patients with multiple myeloma with asymptomatic 
deposition of amyloid plaques found on biopsy would be eligible if all other 
criteria are met) (205) 
o Myelodysplastic syndrome (206) 
 
Other medical conditions (207 - 211 in protocol): 
o History of other malignancy within the past 5 years (other than protocol specified 
exceptions) (207) 
o Known HIV infection, or uncontrolled hepatitis B or C infection (subjects without 
sustained virologic response) (208) 
o Ongoing Graft versus host disease (209) 
o Acute active infection requiring systemic antibiotics, antifungal, antiviral agents 
(except antiviral therapy directed at hepatitis B) within 14 days prior to 
randomization (210) 
o Known cirrhosis (211) 
Cardiopulmonary considerations (214 - 215 in protocol): 
o Uncontrolled hypertension (214) 
o Active congestive heart failure (New York Heart Association Class III to IV) (215) 


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Prior or concomitant therapy (218 - 222, 228 in protocol): 
o Immunotherapy, monoclonal antibody therapy or approved anti-cancer 
chemotherapy within 28 days prior to randomization (218, 219, 220) 
o Glucocorticoid therapy exceeding a cumulative dose of 160mg within 14 days 
prior to randomization (221) 
o Focal radiation therapy within 7 days prior to randomization, radiation to large 
marrow reserves within 28 days (i.e., prior radiation must have been to <30% of 
the bone marrow) (222) 
o Currently receiving treatment in another investigational device or drug study 
within 28 days of randomization (228) 
Organ Function Assessment: 
o Calculated or measured creatinine clearance < 30 mL/min (calculation must be 
based on the Cockcroft and Gault formula) within 28 days prior to randomization 
(244)  
 
Major treatment non-compliance 
o Treatment received different from treatment randomized (IPD Criteria 500). 
o Incorrect carfilzomib dose: under-dosing that meets IPD Criteria 502. 
o Failure to obtain extramedullary plasmacytoma assessment and /or bone lesion 
assessment as part of baseline disease assessment such that the primary 
endpoint cannot be assessed (IPD Criteria 801).  
o Any C1D1 disease assessment or disease specific lab required at baseline is 
missed or collected in such a way that patient is not measurable as defined per 
protocol (IPD Criteria 802). 
o Failure to obtain 2 consecutive disease response assessments that may impact 
the assessment of the primary endpoint (IPD Criteria 803). 
6.4 
Pharmacokinetic/Pharmacodynamic (PK/PDn) Analyses Set(s) 
The PK Analysis Set will include all subjects who have received at least 1 dose of 
carfilzomib and 1 post-dose PK sample collected, as defined by the Schedule of 
Assessments. The PDn Analysis Set will include a subset of subjects in the PK Analysis 
set who have consented to participate in the optional PK/PDn substudy. These subjects 
will be evaluated for pharmacokinetics and pharmacodynamics unless significant 


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protocol deviations affect data analysis or if key dosing, dosing interruption, or sampling 
information is missing. 
6.5 
Interim Analyses Set 
The interim analysis set for interim futility analysis include the first 230 subjects (50% of 
the planned total 460 subjects) who have been randomized and had the opportunity to 
be followed for a BOR assessment by the date when treatment was completed, 
confirmed PD or death occurred, subject was lost to follow-up, withdrew consent, or 
started new antimyeloma therapy, whichever occurred first. 
6.6 
Modified Full Analysis Set 
The modified full analysis set (mFAS) will be used in the sensitivity analysis for primary 
endpoint and key secondary endpoints in order to adjust for the COVID-19 impact on the 
ITT population. The mFAS is a subset of ITT Analysis Set excluding subjects who are 
impacted by COVID-19.  
The COVID-19 impact refers to:  
(1) any COVID-19 adverse events which are identified using the COVID-19 
Standardized MedDRA Query (SMQ) narrow search strategy, and COVID-19 events 
collected on the Confirmed COVID-19 Status CRF;  
(2) the reason for Investigational Product (IP)/Non-IP Dose Change/Withheld/Dose 
Delay is COVID-19 control measures recorded on the CRFs for IP Administration and 
Non-IP Administration;  
(3) the reason for ending IP/Non-IP is COVID-19 control measures recorded on CRFs 
for End of IP Administration and End of Non-IP Administration;  
(4) IPDs related to COVID-19 control measures;  
(5) COVID-19 related protocol deviation: 940 series, 950 series and 960 series of 
protocol deviation codes in the study IPD list. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
An Independent Biostatistics Group (IBG) will perform the interim analyses and provide 
the interim report to an independent Data Monitoring Committee (DMC). The initial 
assessment from this committee will be planned after 30 subjects (approximately 15 for 
the experimental arm and 15 for the control arm) have been enrolled and have finished 
the first cycle of treatment to ensure safety of all arms. Thereafter, the DMC will review 


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all available safety/efficacy data periodically (approximately every 6 months) and 
evaluate the efficacy analysis once for the non-binding interim analysis for futility. The 
primary purpose of the interim futility analysis is to assess the futility in terms of ORR. 
The non-binding interim futility analysis is planned to occur when the first 230 subjects 
(50% of the planned total 460 subjects) have been randomized and had the opportunity 
to be followed for a best overall response (BOR) assessment by the date when 
treatment was completed, confirmed PD or death occurred, subject was lost to follow-up, 
withdrew consent, or started new antimyeloma therapy, whichever occurred first. Using 
an O’Brien-Fleming type beta-spending function, the stopping boundary for futility in p-
value scale is 0.289. The study is futile in terms of ORR if the observed p-value > 0.289. 
With such a stopping boundary, the trial has over 70% probability to stop for futility when 
the null hypothesis of inferiority is true.  
The IBG and DMC will have access to subjects’ individual treatment assignments.  To 
minimize the potential introduction of bias to the conduct of the study, members of the 
DMC and IBG will not have any direct contact with study center personnel or subjects. 
The DMC will communicate major safety concerns and recommendations regarding 
study modification or termination based on the safety data and interim futility stopping 
criteria to Amgen in accordance with the DMC charter. 
Records of all meetings will be maintained by the DMC for the duration of the study.  
Records of all meetings will be transferred and stored in the TMF (in accordance with 
SOP-427356) at the conclusion of the study.  
Further details are provided in the DMC charter. 
Data will be subject to ongoing checks for integrity, completeness, and accuracy in 
accordance with the Data Management Plan with the expectation that all outstanding 
data issues are resolved ahead of the snapshot.  The data will be locked to prevent 
further changes, and a snapshot of the locked database will be used in the analysis. 
7.2 
Primary Analysis 
The primary analysis corresponds to the final analysis. 
7.3 
Final Analysis 
The final analysis will be performed after all subjects have completed the study. Final 
analysis will be based on a clean database lock.   
The hypotheses for the primary and key secondary objectives (ORR, PFS, and 
convenience after cycle 4 of treatment) will be tested using a fixed sequence hierarchical 


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testing procedure to control the family-wise type I error rate at 1-sided 0.025 level.  The 
testing is ordered as follows: non-inferiority of ORR, non-inferiority of PFS, and 
superiority of patient-reported convenience after cycle 4 of treatment.  
Starting with the hypothesis of ORR, if any null hypothesis in the sequence is rejected at 
a 1-sided significance level of 0.025, then the subsequent null hypothesis will be tested.  
Otherwise, if any null hypothesis failed to be rejected, then the subsequent hypotheses 
will not be tested.   
For the primary endpoint, the stopping boundary is 0.025 in p-value scale in the final 
analysis.  
The final analysis of efficacy endpoints will be based on the ITT analysis set, while the 
final analysis of safety endpoints will be based on the safety analysis set. Sensitivity 
analyses of efficacy endpoints based on the per protocol set might be performed only if 
the PP population was less than 90% of the ITT population. 
 
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 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 
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. 
Laboratory data will be collected by COVANCE Central Laboratory Services and 
transferred to Amgen GSO-DM periodically in cumulative files. Quality of life data will be 
collected by ERT and transferred to Amgen GSO-DM periodically in cumulative files. 
The data handling and electronic transfer of data are described in the data management 
plan (DMP). 
8.3 
Handling of Missing and Incomplete Data 
The descriptive statistics will identify the extent of missing data. Rules for handling 
missing data related to endpoints are described in the endpoint definitions or in the 
description of analyses. The handling of incomplete and partial dates for adverse events, 


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concomitant medications, new antimyeloma therapy, death, prior multiple myeloma 
therapy, and relapse/progression to prior multiple myeloma therapy are described in 
Appendix A. 
The calculation of scores and methods to deal with missing data will be handled 
according to the EORTC QLQ-C30 questionnaire's standard scoring guidelines. 
No imputation will be done for the analysis of the primary and key secondary endpoints.  
The frequency of missing disease assessments and deviation of the actual disease 
assessment times from the scheduled assessment times will be summarized by 
treatment arms.  Sensitivity analyses will be performed to assess the impact of missing 
any disease or response assessment on the analysis of ORR and PFS (i.e., analysis in 
Per Protocol Set).  Similar analysis will be performed for QOL endpoints. 
8.4 
Detection of Bias 
If applicable the methods to detect bias are described in the analyses of particular 
endpoints (Section 9). 
8.5 
Outliers 
Any suspected outliers will be investigated by the study team and will be included in the 
database unless determined to be an error or there is supporting evidence or 
explanation to justify the exclusion. Any outliers excluded from the analysis will be 
discussed in the Clinical Study Report (CSR), including the reasons for exclusion and 
the impact of their exclusion on the study. Pharmacokinetic (PK) plasma 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 
If applicable, the distributional characteristics will be explored for endpoints. The 
statistical assumptions for analysis methods will be assessed. If the assumptions for the 
distributional characteristics are not met, these will be described, and further analyses 
may be carried out using data transformations or alternative analysis methods. The use 
of transformations or alternative analysis methods will be justified in the final study 
report. 
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.   


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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 
Where applicable, descriptive statistics will be provided. For continuous variables, the 
number of subjects with non-missing data (n), mean, standard deviation (STD), median, 
minimum, and maximum will be presented. For categorical variables, the frequency (n) 
and percentage will be summarized in each category. The denominator for percentages 
is the number of subjects in the analysis set of interest for the summary. The binomial 
proportions and the corresponding 95% confidence intervals (CIs) will be based on the 
exact distribution methods (Clopper-Pearson interval) and the treatment comparison will 
be based on Cochran-Mantel-Haenszel (CMH) method. Time to event endpoints will be 
estimated using the Kaplan-Meier (KM) method and will be summarized with the number 
of subjects with events or censored, and censoring reasons, KM quartiles (when 
estimable) and corresponding two-sided 95% CIs, KM proportions at select time points, 
inferential comparison between treatment arms with associated p-values, hazard ratios 
from stratified Cox proportional hazard (PH) model, and KM curves.   
The analyses of efficacy and safety endpoints will be based on the analysis sets defined 
in Section 6.  The primary (final) analyses of the efficacy endpoints and Patient-report 
outcomes will use the ITT population, while the Per Protocol Set will be used for 
sensitivity analyses, if applicable. The analyses of the safety endpoint will be based on 
the safety population. 
The primary analysis of ORR and PFS will be based on IRC assessed outcomes. The 
synthesis approach will be used to show that KRd 56 mg/m2 QW preserves at least 60% 
of KRd 27 mg/m2 BIW effect vs Rd in terms of ORR and 50% in terms of PFS. The null 
hypotheses for the primary and key secondary objectives (ORR, PFS, and convenience 
after cycle 4 of treatment) will be tested using a fixed sequence hierarchical testing 
procedure to control the family-wise type I error rate at 1-sided 0.025 level. The testing is 
ordered as follows: non-inferiority of ORR, non-inferiority of PFS, and superiority of 
patient-reported convenience after cycle 4 of treatment. Starting with the hypothesis of 
ORR, if any null hypothesis in the sequence is rejected, then the subsequent hypothesis 


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will be tested.  Otherwise, if any hypothesis failed to be rejected, then the subsequent 
hypotheses will not be tested. For all other endpoints, the significance testing, if 
performed, will be considered descriptive. 
Subgroup analyses of the primary endpoint will be performed as exploratory analyses for 
selected baseline factors. 
9.2 
Subject Accountability 
The following subject disposition information will be summarized by treatment arm. 
 
Number of subjects screened 
 
Number (%) of subjects screened but not randomized  
 
Number (%) of subjects randomized 
 
Number (%) of subjects randomized but not dosed, along with the reasons for not 
being dosed 
 
Number (%) of subjects who received any cycle of treatment for each study drug 
(carfilzomib, lenalidomide, dexamethasone)  
 
Number (%) of subjects who completed the 12 cycles of treatment for each study 
drug (carfilzomib, lenalidomide, dexamethasone) 
 
Number (%) of subjects who discontinued treatment for each study drug 
(carfilzomib, lenalidomide, dexamethasone), along with the reasons for 
discontinuation of treatment 
 
Number (%) of subjects who discontinued each study drug (carfilzomib, 
lenalidomide, dexamethasone) due to COVID-19 impact 
 
Number (%) of subjects who completed the study, and who discontinued the 
study, along with the reasons for discontinuation 
Key study dates for the first subject enrollment, last subject enrollment, last subject last 
dose of investigational product, and last subject end of study will be presented. 
The number (%) of subjects who were enrolled will be tabulated by region, country and 
investigator site and randomization stratification factors for each treatment arm in ITT 
Analysis Set. 
The listing of unique manufacturing lot numbers and the subject listing of manufacturing 
lot numbers will also be generated. 


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9.3 
Important Protocol Deviations 
IPD 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. The following 
information of IPD and protocol deviations will be summarized, where applicable, with 
respect to the following: 
 
Number (%) of subjects with IPDs and total number of IPDs will be summarized 
by category and sub-category by treatment arm in ITT Analysis Set  
 
Number (%) of subjects with IPDs related to COVID-19 control measures will be 
summarized by treatment arm in ITT Analysis Set 
 
Number (%) of subjects with COVID-19 protocol deviations by protocol deviation 
category (940 series, 950 series and 960 series of protocol deviations codes) 
and by treatment arm in ITT Analysis Set 
 
Subject listing of IPD in ITT Analysis Set, including COVID-19 related IPDs with 
the descriptions 
 
Subject listing of COVID-19 protocol deviations based on protocol deviations 
category (940 series, 950 series and 960 series of protocol deviations codes) in 
ITT Analysis Set 
 
Subject listing of inclusion/exclusion criteria deviations 
9.4 
Demographic and Baseline Characteristics 
The following demographic and baseline disease characteristics will be summarized by 
treatment arm and overall using descriptive statistics for the ITT Analysis Set.  
 
Baseline demographics and characteristics:  
− Age (years) (as continuous variable, as categorical variable: <65, ≥65; 18 - <65,   
65 - <75, ≥75; 18 - <65, 65 - <75, 75 - <85, ≥85, unknown)  
− Sex (female, male)  
− Race (White and other categories depending on frequency observed)  
− Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
− Region (Europe, Non-Europe)  
− Height (cm) 
− Weight (kg) 


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− BSA (m2) (as continuous variable, as categorical variable: ≤2.2, >2.2) 
− Body mass index (BMI) (kg/m2) 
 
Baseline organ function and comorbid conditions:  
− ECOG PS (0-1, 2)  
− Hemoglobin (g/L) 
− Absolute Neutrophil Count (109/L) 
− Platelet Count (109/L) 
− Corrected calcium (mg/dL): calculated by Covance (central laboratory) 
      as [serum calcium (mg/dL) + 0.8 × (4 - serum albumin (g/dL))] (as continuous in 
mg/dL; as categorical variable: ≤11.5, >11.5) 
− Creatinine clearance (CrCl, mL/min) (as continuous variable, as categorical  
   variable: <30, 30 - <50, 50 - <80, ≥80; <50, ≥50) 
   Measured or calculated CrCl according to the Cockcroft-Gault formula by Covance   
   (central laboratory): 
)
85
.0
(
)
/
(
72
)
(
)
140
(
min)
/
(
female
dL
mg
S
kg
Weight
Age
mL
CrCL
Cr





 
− Left ventricular ejection fraction (LVEF) (%) 
− Hypertension history (yes, no) 
− Cardiopulmonary history (yes <by diagnosis category>, no) 
 
Baseline disease characteristics:  
− Original ISS stage (1 or 2, 3) at study entry per IxRS 
− Original ISS stage at baseline (1 or 2, 3) (derived based on the definition in Section 5) 
− Prior lenalidomide treatment (yes vs no)  
− Prior PI treatment (yes vs no) 
− Prior anti-CD38 exposure (yes vs no) 
− Prior bortezomib treatment (yes vs no) 
− Number of prior therapies (1 vs >1; 1 vs 2 vs >2) 
− Cytogenetic risk measured by FISH (high risk (t(4;14), t(14;16), deletion 17p), 
standard risk, missing) 
− Bortezomib refractory status (yes vs no) 
− Lenalidomide refractory status (yes vs no) 
− PI refractory status (yes vs no) 
− Anti-CD38 refractory status (yes vs no) 
− Refractory to the last prior line of therapy (yes vs no) 
− Presence of plasmacytoma (yes, no) 
− Prior transplant (yes, no) 
− Prior tobacco use (yes, no) 


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− β2-microglobulin level (mg/L) (as continuous variable; as categorical variable:  
   <3.5, ≥3.5 and <5.5, ≥5.5) 
− Albumin (g/dL) (as continuous variable; as categorical variable: <3.5, ≥3.5) 
− Time from initial multiple myeloma diagnosis to randomization (months) 
− Immunoglobulin heavy and light chain types (IgA, IgD, IgE, IgM, IgG, None;  
   Kappa, Lambda, Not detectable within each heavy chain type) 
− Time since last relapse (months) 
In addition, the analysis population in each analysis set will be summarized for each 
treatment arm. The listing of randomization will be also generated. 
9.5 
Efficacy Analyses 
The main efficacy analyses will be based on the ITT Analysis Set. Other Analysis Sets 
might be used for various sensitivity analyses. 
Table 9-1. Primary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method  
Sensitivity Analysis 
Overall Response over 
the duration of the 
study 
Response based on IRC 
assessments: 
 
Point estimate of ORR and 
associated 95% CI (Clopper 
Pearson method) by treatment 
arm  
 
Risk ratio and associated 95% 
CI using Cochran-Mantel-
Haenszel (CMH) method 
controlling for randomization 
stratification factors as a 
measure of treatment effect 
 
P-value (1-sided, 2.5% 
significance level in the final 
analysis) of non-inferiority test 
via synthesis approach to show 
that KRd 56 mg/m2 QW 
preserves at least 60% of KRd 
27 mg/m2 BIW effect vs Rd  
 
Response based on 
investigator assessments: 
Same as primary 
summary and analysis 
method  
 
Response based on 
internal computational 
assessments: Same as 
primary summary and 
analysis method based on 
Onyx response computer 
algorithm (ORCA) 
assessments 
 
Unstratified analyses: risk 
ratio and associated 95% 
CI from unstratified CMH 
 
Per Protocol Set: Same as 
primary summary and 
analysis method 
mFAS: Same as primary 
summary and analysis 
method 


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Table 9-2. Secondary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method 
Sensitivity Analysis 
PFS over the duration 
of the study 
PD based on IRC assessments: 
 
KM estimates for PFS 
distribution by treatment arm 
and PFS rates with 95% CI at 6 
and 12 months 
 
Hazard ratio and 95% CI from 
stratified Cox proportional 
hazards (PH) model 
 
P-value (1-sided, 2.5% 
significance level) of non-
inferiority test via synthesis 
approach to show that KRd 
56 mg/m2 QW preserves at 
least 50% of KRd 27 mg/m2 
BIW effect vs Rd. The testing is 
done once at the primary (final) 
analysis on ITT analysis set. 
 
Restricted mean survival 
time (RMST) with 95% CI in 
each arm and the between-
arm difference in RMST with 
95% CI based on ITT analysis 
set 
 
Observed treatment effect 
retention rate based on ITT 
analysis set 
 
PD based on investigator 
assessments: Same as 
primary summary and 
analysis method  
 
PD based on internal 
computational 
assessments (ORCA): 
Same as primary 
summary and analysis 
method  
 
Unstratified analyses: 
hazard ratio and 95% CI 
from unstratified Cox PH 
model 
 
Per Protocol Set: Same as 
primary summary and 
analysis method 
 
mFAS: Same as primary 
summary and analysis 
method 
 
Initiation of new anti-
myeloma therapy treated 
as PFS Event: The data 
censoring rules are 
same as those for the 
primary analysis of PFS 
except that the use of 
new anti-myeloma 
therapy will be treated 
as an event rather than a 
mechanism for 
censoring. The same 
analysis method as for 
primary analysis will be 
used. 
 
Initiation of new anti-
myeloma therapy treated 
as neither a PFS event 
nor a censoring event: 
The data censoring rules 
are same as those for 
the primary analysis of 
PFS except that the 
initiation of new anti-
cancer therapy will be 
excluded as a 
mechanism for 
censoring. The same 


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Endpoint 
Primary Summary and Analysis 
Method 
Sensitivity Analysis 
analysis method as for 
primary analysis will be 
used 
 
Analysis based on 
scheduled assessment 
dates: same as primary 
summary and analysis 
methods, except that the 
analysis is based on the 
scheduled assessment 
dates instead of actual 
assessment dates 
 
Analysis using interval 
censoring: PFS data will 
be treated as interval-
censored (Section 9.5.2) 
Patient-reported 
Convenience with 
Carfilzomib-dosing 
Schedule Question 
after cycle 4 of 
treatment 
 
Proportion of patient-reported 
convenience and 95% CI 
(Clopper Pearson method) by 
treatment arm  
 
Odds ratio (OR) with 95% CI 
from the CMH method stratified 
by the randomization 
stratification factors as a 
measure of treatment effect for 
whether carfilzomib dosing is 
reported as convenient or 
inconvenient 
 
P-value (1-sided, 2.5% 
significance level) from the 
CMH chi-square test controlling 
for the randomization 
stratification factors. The 
testing is done once at the 
primary (final) analysis on ITT 
analysis set. 
 
Logistic regression model 
including the 
randomization 
stratification factors and 
treatment arm 
 
mFAS: Same as primary 
summary and analysis 
method 
Time to response  
Response based on IRC 
assessments: 
 
Descriptive statistics (mean, 
STD, median, minimum and 
maximum) among responders 
by treatment arm 
 
Response based on 
investigator assessments: 
Same as primary 
summary and analysis 
method  
Duration of response 
(DOR) 
Response based on IRC 
assessments: 
 
KM estimates for DOR 
distribution by treatment arm 
 
Response based on 
investigator assessments: 
Same as primary 
summary and analysis 
method  
Time to progression 
(TTP) 
PD based on IRC assessments: 
 
KM estimates by treatment arm  
 
PD based on investigator 
assessments: Same as 


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Endpoint 
Primary Summary and Analysis 
Method 
Sensitivity Analysis 
 
Stratified Cox PH model 
primary summary and 
analysis method 
OS over the duration of 
the study 
 
KM estimates for OS 
distribution by treatment arm 
and OS rate with 95% CI at 6 
and 12 months 
 
Hazard ratio and 95% CI from 
stratified Cox proportional 
hazards (PH) model 
 
Unstratified analyses: 
hazard ratio and 95% CI 
from unstratified Cox PH 
model 
 
Per Protocol Set: Same as 
primary summary and 
analysis method 
MRD[-]CR 
CR or better response component 
based on IRC assessments: 
 
MRD[-]CR rate and 95% CI 
(Clopper Pearson method) by 
treatment arm  
 
OR with 95% CI as a measure 
of treatment effect estimated 
by CMH method stratified by 
the randomization stratification 
factors 
 
Response based on 
investigator assessments 
for CR or better: Same as 
primary summary and 
analysis method  
 
Response based on 
internal computational 
assessments (ORCA): 
Same as primary 
summary and analysis 
method  
 
MRD[-] status at 12 
months from 
randomization 
 
MRD[-] rate and 95% CI 
(Clopper Pearson method) by 
treatment arm  
 
OR with 95% CI as a measure 
of treatment effect estimated 
by CMH method stratified by 
the randomization stratification 
factors 
 
Physical functioning 
and role functioning 
(scales of 
EORTC QLQ-C30) 
over time 
 
Repeated measures analysis of 
covariance (ANCOVA) 
adjusting for the baseline 
covariates (treatment arm, 
randomization stratification 
factors, baseline score and 
visit) for the comparison of 
mean score over time between 
treatment arms 
 
Per Protocol Set: Same as 
primary summary and 
analysis method 
 
Restricted maximum 
likelihood-based mixed 
model for repeated 
measures (MMRM) for the 
comparison of mean score 
over time between 
treatment arms 
Patient-reported 
treatment satisfaction 
(the SWT scale of 
CTSQ) after cycle 4 of 
treatment 
 
ANCOVA at the corresponding 
fixed time point 
 


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Table 9-3. Exploratory Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method 
Sensitivity Analysis 
Described in Section 
2.1 table 
Will be described in a supplemental 
analysis plan (SSAP) finalized 
before database lock 
Will be described in a SSAP 
finalized before database lock 
 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
The ORR will be calculated by treatment arm and the associated 95% CI will be 
estimated using the Clopper Pearson method (Clopper CJ and Pearson, 1934). As a 
measure of treatment effect, relative risk (risk ratio) and associated 95% CI will be 
estimated using CMH method controlling for randomization stratification factors. The 
KRd 27 mg/m2 BIW arm will serve as the reference treatment arm in the calculation of 
the risk ratio. The non-inferiority comparison of ORR between treatment arms will be 
performed using the synthesis approach (FDA, 2016) to show that KRd 56 mg/m2 QW 
preserves at least 60% of KRd 27 mg/m2 BIW effect vs Rd under the constancy 
assumption (the effect of KRd 27 mg/m2 BIW in the current study is consistent with the 
effect that was observed in the historical study ASPIRE). The 1-sided p-value from the 
non-inferiority test will be reported. 
The null and alternative hypotheses are expressed as: 
      H0: Un ≤ (1-r)*Uh     versus      Ha: Un > (1-r)*Uh 
 
The synthesis test statistic is calculated as: 
        [𝑈𝑛−(1 −𝑟) ∗𝑈ℎ] √𝑆𝐸𝑛2 + (1 −𝑟)2 ∗𝑆𝐸ℎ
2
⁄
  , where 
        r = retention rate = 60% 
       Uh = log-relative risk of ORR of Rd vs KRd 27mg/m2 BIW by cycle 12 from the 
historical study ASPIRE = log (0.755) 
       SEh = standard error of Uh = 0.041 
       Un = log-relative risk of ORR of KRd 56 mg/m2 QW vs KRd 27 mg/m2 BIW from this  
               non-inferiority study 
       SEn = standard error of Un  
In the primary (final) analysis, the H0 will be rejected if the synthesis test statistic > Z0.975, 
where Z0.975 is the critical value corresponding to a test of 1-sided Type I error rate of 
0.025. 
SAS code for calculating 1-sided p-value for the non-inferiority test: 


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data test; 
r = 0.6; 
Uh = log(0.755); 
SEh = 0.041; 
RR = x.xxx /*relative risk of ORR (QW arm vs BIW arm), driven by the   
             data from ARROW2 study*/ 
lowerCI = x.xxxx; upperCI = x.xxxx /*95% CI for RR, driven by the data  
                                     from ARROW2 study*/ 
Un = log(RR);  
SEn = (log(upperCI)-log(lowerCI))/(2*probit(1-0.05/2));  
SE_syn = sqrt(SEn**2+((1-r)*SEh)**2); 
z = (Un-(1-r)*Uh)/SE_syn;  
pvalue_1sided = 1-probnorm(z);  
run; 
 
In order to check the adequacy of the constancy assumption, the summaries of baseline 
demographics and characteristics in KRd 27mg/m2 BIW treatment arm from ARROW2 
study will be clinically evaluated by the DMC against those in ASPIRE historical study for 
clinical judgement on the consistency of the two trial populations.  
The primary analysis of ORR will be based on the IRC response assessments for the 
ITT Analysis Set. Several sensitivity analyses will be considered for ORR following the 
same method as the primary analysis: (1) analysis based on investigator assessment in 
ITT Analysis Set; (2) analysis based on ORCA assessments in ITT Analysis Set; (3) 
analysis based on the IRC assessments using unstratified model in ITT Analysis Set; (4) 
analysis based on the IRC assessments in Per Protocol Set; (5) analysis based on the 
IRC assessments in mFAS. The concordance rate between the results from the IRC, 
investigator and ORCA will be summarized.  
In order to align with the European Medicines Agency (EMA) “Guidance on the 
Choice of the Non-inferiority Margin” for non-inferiority trials (EMA, 
https://www.ema.europa.eu/documents/scientific-guideline/guidelinechoice-non-
inferioritymargin_en.pdf, 2005) and help with the interpretability of the results, 0.87 
is considered as a margin for RR estimated from primary analysis of ORR. This 
value is outside the 95% CI for RR of response rates by Cycle 12 (Rd vs KRd 27 
mg/m2 BIW) from the historical trial ASPRE (0.70, 0.82), and it was chosen in 
corroboration with clinical considerations for this patient population. 
Subgroup analyses will be performed to explore the consistency of the treatment effect 
on ORR for subgroups described in Section 4.2. The estimate of risk ratio with 95% CI 
using CMH method controlling for randomization stratification factors will be 
provided for ORR between the treatment arms. A forest plot will be produced for the 
estimated risk ratio with 95% CI of each subgroup. 


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9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
Key secondary efficacy endpoints 
 
If the null hypothesis for ORR is rejected at a 1-sided significance level of 0.025, then 
the key secondary endpoints will be tested by sequential testing in the order of non-
inferiority of PFS and superiority of patient-reported convenience after cycle 4 of 
treatment. Otherwise, if any null hypothesis failed to be rejected, then the subsequent 
hypotheses will not be tested.   
 
PFS is defined in Section 5. The number of subjects with PFS events or censored, and 
censoring reasons will be presented by treatment arm. The subcategory of death with 
the primary reason of COVID-19 infection or COVID-19 pneumonia will be included in 
the PFS events. The distribution of PFS time including median and other quartiles will be 
summarized descriptively using the KM method (Klein and Moeschberger, 1997). The 
corresponding 95% confidence intervals for the median and other quartiles will be 
constructed using KM method with log-log transformation. PFS rates at 6 and 12 months 
will be estimated, and the corresponding 95% CIs will be calculated using the method of 
Kalbfleisch and Prentice (1980). The duration of the follow-up for PFS will be estimated 
by reverse Kaplan-Meier method (Schemper and Smith 1996). KM curves will also be 
presented. The HR and its 95% CI will be estimated using a Cox proportional hazards 
model stratified by the randomization stratification factors. The KRd 27 mg/m2 BIW arm 
will serve as the reference treatment arm in the calculation of the HR.  
The non-inferiority comparison of PFS between treatment arms will be performed using 
the synthesis approach to show that KRd 56 mg/m2 QW preserves at least 50% of KRd 
27 mg/m2 BIW effect vs Rd. The 1-sided p-value from the non-inferiority test at 2.5% 
significance level will be reported. The synthesis test statistic and p-value will be 
calculated in the same way as for ORR analysis except that r (retention rate) = 50% and 
the HR will be used as the measure of relative risk. The testing is done once at the 
primary (final) analysis on ITT analysis set. 
The null and alternative hypotheses are expressed as: 
      H0: Un ≥ (1-r)*Uh     versus      Ha: Un < (1-r)*Uh 
 
The synthesis test statistic is calculated as: 
        [𝑈𝑛−(1 −𝑟) ∗𝑈ℎ] √𝑆𝐸𝑛2 + (1 −𝑟)2 ∗𝑆𝐸ℎ
2
⁄
  , where 
       r = retention rate = 50% 
       Uh = log-hazard ratio of PFS of Rd vs KRd 27mg/m2 BIW by cycle 12 from the   


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               historical study ASPIRE = log (1.812) 
       SEh = standard error of Uh = 0.137 
       Un = log-hazard ratio of PFS of KRd 56 mg/m2 QW vs KRd 27 mg/m2 BIW from this  
               non-inferiority study 
       SEn = standard error of Un  
The H0 will be rejected if the synthesis test statistic < Z0.025, where Z0.025 is the critical 
value corresponding to a test of 1-sided Type I error rate of 0.025. 
 
SAS code for calculating 1-sided p-value for the non-inferiority test: 
data test; 
r = 0.5; 
Uh = log(1.812); 
SEh = 0.137; 
HR = x.xxx /*hazard ratio (QW arm vs BIW arm), driven by the data from  
             ARROW2 study*/ 
Un = log(HR);  
SEn = x.xxx; /*number x.xxx is driven by the data from ARROW2 study*/ 
SE_syn = sqrt(SEn**2+((1-r)*SEh)**2); 
z = (Un-(1-r)*Uh)/SE_syn;  
pvalue_1sided = probnorm(z)  
run; 
 
The primary analysis of PFS will be based on the IRC assessments of PD for the ITT 
Analysis Set. Similar to the primary analysis, several sensitivity analyses will be 
performed including recommendations from the “Appendix 1 to the guideline on 
the evaluation of anticancer medicinal products in man” (EMA, 
https://www.ema.europa.eu/en/documents/scientific-guideline/appendix-1-
guideline-evaluation-anticancer-medicinal-products-man-methodological-
consideration-using_en.pdf, 2013): (1) analysis based on investigator assessment in 
ITT Analysis Set; (2) analysis based on ORCA assessments in ITT Analysis Set; (3) 
analysis based on the IRC assessments using unstratified model in ITT Analysis Set; (4) 
analysis based on the IRC assessments in PP Analysis Set; (5) analysis based on the 
IRC assessments in mFAS; (6) initiation of new anti-myeloma therapy treated as 
PFS Event in ITT Analysis Set; (7) initiation of new anti-myeloma therapy treated 
as neither a PFS event nor a censoring event in ITT Analysis Set; (8) analysis 
based on scheduled assessment dates instead of actual assessment dates in ITT 
Analysis Set; (9) analysis using interval censoring in ITT Analysis Set: PFS data 
will be treated as interval-censored. The interval will be constructed as follows: (i) 
if the PFS event is PD, then interval will be (date of last assessment before PD, 


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date of the assessment indicating PD]; (ii) if the PFS event is death, then interval 
will be [date of death, date of death]; and (iii) if no PFS event is observed, then the 
interval will be (date of last assessment, ]. These intervals will then be 
transformed from calendar time scale to time-since-randomization scale by 
subtracting individual randomization dates plus 1 day. The non-parametric 
maximum likelihood estimate of the survival curves will be computed based on 
the interval censored PFS data using the Expectation-Maximization iterative 
convex minorant algorithm (EM-ICM) (Wellner & Zhan, 1997).  
The concordance in the assessment of progressive disease by the IRC, investigator, and 
ORCA will be summarized for ITT Analysis Set.  
The observed treatment effect retention rate in ITT Analysis Set, calculated as (Uh 
– Un) / Uh, where Uh and Un are defined above, will be reported as the supportive 
information. 
The adequacy of the proportional hazard assumption will be assessed using the plot of 
the logarithm of the estimated hazard function based on the KM method against the 
logarithm of time-to-event endpoints. The scaled Schoenfeld residuals by time plot will 
be examined for evidence of a non-zero correlation, which indicates non-proportionality. 
In addition, an interaction between treatment and the logarithm of the time to event will 
be tested using a Cox model stratified by randomization stratification factors to test for 
non-proportionality. 
Piecewise Cox models may be explored in ITT Analysis Set given evidence of non-
proportional hazards (Collett, 2003). This method will allow estimation of an overall 
weighted hazard ratio (weights equal to fraction of total events in each interval (Lu & 
Pajak, 2000)) as well as within interval treatment hazard ratio. Additional analysis may 
be performed to explore potential sources for non-proportionality by considering baseline 
prognostic factors and other potential confounding factors. 
Further, the restricted mean survival time (RMST) will be considered as an 
alternative measure of treatment effect (Uno, 2015; Weir, 2018). With an RMST 
boundary time of 13 months, the RMST (area under the survival curve) with 95% CI 
in each arm, and the between-arm difference in RMST (the area between the 
survival curves of the 2 arms) with its corresponding 95% CI (Wald) will be 
estimated in the ITT Analysis Set. 


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Subgroup analyses will be performed to explore the consistency of the treatment 
effect on PFS for subgroups described in Section 4.2. The estimate of hazard ratio 
with 95% CI using a stratified Cox model will be provided between the treatment 
arms. A forest plot will be produced for the estimated hazard ratio with 95% CI of 
each subgroup. 
Patient-reported convenience at each reporting cycle (2, 5,12, safety follow-up) and 
after Cycle 4 are defined in Section 5.  
The frequency and proportion of each category will be summarized by treatment arm at 
Cycle 2, Cycle 5, Cycle 12 and safety follow-up based on all randomized subjects (ITT 
Analysis Set) as well as all expected subjects at the scheduled visit (i.e., randomized 
subjects who are still alive and remaining on carfilzomib treatment at the scheduled visit, 
subjects who have ended all study treatment and are remaining on study for safety 
follow-up visit). The 95% CI will be estimated using Clopper Pearson method for the 
proportion of the Convenient category based on all randomized subjects in each 
arm.  
For the key secondary endpoint analysis (Convenience after Cycle 4), Cochran-
Mantel-Haenszel method stratified by the randomization stratification factors will be used 
to evaluate the treatment effect (OR with associated 95% CI) and the 1-sided p-value 
for whether carfilzomib dosing is reported as convenient after cycle 4. The superiority 
test significance level will be 2.5%. The comparison analyses will be done once at the 
primary (final) analysis using the data collected at Cycle 5, Cycle 12, and safety follow-
up based on the ITT Analysis Set. Following the same method, a sensitivity analysis will 
be performed based on mFAS. A logistic regression model including the randomization 
stratification factors and treatment arm will be also considered for sensitivity analysis of 
the comparison between treatment arms in ITT Analyses Set. The missing data of 
outcome will not be imputed and will not be included in the analysis of the comparison 
between treatment arms. 
 
Other secondary efficacy endpoints 
 
TTR is defined in Section 5. TTR will be summarized descriptively by the non-missing 
sample size (n), mean, STD, median, minimum and maximum among responders by 
treatment arm based on IRC. Similar analysis will be performed using the Investigator 
assessment of response as a sensitivity analysis on ITT Analysis Set. 


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DOR is defined in Section 5. DOR will be summarized descriptively by treatment arm 
based on IRC assessment of response. The distribution of DOR, including the median 
and other quartiles and their corresponding 95% CIs, will be characterized using the KM 
method based on the subjects who achieve a best response of PR or better. No 
inferential comparison between treatment arms will be made for DOR. A similar analysis 
will be performed by using the Investigator disease assessment as a sensitivity analysis 
on ITT Analysis Set. 
TTP is defined in Section 5. Analysis of TTP will be performed in the same way as the 
primary PFS analysis. The distribution of TTP will be characterized using the KM 
method. The HR and its 95% CI will be estimated using a Cox model stratified by the 
randomization stratification factors. A similar analysis will be performed by using the 
Investigator disease assessment as a sensitivity analysis on ITT Analysis Set. 
OS is defined in Section 5. Analysis of OS will be performed in the same way as the 
primary PFS analysis based on the ITT Analysis Set. The number of subjects with OS 
events or censored, and censoring reasons will be presented by treatment arm. The 
subcategory of death with the primary reason of COVID-19 infection or COVID-19 
pneumonia will be included in the OS events. The distribution of OS time including 
median and other quartiles will be summarized descriptively using the KM method (Klein 
and Moeschberger, 1997). The corresponding 95% CIs for the median and other 
quartiles will be constructed using KM method with log-log transformation. OS rates at 6 
and 12 months will be estimated, and the corresponding 95% CIs will be calculated 
using the method of Kalbfleisch and Prentice (1980). The duration of the follow-up for 
OS will be estimated by reverse Kaplan-Meier method (Schemper and Smith 1996). KM 
curves will also be presented. The HR and its 95% CI will be estimated using a Cox 
proportional hazards model stratified by the randomization stratification factors. The KRd 
27 mg/m2 BIW arm will serve as the reference treatment arm in the calculation of the 
HR. The adequacy of the proportional hazard assumption will be assessed using 
the same method as described for the PFS. Piecewise Cox models may be 
explored in ITT Analysis Set given evidence of non-proportional hazards (Collett, 
2003). 
Similar to the primary analysis of OS, the sensitivity analyses will be performed based on 
unstratified method for the ITT Analysis Set, or for the Per Protocol Set. 
Subgroup analyses will be performed to explore the consistency of the treatment 
effect on OS for subgroups described in Section 4.2. The estimate of hazard ratio 


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with 95% CI using a stratified Cox model will be provided between the treatment 
arms. A forest plot will be produced for the estimated hazard ratio with 95% CI of 
each subgroup. 
MRD[-]CR is defined in Section 2.1. The MRD[-]CR rate (defined in Section 5) will be 
calculated by treatment arm and the associated 95% CI will be estimated using the 
Clopper Pearson method. As a measure of treatment effect, OR and associated 95% CI 
will be estimated using CMH method controlling for randomization stratification factors. 
The KRd 27 mg/m2 BIW arm will serve as the reference treatment arm in the calculation 
of the OR. The analysis of MRD[-]CR will be based on the IRC assessments of response 
for the ITT Analysis Set where patients without MRD assessment will be considered as 
having MRD positive status.   
Similar to the primary analysis of MRD[-]CR, the sensitivity analyses will be performed 
based on investigator assessments and ORCA assessments for CR or better. 
MRD[-] status at 12 months is defined in Section 2.1. MRD[-] rate at 12 months (defined 
in Section 5) will be analyzed similarly to MRD[-]CR rate in the primary analysis of       
MRD[-]CR.  
Physical functioning and role functioning (EORTC QLQ-C30) over time:  Physical 
Functioning and Role Functioning are measured by the Physical Functioning and Role 
Functioning scales of the European Organization for Research and Treatment of Cancer 
Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and will be administered 
before dosing on Day 1 of Cycle 1, 3, 5, 7, 9, 12, and safety follow-up. The scale scores 
are linearly converted to range from 0-100. Principles for scoring are detailed in 
Appendix B. A higher score for functional scales represents a better functional status.  
The scale scores will be summarized descriptively with the non-missing data (n), mean, 
STD, median, minimum and maximum by treatment arm at each visit. Change from 
baseline at each visit will be also summarized using the same statistics. 
The completion rate for scale score will be presented by treatment arm and by visit 
based on all randomized subjects (ITT Analysis Set) as well as all subjects expected to 
have an assessment at the scheduled visit (i.e., randomized subjects who are still alive 
and remaining on study treatment at the scheduled visit, subjects who have ended all 
study treatment and are remaining on study for safety follow-up visit).  
In addition to descriptive analyses, the comparison of mean score over time between 
treatment arms will be performed using repeated measures analysis of covariance 


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(ANCOVA) adjusting for the baseline covariates in a multivariate model. The dependent 
variable of the models will be the scale scores measured at each post-baseline visit. The 
model will include treatment arm, randomization stratification factors, the baseline score 
(covariate, the scale score on cycle 1 day 1 before dosing) and visit as a repeated 
measure. The least square mean by treatment arm and the overall least square mean 
difference between treatment arms will be reported along with the corresponding 95% 
CI.  
All the above analyses will be based on the ITT Analysis Set. A similar analysis will be 
performed on Per Protocol Set as a sensitivity analysis. 
In the repeated measure ANCOVA, the missing scale scores will be imputed using 
multiple imputation (MI) method (Rubin DB, 1976; SAS Institute Inc., 2015) with the 
assumption of missing at random (MAR). The steps are as follows.  
 
Assuming the missing data pattern is arbitrary, the MI will be performed by 
treatment group using the fully conditional specification (FCS) method with linear 
regression models, which is implemented with SAS 9.4’s PROC MI under the 
FCS statement. The imputation model will include all the variables specified in 
ANCOVA model (treatment arm, randomization stratification factors, the baseline 
scale score). There are 50 imputed datasets to be generated. The seed of the 
pseudorandom number generator used to randomly generate imputations for the 
missing values is specified as seed=54321. Prior to MI, the dataset needs to be 
converted from a long to the wide format (one record per subject).  
 
Repeated measures analysis of ANCOVA will be performed on each imputed 
dataset generated in MI. Prior to analysis of the completed dataset, the dataset 
needs to be restructured into a long format.  
 
The parameter estimates from the repeated measures analysis of ANCOVA 
based on each imputed dataset will be combined using SAS PROC MIANALYZE 
with MODELEFFECTS statement.  
A restricted maximum likelihood-based mixed model for repeated measures (MMRM) 
under the assumption of MAR will be also considered as sensitivity analysis to test the 
difference between the overall least squares mean of the treatment arms. The 
dependent variable of the models will be the scale scores measured at each visit. The 
model will include treatment arm, visit (coded using integers representing cycle number), 
treatment-by-visit interaction, randomization stratification factors, the baseline score 


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(covariate), and baseline score-by-visit interaction as the fixed effect; subject as the 
random effect. An empirical structure will be assumed for the variance-covariance matrix 
of the fixed effect parameters and an unstructured covariance matrix will be used for the 
random effect. The least square mean by treatment arm and the least square mean 
difference between treatment arms will be reported along with the corresponding 95% 
CI. 
Patient-reported treatment satisfaction (the Satisfaction with Therapy scale of CTSQ) 
after cycle 4 of treatment: Patient-reported treatment satisfaction are measured by the 
Satisfaction with Therapy (SWT) scale of the Cancer Therapy Satisfaction Questionnaire 
(CTSQ) and will be collected on Day 1 of Cycle 2, Cycle 5, Cycle 12 before dosing, and 
safety follow-up. The scale scores will be converted to range from 0-100, with a higher 
score associated with the best outcome on each domain. Principles for scoring are 
detailed in Appendix B.  
Patient-reported treatment satisfaction (CTSQ) after cycle 4 of treatment will be 
analyzed at the corresponding fixed time point using ANCOVA method. The dependent 
variable of the models will be the scale scores measured at each visit (Cycle 5 Day 1, 
Cycle 12 Day 1 and safety follow-up). The model will include treatment arm, 
randomization stratification factors and the scale score measured at Cycle 2 Day 1. 
The mean score difference with 95% CI between treatment arms will be reported. The 
analyses will be performed for the ITT Analysis Set.  
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
Details regarding the analyses of exploratory endpoints of COA will be provided in a 
SSAP. 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Safety and tolerability will be assessed where applicable, by incidence, severity, 
seriousness, and changes from baseline for all relevant parameters including AEs, 
deaths, laboratory tests, vital signs, electrocardiogram (ECG) and left ventricular ejection 
fraction (assessed by echocardiogram (ECHO)). All safety analyses will be based on the 
Safety Analysis Set. 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.1 or later will be 
used to code all adverse events (AEs) to a system organ class (SOC) and a preferred 


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term (PT). AEs will be graded for severity using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. The events of 
interest (EOI) search strategies will be based on the standardized MedDRA query 
(SMQ) and/or Amgen customized MedDRA query (AMQ). Incomplete AE start dates will 
be imputed according to the specifications described in Appendix A. 
The number and percentage of subjects experiencing AEs will be summarized for all 
treatment-emergent adverse events (TEAEs), grade 3 or higher TEAEs, serious TEAEs, 
treatment-related TEAEs, TEAEs leading to discontinuation of investigational 
product/non-investigational product, TEAEs leading to discontinuation of any study drug,  
TEAEs leading to dose reduction or interruption of investigational product/non-
investigational product, TEAEs leading to dose reduction or interruption of any study 
drug, fatal TEAEs and treatment-emergent EOI. The subject incidence will be presented 
by treatment arm and tabulated by SOC (in alphabetical order) and/or PT (in descending 
order of frequency), and/or severity. If a subject experiences repeated episode of the 
same AE, the subject will be counted only once within each SOC and similarly counted 
once within each PT and the event with the highest severity grade will be used for 
purposes of incidence tabulations. 
In addition, summaries of TEAEs and serious TEAEs occurring in at least 5% of the 
subjects by PT in any treatment arm will be provided in descending order of frequency.   
A summary of the number of deaths and the cause of death, classified by deaths within 
30 days of last dose of study drug and deaths more than 30 days after the last dose of 
study drug, will be provided. 
9.6.3 
Laboratory Test Results 
Laboratory test results will be graded for severity using the NCI-CTCAE version 5.0 and 
will be summarized for each treatment arm using descriptive statistics for baseline 
values and changes from baseline values by cycle (per table 2-1 from protocol), and a 
summary of subject incidence of grade 3 and 4 laboratory abnormalities.  
For the summary of changes from baseline values, subjects without a baseline and/or 
post-baseline value will be excluded; values from unscheduled assessments will not be 
included. Laboratory results from samples taken > 30 days after the last administration 
of protocol therapy will be excluded from all laboratory summaries. 
Shifts in laboratory toxicity grades to outside the normal range will be evaluated for 
laboratory parameters by assessing the maximum increase and/or decrease observed 


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during the course of study treatment relative to the baseline toxicity grade. The following 
selected laboratory parameters may be considered in this analysis. 
(1) hematology analytes in decreasing direction: Hemoglobin, Lymphocyte, Absolute 
Neutrophil Count (ANC), Platelet, White Blood Cell (WBC);  
(2) chemistry analytes in increasing direction: Alanine Aminotransferase (ALT), 
Aspartate Aminotransferase (AST), Total Bilirubin, Corrected Calcium, Serum 
Creatinine, Potassium, Sodium, Magnesium, Uric Acid;  
(3) chemistry analytes in decreasing direction: Albumin, Corrected Calcium, Potassium, 
Magnesium, Phosphorus, Sodium. 
The subject incidence of Grade 3 and 4 hematological laboratory abnormalities 
and the subject incidence of Grade 3 and 4 nonhematological toxicities (including liver 
function test (LFT), creatinine) will be provided by treatment arm in the same table.   
The summary table for ALT, AST, Total Bilirubin, and the potential Hy’s Law cases will 
also be considered. 
9.6.4 
Vital Signs 
Vital sign results (systolic/diastolic blood pressure, heart rate, respiratory rate, and 
temperature) will be summarized using descriptive statistics for baseline values and 
changes from baseline by cycle for each treatment arm. 
For the summary of changes from baseline, subjects without a baseline and/or post-
baseline value will be excluded; values from unscheduled assessments will not be 
included. Vital sign results taken > 30 days after the last administration of protocol 
therapy will be excluded from all vital sign summaries. 
9.6.5 
Physical Measurements 
The baseline physical measurements (height (cm), weight (kg), BSA (m2)) and the 
change from baseline of weight and BSA will be summarized by cycle for each treatment 
arm.  
9.6.6 
Electrocardiogram 
The electrocardiogram (ECG) measurements from this clinical study were performed as 
per standard of care for routine safety monitoring, rather than for purposes of 
assessment of potential QTc effect. ECG data might be presented in listings. 


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9.6.7 
Left Ventricular Ejection Fraction (LVEF) 
LVEF (assessed by ECHO) and the change of LVEF from baseline will be summarized 
using descriptive statistics by treatment arm by visit. 
9.6.8 
Exposure to Investigational Product and Non-Investigational 
Products 
Descriptive statistics will be produced to describe the exposure to all study drugs 
(carfilzomib, lenalidomide, and dexamethasone) by treatment arm for subjects in the 
Safety Analysis Set. The extent of exposure will be evaluated, where applicable, with 
respect to the following: 
 
Number of treatment cycles subject dosed  
For all study drugs, it is defined as the total number of treatment cycles in which at 
least one dose of any study drug is administered. For each study drug (carfilzomib, 
lenalidomide, dexamethasone), it is defined as the total number of treatment cycles 
in which at least one dose of carfilzomib/lenalidomide/dexamethasone, respectively, 
is administered. 
 
Number of subjects dosed in each cycle for all study drugs and each study drug 
 
Treatment duration (week): (last dose date – first dose date + 1) / 7 
For all study drugs, the last/first dose date refers to the last/first dose date of any 
study drug. For carfilzomib/lenalidomide/dexamethasone, the last/first dose date 
refers to the last/first dose date of carfilzomib/lenalidomide/dexamethasone, 
respectively. 
 
Number of doses administered (non-zero dose) of each study drug during the 
treatment period of the study 
 
Cumulative dose received (mg, mg/m2) of each study drug during the treatment 
period of the study, defined in Section 5. 
 
Average dose per administration (mg, mg/m2) of each study drug during the 
treatment period of the study, defined as the total cumulative dose received divided 
by the number of doses administered. 
 
Average dose per administration (mg, mg/m2) excluding the 20 mg/m2 of carfilzomib 
on cycle 1 day 1 and/or day 2 during the treatment period of the study, defined as the 
total cumulative dose received divided by the number of doses administered. 
 
Relative dose intensity of each study drug defined in Section 5. 


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 
The number (%) of subjects with dose modifications of each study drug will be 
tabulated and the reasons for dose modification will also be summarized. If the 
reason for dose modification is COVID-19 control measures which is recorded in the 
specified field (Other) on the CRF, then the number (%) with COVID-19 control 
measures will also be presented. 
Dose modifications will include the following: 
− Dose missed (for each study drug, derived based on the Carfilzomib/ 
Lenalidomide/Dexamethasone Investigational Product Administration CRF)  
− Dose reduction (each study drug, derived based on the Carfilzomib/ 
Lenalidomide/Dexamethasone Investigational Product Administration CRF)  
− Dose delay (for carfilzomib only, as captured on the Investigational Product 
Administration (Carfilzomib) CRF)  
− Dose interruption (for carfilzomib only, as captured on the Investigational Product 
Administration (Carfilzomib) CRF)  
The primary reason for study drug discontinuation will be summarized along with the 
summary of subject disposition (Section 9.2). 
9.6.9 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications from study 
day 1 through 30 days of the last dose of any study drug will be summarized by 
preferred term or category for each treatment arm as coded by the World Health 
Organization Drug (WHO DRUG) dictionary by treatment arm in the Safety Analysis Set. 
For the purpose of determining if a medication should be noted as a concomitant 
medication, the imputation rules stated in Appendix A will be used. 
9.7 
Other Analyses 


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9.7.2 
Analyses of Clinical Outcome Assessments (COA) 
The analyses of the secondary endpoints of COA (patient-reported convenience after 
cycle 4 of treatment, physical functioning and role functioning (EORTC QLQ-C30) over 
time, and patient-reported treatment satisfaction (CTSQ) after cycle 4 of treatment) are 
described in Section 9.5.2. Details regarding the analyses of exploratory endpoints of 
COA will be provided in a supplemental statistical analysis plan by the Department of 
Health Economics and Outcomes Research (HEOR). 
9.7.3 
Analyses of Biomarker Endpoints 
Analyses of biomarker endpoints MRD[-] CR rate and MRD[-] rate are described in 
Section 9.5.2. 
10. 
Changes from Protocol-specified Analyses 
 The RMST and observed treatment effect retention rate are included as additional 
analyses for PFS. The non-inferiority margin for ORR is specified in Section 9.5. 
11. 
Literature Citations / References 
Clopper CJ and Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of the binomial, Biometrika. 1934; 26(4):404-413. 
Collett D. Modelling Survival Data in Medical Research. 2nd edition. London, UK: 
Chapman & Hall/CRC; 2003. 
Durie BG, Harousseau JL, Miguel JS, et al. International Myeloma Working Group. 
International uniform response criteria for multiple myeloma. Leukemia. 2006; 
20(9):1467–73. Erratum in: Leukemia 2006; 20(12):2220. Leukemia 2007; 21(5):1134. 
European Medicines Agency (EMA). Guideline on the Choice of the Non-Inferiority 
Margin. July 2005. 


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European Medicines Agency (EMA). Appendix 1 to the guideline on the evaluation 
of anticancer medicinal products in man - methodological consideration for using 
progression-free survival (PFS) or disease-free survival (DFS) in confirmatory 
trials - Scientific guideline. July 2013. 
FDA. Non-inferiority clinical trials to establish effectiveness. Guidance for Industry. 
November 2016.  
Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple 
myeloma. J Clin Oncol. 2005; 23(15):3412–20. 
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; 17:328-346.  
Kalbfleisch, J. D. and Prentice, R. L. The Statistical Analysis of Failure Time Data, New  
York: John Wiley & Sons; 1980 
Klein, J. P. and Moeschberger, M. L. (1997), Survival Analysis: Techniques for Censored 
and Truncated Data, New York: Springer-Verlag.Longo D, Duffey P, DeVita V, Wesley 
M, Hubbard S, Young R. The calculation of actual or received dose intensity: A 
comparison of published methods. Journal of Clinical Oncology. 1991; 9:2042-2051. 
Lu, J., and Pajak, T. F. Statistical Power for a Long-Term Survival Trial with a Time-
Dependent Treatment Effect, Controlled Clinical Trials. 2000; 21, 561–573. 
Mosteller RD. Simplified calculation of body surface area. N Engl J Med 1987; 
317(17):1098 (letter). 
Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for 
Multiple Myeloma: a report from International Myeloma Working Group, J Clin Oncol, 33 
(26) (2015), pp. 2863–2869 
Rajkumar S, et al. Consensus recommendations for the uniform reporting of clinical 
trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 
117:4691-4695. 
Rubin DB. Inference and missing data. Biometrika. 1976; 63: 581-592. 
SAS Institute I. Sas/stat 9.4 user’s guide: the MI procedure. Cary (NC): SAS 
Institute Inc. 2015. 
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. 
Controlled Clinical Trials. 1996; 17:343–346. 
Uno H, et al. Alternatives to hazard ratios for comparing the efficacy or safety of 
therapies in noninferiority studies. Ann Intern Med. 2015; 163:127-134. 
Weir IR and Trinquart L. Design of non-inferiority randomized trials using the 
difference in restricted mean survival times. Clin Trials. 2018; 15(5): 499-508 
Wellner JA and Zhan Y. A hybrid algorithm for computation of the NPMLE from 
censored data. J. Amer. Statist. Assoc. 1997; 92(439): 945-959 


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12. 
Appendices 
 
Appendix A.  Handling of Incomplete Dates and Missing Dates  
 
A1. Imputation Rules for Adverse Events and Concomitant Medications (other 
than the new anti-myeloma therapy) dates 
Imputation Rules for Partial or Missing Start Dates: 
 Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial:  
yyyymm 
Partial:  
yyyy 
Missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
2 
1 
n/a 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
3 
1 
3 
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 
 
Note: If the start date imputation leads to a start date that is after the stop date, then do not 
impute the start date. 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 or first day of year if 
month is also missing. 
 
Imputation Rules for Partial or Missing Stop Dates: 
 
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. (i.e., set the stop date as 
missing). 


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A2. Imputation Rules for New Antimyeloma Therapy Start Date 
If the start day of new antimyeloma therapy is missing and month and year are not the 
same as last dosing date of study treatment, it will be assumed to be the first day of the 
month. If the start day of new antimyeloma therapy is missing and month and year are 
same as last dosing date of study treatment, the start date will be assumed as last 
dosing date of study treatment. In other situations, do not impute. 
 
A3. Imputation Rules for Partial or Missing Death Dates: 
1. If death year and month are available but day is missing:  
 
If mmyyyy for last known alive date = mmyyyy for death date, set death date to 
the day after the last known alive date.  
 
If mmyyyy for last known alive date < mmyyyy for death date, set death date to 
the first day of the death month.  
 
If mmyyyy for last known alive date > mmyyyy for death date, data error and do 
not impute.  
2. If death year is available but both month and day are missing for death date: 
 
If yyyy for last known alive date = yyyy for death date, set death date to the day 
after the last known alive date. 
 
If yyyy for last known alive date < yyyy for death date, set death date to the first 
day of the death year. 
 
If yyyy for last known alive date > yyyy for death date, data error and do not 
impute. 
3. If a death date is totally missing, do not impute.  
The imputed death date will be used in calculation of duration of response, PFS and OS. 
 
A4. Imputation Rules for Dates of Prior Multiple Myeloma Therapy and 
Relapse/progression to Prior Multiple Myeloma Therapy: 
If the day of prior multiple myeloma therapy or relapse/progression to prior multiple 
myeloma therapy is missing but month and year are available, then impute the date to 
15th of the month. If the date imputation leads to a stop date that is before the start 
date, then do not impute the date. If month or year is missing or the date is completely 
missing, do not impute. 


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Appendix B.  Clinical Outcome Assessment Forms/Instruments 
 
EORTC QLQ-C30 Functional Scale Scoring: 
 
The following sections describe the scoring algorithms for functional scales used in 
EORTC QLQ-C30 questionnaire. Scoring procedures can be found in the EORTC QLQ-
C30 Scoring Manual, ver. 3 (Fayers et al. 2001) and Cocks et al (2007). All scale scores 
range from 0 to 100. 
For all scales, calculate the raw score (RS) of a scale using the mean of the item scores 
in the scale as follows: 
RS = (S1 + S2 + …+Sn) / n 
where Si: i=1, …, n, are the item scores, and n is the number of items with valid scores, 
assuming the number of items with valid scores meets the minimum requirement as 
specified in Table 12-1 or this scale score will be assumed missing. 
Use a linear transformation to standardize the raw score in order that scores will range 
from 0-100. For the functional scales in QLQ-C30, a higher score represents a better 
health state. 
Functional Scales = {1- (RS-1)/range} * 100 
where range for each scale is defined in Table 12-1. 
Table 12-1. EORTC QLQ-C30 Functional Scales and Scoring Details 
 
Number 
of Items 
Item 
Range a 
Item 
Numbers 
Minimum Not 
Missing 
QLQ-C30 
 
 
 
 
 
 
 
 
 
Functional Scales 
 
 
 
 
  Physical Functioning  
5 
3 
1 to 5 
3 
  Role Functioning  
2 
3 
6, 7 
1 
  Emotional Functioning  
4 
3 
21 to 24 
2 
  Cognitive Functioning  
2 
3 
20, 25 
1 
  Social Functioning  
2 
3 
26, 27 
1 
 
 
 
 
 
a Item range is the difference between the maximum possible value of the Raw Score and the minimum 
possible value. 
Only Physical Functioning and Role Functioning will be included in the analysis. 
 
 
 


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  22 May 2023 
Page 65 of 66 
CONFIDENTIAL  
 
 
 
Internal Use Only Compliance 
CTSQ SWT Scale Scoring: 
The following sections describe the scoring algorithms for SWT scale used in CTSQ 
questionnaire. Scoring procedures can be found in the CTSQ Administration & Scoring 
Guide v1.0 (2006). These procedures result in a score ranging from 0 to 100 for each 
CTSQ domain, with a higher score associated with the best outcome on each domain. 
Table 12-2 provides a summary of the domain structure and critical information required 
for scoring SWT domain in CTSQ. 
Table 12-2. Scoring information for SWT Domain in CTSQ 
CTSQ Domain  
Description of Content of 
Items in Domain 
Item 
numbers* 
Total # 
of items 
Minimum # of 
completed 
items required 
to score 
Satisfaction with 
Therapy (SWT)  
Worth taking even with side 
effects, Think about 
stopping CT, How 
worthwhile was CT, 
Benefits meet expectations, 
Satisf. with form of CT, 
Satisf. with recent CT, 
Would you take this CT 
again  
Q7, Q9R, 
Q10, Q12, 
Q14, Q15, 
Q16  
 
7 
5 
* “R” following item number indicates that reverse-coded version of the item is used in calculating the 
domain score. 
 
Step 1. Reverse-Coding Required for the Item 
The first step in scoring the SWT is to create new variables containing the reverse-coded 
response values for the CTSQ items Q9. This is done by subtracting the initial (raw) 
response value for each of these items from 6:  
      Q9R = 6 – Q9;  
Creating new variables containing the reverse-coded response values for the item 
ensures that the highest-coded value (5) for the item is associated with the best possible 
response (greater satisfaction with therapy), and the lowest-coded value (1) is 
associated with the worst possible response. 
Step 2. Scoring Procedures  
If the number of completed items is greater than or equal to the minimum number 
indicated in Table 12-2 the domain is scored using the formula:  
Domain score = [(Sum of completed item responses / Number of completed items) - 1] x 
100 / (Maximum possible item response value – Minimum possible item response value)  


Product:  Carfilzomib 
Protocol Number:  20180015 
Date:  22 May 2023 
Page 66 of 66 
CONFIDENTIAL  
 
 
 
Internal Use Only Compliance 
However, if fewer items are completed than the minimum number indicated in Table 
12-2, then the domain is not scored (i.e. a missing value is assigned).  
Since the maximum possible item response value is 5 and the minimum possible 
response value is 1 for all CTSQ items, a simpler way to represent the above formula for 
the CTSQ domains is:  
           CTSQ domain score = (Mean of completed item responses – 1) x 25  
In terms of SAS programming code, the scoring procedure can be performed as follows: 
if n(of Q7 Q9R Q10 Q12 Q14 Q15 Q16) >= 5 then SWT = (mean(of Q7 Q9R Q10 
Q12 Q14 Q15 Q16)-1)*25;  
else SWT = . ;