Conditions: Relapsed or Refractory Multiple Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
The primary objective was to describe the safety profile of carfilzomib plus dexamethasone regimen in adults with relapsed or refractory multiple myeloma (RRMM) with 1 to 3 prior lines of therapy at study entry.

Detailed description:
This is a phase 2, multicenter, open-label study in adults with RRMM in US community oncology centers. Adults with 1-3 prior lines of therapy at study entry are eligible to be screened for participation. Patients refractory to their last line of treatment are eligible to participate as long as their last line of treatment did not include a proteasome inhibitor (PI). The study will consist of a screening period of up to 28 days for bone marrow assessments and up to 21 days for all other assessments, up to 12 cycles of treatment, and a 30-day safety follow-up period following the last dose of study drug.

Arms:
arm 1: Participants received carfilzomib administered as an intravenous (IV) infusion twice-weekly for up to six 28-day cycles followed by once-weekly for another six 28-day cycles. The carfilzomib dose was 20 mg/m² on days 1 and 2 of cycle 1, 56 mg/m² for the remaining days of cycle 1 (days 8, 9, 15, and 16) and then on days 1, 2, 8, 9, 15, and 16 of each cycle for cycles 2 to 6, and 70 mg/m² on days 1, 8, and 15 of each cycle for cycles 7 to 12.

Participants also received dexamethasone either orally or by IV infusion at a dose of 20 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 of cycles 1 to 6 and at a dose 40 mg once daily on days 1, 8, 15 of cycles 7 to 12.

Interventions: intervention 1: Dexamethasone intervention 2: Carfilzomib
Intervention descriptions: intervention 1: Dexamethasone will be taken orally or by IV infusion at a dose of 20 mg once-daily on days 1, 2, 8, 9, 15, 16, 22, and 23 of cycles 1-6, and at a dose 40 mg once-daily on days 1, 8, 15 of cycles 7-12. intervention 2: Carfilzomib will be administered at 20 mg/m² on days 1 and 2 of the first cycle. After that, carfilzomib will be administered at 56 mg/m² on days 8, 9, 15, and 16 of the first cycle, and then on days 1, 2, 8, 9, 15, and 16 on each 28-day cycle for the cycles 2 through 6. Starting with cycle 7 through cycle 12, carfilzomib will be administered at 70 mg/m² on days 1, 8, and 15 of each 28-day cycle. All

Protocol document:
Prot_000.pdf: 
Product:  Carfilzomib 
Protocol Number:  20170596 
Date:  20 May 2019 
 
Page 1 of 132 
CONFIDENTIAL 
 
 
Title Page 
Protocol Title: 
An Open-label Phase 2 Study of Carfilzomib 
Combinations (Carfilzomib Plus Dexamethasone, 
Carfilzomib Plus Lenalidomide and 
Dexamethasone, and Carfilzomib Plus 
Pomalidomide and Dexamethasone), To Assess 
Tolerability and Adherence in Subjects With 
Relapsed or Refractory Multiple Myeloma at US 
Community Oncology Centers 
Short Protocol Title: 
A Study of Carfilzomib Combinations in Subjects 
With Relapsed or Refractory Multiple Myeloma at 
US Community Oncology Centers 
Protocol Number: 
20170596 
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: 
NCT Number: 
NCT03512353 
Protocol Date: 
Document Version 
Date 
Original 
Superseding original 
Protocol Amendment 1 
04 January 2018 
26 January 2018 
06 March 2018 
Protocol Amendment 2 
Protocol Amendment 3 
Protocol Amendment 4 
05 October 2018 
29 March 2019 
20 May 2019 
Version/Date: 
Data Element Standards Version 
5.0 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20170596 
Date:  20 May 2019 
 
Page 2 of 132 
CONFIDENTIAL 
 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1-800-77-AMGEN. 
Approved 
 
 


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Protocol Number:  20170596 
Date:  20 May 2019 
 
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Investigator’s Agreement: 
I have read the attached protocol entitled An Open-label Phase 2 Study of Carfilzomib 
Combinations (Carfilzomib Plus Dexamethasone, Carfilzomib Plus Lenalidomide and 
Dexamethasone, and Carfilzomib Plus Pomalidomide and Dexamethasone), To Assess 
Tolerability and Adherence in Subjects With Relapsed or Refractory Multiple Myeloma at 
US Community Oncology Centers, dated 20 May 2019, and agree to abide by all 
provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by: me 
(including, if applicable, my spouse [or legal partner] and dependent children) and my 
subinvestigators (including, if applicable, their spouses [or legal partners] and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator 
Date (DD Month YYYY) 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20170596 
Date:  20 May 2019 
 
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Table of Contents 
Table of Contents ............................................................................................................ 4 
1. 
Protocol Synopsis ................................................................................................. 10 
2. 
Study Schema and Schedule of Activities ............................................................. 17 
2.1 
Study Schema ........................................................................................... 17 
2.2 
Schedule of Activities ................................................................................ 18 
3. 
Introduction ........................................................................................................... 26 
3.1 
Study Rationale ......................................................................................... 26 
3.2 
Background ............................................................................................... 28 
3.2.1 
Disease ..................................................................................... 28 
3.2.2 
Amgen Investigational Product Background:  
Carfilzomib ................................................................................ 29 
3.2.3 
Benefits of Once-weekly Dosing ................................................ 30 
3.3 
Benefit/Risk Assessment ........................................................................... 31 
3.3.1 
Therapeutic Context .................................................................. 31 
3.3.2 
Key Benefits .............................................................................. 32 
3.3.3 
Key Risks .................................................................................. 34 
3.3.3.1 
Risks ....................................................................... 34 
4. 
Objectives, Endpoints and Hypotheses ................................................................. 38 
4.1 
Objectives and Endpoints .......................................................................... 38 
4.2 
Hypotheses ............................................................................................... 38 
5. 
Study Design ........................................................................................................ 39 
5.1 
Overall Design .......................................................................................... 39 
5.2 
Number of Subjects ................................................................................... 39 
5.2.1 
Replacement of Subjects ........................................................... 39 
5.2.2 
Number of Sites ......................................................................... 39 
5.3 
End of Study ............................................................................................. 40 
5.3.1 
End of Study Definition .............................................................. 40 
5.3.2 
Study Duration for Subjects ....................................................... 40 
5.4 
Justification for Investigational Product Dose ............................................ 40 
5.4.1 
Justification for Investigational Product Dose for Kd 
Arm ........................................................................................... 40 
5.4.2 
Justification for Investigational Product Dose for KRd 
and KPd Arms ........................................................................... 42 
5.5 
Patient Input on Study Design ................................................................... 43 
6. 
Study Population .................................................................................................. 43 
6.1 
Inclusion Criteria  ...................................................................................... 43 
6.2 
Exclusion Criteria ...................................................................................... 44 
6.3 
Subject Enrollment .................................................................................... 48 
6.4 
Screen Failures ......................................................................................... 48 
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7. 
Treatments ........................................................................................................... 49 
7.1 
Treatment Procedures............................................................................... 49 
7.1.1 
Investigational Products ............................................................ 49 
7.1.1.1 
Dosage Formulation ................................................ 49 
7.1.1.2 
Dosage, Administration, and Schedule .................... 49 
7.1.2 
Non-investigational Products ..................................................... 52 
7.1.2.1 
Dexamethasone: Dosage, Administration, 
and Schedule .......................................................... 52 
7.1.2.2 
Lenalidomide ........................................................... 52 
7.1.2.3 
Pomalidomide ......................................................... 53 
7.1.3 
Medical Devices ........................................................................ 54 
7.1.4 
Other Protocol-required Therapies ............................................ 54 
7.1.4.1 
Antiviral Prophylaxis ................................................ 54 
7.1.4.2 
Thromboprophylaxis ................................................ 54 
7.1.4.3 
Tumor Lysis Syndrome Prophylaxis ........................ 55 
7.1.4.4 
Proton-pump Inhibitor .............................................. 55 
7.1.4.5 
Other Permitted Therapies ...................................... 55 
7.1.5 
Other Treatment Procedures ..................................................... 56 
7.1.6 
Product Complaints ................................................................... 56 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 56 
7.2 
Method of Treatment Assignment ............................................................. 57 
7.3 
Blinding ..................................................................................................... 57 
7.4 
Dose Modification ...................................................................................... 57 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 57 
7.4.1.1 
Amgen Investigational Product:  
Carfilzomib .............................................................. 57 
7.4.1.2 
Non-Amgen/Amgen Non-investigational 
Product:  Dexamethasone ....................................... 62 
7.4.1.3 
Conditions Not Requiring Dose Reduction .............. 65 
7.4.1.4 
Non-Amgen Non-investigational Product:  
Lenalidomide ........................................................... 65 
7.4.1.5 
Non-Amgen Non-investigational Product:  
Pomalidomide ......................................................... 66 
7.4.2 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 66 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 66 
7.6 
Treatment Compliance .............................................................................. 66 
7.7 
Treatment of Overdose ............................................................................. 66 
7.8 
Prior and Concomitant Treatment ............................................................. 66 
7.8.1 
Prior Treatment ......................................................................... 66 
7.8.2 
Concomitant Treatment ............................................................. 66 
8. 
Discontinuation Criteria ......................................................................................... 67 
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8.1 
Discontinuation of Study Treatment........................................................... 67 
8.2 
Discontinuation From the Study ................................................................ 68 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 68 
8.2.2 
Reasons for Removal From Study ............................................. 69 
8.3 
Lost to Follow-up ....................................................................................... 69 
9. 
Study Assessments and Procedures .................................................................... 69 
9.1 
General Study Periods .............................................................................. 70 
9.1.1 
Screening and Enrollment ......................................................... 70 
9.1.2 
Treatment Period ....................................................................... 70 
9.1.3 
Safety Follow-up ........................................................................ 71 
9.2 
Description of General Study Assessments and Procedures ..................... 71 
9.2.1 
General Assessments ............................................................... 71 
9.2.1.1 
Informed Consent .................................................... 71 
9.2.1.2 
Demographics ......................................................... 71 
9.2.1.3 
Medical History ........................................................ 71 
9.2.1.4 
Physical Examination .............................................. 72 
9.2.1.5 
Physical Measurements .......................................... 72 
9.2.1.6 
Substance Abuse History ........................................ 72 
9.2.1.7 
Performance Status................................................. 72 
9.2.2 
Efficacy Assessments ................................................................ 72 
9.2.2.1 
Bone Marrow Sample Evaluation Including 
FISH Assessment ................................................... 73 
9.2.2.2 
Bone Lesion Assessment (Skeletal 
Survey, Computed Tomography, or 
Positron Emission Tomography/Computed 
Tomography) ........................................................... 73 
9.2.2.3 
Extramedullary Plasmacytoma ................................ 73 
9.2.2.4 
Progressive Disease Assessment ........................... 74 
9.2.3 
Safety Assessments .................................................................. 74 
9.2.3.1 
Adverse Events ....................................................... 75 
9.2.3.2 
Vital Signs ............................................................... 77 
9.2.3.3 
Electrocardiograms (ECGs) ..................................... 77 
9.2.3.4 
Other Safety ............................................................ 78 
9.2.4 
Echocardiogram ........................................................................ 78 
9.2.5 
Clinical Laboratory Assessments ............................................... 78 
9.2.5.1 
Pregnancy Testing .................................................. 78 
9.2.6 
Clinical Outcome Assessments ................................................. 79 
9.2.6.1 
European Organization for Research and 
Treatment of Cancer Quality-of-life 
Questionnaire Core 30 (EORTC 
QLQ-C30) ............................................................... 79 
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9.2.6.2 
European Organization for Research and 
Treatment of Cancer Quality-of-life 
Questionnaire Multiple Myeloma Module 
(EORTC QLQ-MY20) .............................................. 79 
10. 
Statistical Considerations ...................................................................................... 80 
10.1 
Sample Size Determination ....................................................................... 80 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 81 
10.2.1 
Analysis Sets ............................................................................. 81 
10.2.2 
Covariates ................................................................................. 81 
10.2.3 
Subgroups ................................................................................. 82 
10.2.4 
Handling of Missing and Incomplete Data .................................. 82 
10.3 
Statistical Analyses ................................................................................... 82 
10.3.1 
Planned Analyses ...................................................................... 82 
10.3.1.1 
Data Review Team .................................................. 82 
10.3.1.2 
Final Analysis .......................................................... 83 
10.3.2 
Methods of Analyses ................................................................. 83 
10.3.2.1 
General Considerations ........................................... 83 
10.3.2.2 
Efficacy Analyses .................................................... 83 
10.3.2.3 
Safety Analyses ...................................................... 84 
10.3.2.4 
Other Analyses ........................................................ 85 
11. 
References ........................................................................................................... 86 
12. 
Appendices ........................................................................................................... 90 
12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 91 
12.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 94 
12.3 
Appendix 3.  Study Governance Considerations ....................................... 95 
Regulatory and Ethical Considerations ...................................................... 95 
Recruitment Procedures ............................................................................ 96 
Informed Consent Process ........................................................................ 96 
Data Protection/Subject Confidentiality ..................................................... 97 
Publication Policy ...................................................................................... 98 
Investigator Signatory Obligations ............................................................. 99 
Data Quality Assurance ............................................................................. 99 
Source Documents .................................................................................. 100 
Study and Site Closure............................................................................ 101 
Compensation ......................................................................................... 102 
12.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..................................... 103 
Definition of Adverse Event ..................................................................... 103 
Definition of Serious Adverse Event ........................................................ 104 
Recording Adverse Events and Serious Adverse Events ........................ 105 
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Evaluating Adverse Events and Serious Adverse Events ........................ 105 
Reporting of Serious Adverse Event ........................................................ 106 
12.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ...................................................... 112 
Definition of Females of Childbearing Potential ....................................... 112 
Collection of Pregnancy Information ........................................................ 114 
Collection of Lactation Information .......................................................... 115 
12.6 
Appendix 6.  Sample Storage and Destruction ........................................ 118 
12.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 119 
12.8 
Appendix 8.  International Uniform Response Criteria for Multiple 
Myeloma ................................................................................................. 120 
12.9 
Appendix 9.  Guidance for Dyspnea Adverse Events .............................. 123 
12.10 Appendix 10.  Eastern Cooperative Oncology Performance 
Status ...................................................................................................... 124 
12.11 Appendix 11.  Guidelines for Documenting Prior Treatment .................... 125 
12.12 Appendix 12.  2014 Antihypertensive Management by Joint 
National Committee 8 (JNC8) .................................................................. 126 
12.13 Appendix 13.  Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) Equation .......................................................... 127 
12.14 Appendix 14.  Venous Thromboembolic Disease (VTE) Risk 
Assessment and Prophylaxis for Multiple Myeloma ................................. 128 
12.15 Appendix 15.  2013 European Society of 
Hypertension/European Society of Cardiology Office Blood 
Pressure Measurement ........................................................................... 129 
12.16 Appendix 16.  Overview of QLQ-C30 and QLQ-MY20 Scales ................. 130 
List of Tables 
Table 2-1.  Schedule of Activities ................................................................................... 18 
Table 7-1.  Carfilzomib Dosage ..................................................................................... 50 
Table 7-2.  Dose Decrements for Carfilzomib ................................................................ 58 
Table 7-3.  Dose Modification Guidelines for Thrombocytopenia and 
Neutropenia ............................................................................................ 59 
Table 7-4.  Dose Modification Guidelines for Nonhematologic Toxicities ....................... 60 
Table 7-5.  Dose Decrements for Dexamethasone ........................................................ 63 
Table 7-6.  Treatment Guidelines for Dexamethasone-related Toxicity .......................... 64 
Table 12-1.  Analyte Listing ........................................................................................... 94 
Table 12-2.  CKD-EPI Equation for Estimating Glomerular Filtration Rate 
(GFR) Expressed for Specified Race, Sex, and Serum 
Creatinine in mg/dL .............................................................................. 127 
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List of Figures 
Figure 2-1.  Study Schema ............................................................................................ 17 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form ................ 107 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet .................................... 116 
 
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1. 
Protocol Synopsis 
Protocol Title:  An Open-label Phase 2 Study of Carfilzomib Combinations (Carfilzomib 
Plus Dexamethasone, Carfilzomib Plus Lenalidomide and Dexamethasone, and 
Carfilzomib Plus Pomalidomide and Dexamethasone), To Assess Tolerability and 
Adherence in Subjects With Relapsed or Refractory Multiple Myeloma at US Community 
Oncology Centers 
Short Protocol Title:  A Study of Carfilzomib Combinations in Subjects With Relapsed 
or Refractory Multiple Myeloma at US Community Oncology Centers 
Study Phase:  2 
Indication:  relapsed or refractory multiple myeloma (RRMM) 
Rationale 
The ENDEAVOR study demonstrated the superiority of the combination of carfilzomib 
(Kyprolis) with dexamethasone (Kd; 56 mg/m2 twice weekly) over bortezomib with 
dexamethasone (Vd; 1.3 mg/m2 twice weekly).  Superiority of the Kd regimen was 
demonstrated in terms of both progression-free survival (PFS) (18.7 months vs 
9.4 months, hazard ratio [HR] = 0.53) and overall survival (OS) (median 47.6 months vs 
40.0 months, HR = 0.791, one-sided p = 0.010) (Dimopoulos et al, 2016; 
Dimopoulos et al, 2017).  Despite the favorable benefit-risk profile of the Kd regimen, as 
demonstrated in the ENDEAVOR study, logistical challenges of the twice-weekly dosing 
have been reported within the United States (US) community practice setting.  With the 
results from the A.R.R.O.W. study, the Kd 70mg/m2 once weekly dosing schedule was 
approved in the US, providing the US practicing centers one more option to treat MM 
patients with relapse/refractory disease.   
Triplet therapy combining a proteasome inhibitor (PI) with an immunomodulatory agent 
(IMiD) and steroid remains an important and commonly used option for many patients 
with RRMM.  Patients refractory to PIs and IMiDs have extremely poor prognosis with 
median OS of approximately 13 months and PFS about 5 months (Kumar et al, 2017). 
Current treatment practices lead to a high prevalence of dual, lenalidomide-bortezomib 
refractory relapses in later lines of therapy.   
The ASPIRE study demonstrated the superiority of the combination of carfilzomib with 
lenalidomide and dexamethasone (KRd; 27 mg/m2 twice-weekly) over lenalidomide with 
dexamethasone.  Superiority of the KRd regimen was demonstrated in terms of median 
PFS (26.3 vs 17.6 months, HR = 0.69), overall response rate (87.1% vs 66.7%,  
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odds ratio = 3.47) (Stewart et al, 2015), health-related quality-of-life (Stewart et al, 2016), 
as well as 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. 
Pomalidomide and dexamethasone (Pd) has been approved for subjects with RRMM 
and has proven efficacy in subjects who were refractory to both bortezomib and 
lenalidomide.  Several phase 2 studies have demonstrated improved efficacy and safety 
of adding carfilzomib to Pd (KPd) in advanced RRMM compared to historical outcomes 
with Pd.  The key benefits of carfilzomib, pomalidomide, dexamethasone as a triplet-
therapy for patients with relapsed and refractory multiple myeloma include increases in 
PFS, OS, and ORR (San Miguel et al, 2013). 
The purpose of this study is to:  
• 
Describe the safety profile of 3 different weekly carfilzomib based regimens:  
o carfilzomib plus dexamethasone regimen (Kd 56 mg/m2 twice weekly in 
cycles 1-2 followed by Kd 70 mg/m2 once weekly in cycles 3–12);  
o carfilzomib plus lenalidomide and dexamethasone regimen (KRd 27 mg/m2 twice 
weekly in cycles 1-2 followed by KRd 56 mg/m2 once weekly in cycles 3-12);  
o carfilzomib plus pomalidomide and dexamethasone regimen  
(KPd 27 mg/m2 twice weekly in cycles 1-2 followed by KPd 56 mg/m2 once 
weekly in cycles 3-12) in subjects with RRMM with 1–3 prior lines of therapy at 
study entry.   
• 
Describe subjects’ adherence these carfilzomib based regimens.  
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Objectives/Endpoints 
 
Objectives 
Endpoints 
Primary 
Describe adherence and treatment safety 
across all 12 cycles of carfilzomib based 
regimens in subjects with relapsed or 
refractory multiple myeloma with 1-3 prior 
lines of therapy at study entry. 
• 
proportion of subjects completing 
12 cycles of treatment 
• 
proportion of actual cumulative dose 
received to the full intended cumulative 
dose in cycles 1-12 
• 
relative dose intensity in cycles 1-12  
• 
dose modifications and reasons in 
cycles 1-12  
• 
treatment-emergent adverse events and 
serious adverse events 
Secondary 
Assess subject health-related quality-of--life 
(HRQoL) with the Kd, KRd, and KPd 
regimens. 
• 
European Organization for Research and 
Treatment of Cancer Quality-of-life 
Questionnaire (EORTC QLQ) Core 30 
(C30) and EORTC QLQ Multiple 
Myeloma Module (MY20) scores through 
cycle 12 or up to disease progression  
Assess response to the Kd, KRd, and KPd 
regimens. 
• 
response rate (stringent complete 
response [sCR], complete response 
[CR], very good partial response [VGPR], 
partial response [PR], minimal response 
[MR], stable disease [SD], progressive 
disease [PD], Not evaluable [NE]). 
• 
progression-free survival (PFS) at 1 year 
• 
response rate and PFS by line of prior 
therapy 1 vs ≥ 2 
 
Hypotheses 
Carfilzomib combinations (Kd, KRd, and KPd) have acceptable tolerability and 
adherence in subjects with RRMM in a community-based setting.   
Overall Design 
This is a phase 2, multicenter, open-label study in subjects with RRMM in US community 
oncology centers.  Subjects with 1-3 prior lines of therapy at study entry are eligible to be 
screened for participation.  Subjects refractory to their last line of treatment are eligible to 
participate as long as their last line of treatment did not include a proteasome inhibitor 
(PI).  The study will consist of a screening period of up to 28 days for bone marrow 
aspirate, bone lesion assessment, and plasmacytoma assessment and up to 21 days for 
all other assessments, up to 12 cycles of treatment, and a 30-day safety follow-up period 
following the last dose of study drug.   
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During the treatment period, subjects in the Kd arm will be treated with Kd 20/56 mg/m2 
twice weekly for two 28-day cycles followed Kd 70 mg/m2 once weekly for an additional  
ten 28-day cycles; subjects in the KRd arm will be treated with KRd 20/27 mg/m2 twice 
weekly for two 28-day cycles followed by KRd 56 mg/m2 once weekly for an additional 
ten 28-day cycles; and subjects in the KPd arm will be treated with KPd 20/27 mg/m2 
twice weekly for two 28-day cycles followed by KPd 56 mg/m2 once weekly for an 
additional ten 28-day cycles.   
After discontinuation of study drugs, subjects in all treatment arms will be followed for 
30 days for safety. 
Number of Subjects 
A total of approximately 75 subjects will be enrolled in the study, with approximately  
25 subjects in each arm.   
Summary of Subject Eligibility Criteria 
This study will enroll adults ≥ 18 years of age with RRMM.  Subjects must have 
measurable disease, Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) of 0 to 1, and at least 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 (MM).   
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.2. 
Treatments 
For all arms 
Dexamethasone will be taken orally or by IV infusion at a dose of 20 mg once-daily on 
days 1, 2, 8, 9, 15, 16, 22, and 23 of cycles 1-2, and at a dose 40 mg once-daily on days 
1, 8, 15 of cycles 3-12.  All doses should be administered on the scheduled days  
± 2 days but prior to carfilzomib infusion except for days 22 and 23 of cycles 1-2.   
Dexamethasone will be administered at least 30 minutes (but no more than 4 hours) 
prior to carfilzomib.  Subjects receiving dexamethasone IV on days 1, 2, 8, 9, 15, and 16, 
may receive the day 22 and day 23 dose orally. 
Kd arm 
Carfilzomib will be administered in the clinic by a qualified healthcare provider as an 
intravenous (IV) infusion.   
Carfilzomib will be administered at 20 mg/m2 on days 1 and 2 of the first cycle 
(see Table 7-1).  After that, carfilzomib will be administered at 56 mg/m2 on days 8, 9, 
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Page 14 of 132 
CONFIDENTIAL 
 
 
15, and 16 of the first cycle, and then on days 1, 2, 8, 9, 15, and 16 for cycle 2.  Starting 
with cycle 3 through cycle 12, carfilzomib will be administered at 70 mg/m2 on days 1, 8, 
and 15 of each 28-day cycle.  All 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.   
KRd arm 
Carfilzomib will be administered in the clinic by a qualified healthcare provider as an  
IV infusion.   
Carfilzomib will be administered at 20 mg/m2 on days 1 and 2 of the first cycle 
(see Table 7-1).  After that, carfilzomib will be administered at 27 mg/m2 on days 8, 9, 
15, and 16 of the first cycle, and then on days 1, 2, 8, 9, 15, and 16 for cycle 2.  Starting 
with cycle 3 through cycle 12, carfilzomib will be administered at 56 mg/m2 on days 1, 8, 
and 15 of each 28-day cycle.  All 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.   
Lenalidomide will be taken QD orally at a dose of 25 mg on days 1 to 21 of each cycle 
(cycles 1-12). 
KPd arm 
Carfilzomib will be administered in the clinic by a qualified healthcare provider as an  
IV infusion.   
Carfilzomib will be administered at 20 mg/m2 on days 1 and 2 of the first cycle 
(see Table 7-1).  After that, carfilzomib will be administered at 27 mg/m2 on days 8, 9, 
15, and 16 of the first cycle, and then on days 1, 2, 8, 9, 15, and 16 for cycle 2.  Starting 
with cycle 3 through cycle 12, carfilzomib will be administered at 56 mg/m2 on days 1, 8, 
and 15 of each 28-day cycle.  All 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.   
Pomalidomide will be taken QD orally at a dose of 4 mg on days 1 to 21 of each cycle 
(cycles 1-12).   
Procedures 
Written informed consent must be obtained from all subjects before any study-specific 
screening procedures are performed.  
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Screening procedures will include:  
• 
Collection of medical history; physical examination and measurements, 
electrocardiogram (ECG), vital signs, ECOG PS, echocardiogram, and pregnancy 
test for females of childbearing potential (FCBP). 
• 
Multiple myeloma disease assessments to confirm measurable disease: serum 
protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), serum free 
light chain (SFLC), serum immunofixation (SIFE), urine immunofixation (UIFE), 
plasmacytoma evaluation, bone lesion assessment, and bone marrow aspirate with 
fluorescence in-situ hybridization (FISH). 
At specified visits, outlined in the Schedule of Activities (Table 2-1), the following 
measurements will be collected: weight, vital signs, recording of concomitant 
medications, as well as review of adverse events and serious adverse events.  Blood will 
be collected for local laboratory testing, including hematology and chemistry.  
Additionally, in FCBP a urine or serum pregnancy test will be performed locally.   
Investigators are required to follow International Myeloma Working Group (IMWG) 
criteria for assessment of response and disease progression (see Section 12.8).  
Disease assessments based on local laboratory data will be performed per the Schedule 
of Activities (Table 2-1) and include:  SPEP, UPEP, SFLC, SIFE, UIFE. 
Clinical outcome assessments (COAs) will be measured using 3 questionnaires:  
HRQoL and 
 
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 
With a sample size of 25 subjects in each treatment arm, assuming 50%, 75%, or 90% 
of subjects complete 12 cycles of treatment, the expected half-widths of the 
95% confidence interval (CI) for estimating the proportion of subjects completing 
12 cycles of treatment are provided below. 
Sample Size 
95% Confidence Interval Half-width (%) 
50% 
75% 
90% 
25 
20.5 
18.1 
13.5 
The full analysis set will be the same as the safety analysis set, which will include all 
enrolled subjects who received at least 1 dose of any study treatment (ie, carfilzomib, 
lenalidomide, pomalidomide, or dexamethasone).  Unless otherwise specified, following 
analyses will be based on the safety analysis set. 
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For primary endpoints, the proportion of subjects completing 12 cycles of carfilzomib 
based regimens will be calculated.  The proportion of actual cumulative dose received to 
the full intended cumulative dose in cycles 1-12 will be summarized descriptively.  The 
full intended cumulative dose is defined as all therapy specified per  
Sections 7.1.1.2 and 7.1.2 without consideration for dose modification or skipped doses.  
Relative dose intensity in cycles 1-12 will be summarized descriptively.  Dose 
modifications including dose reduction, dose withheld, and dose delay in cycles 1-12 will 
be summarized along with reasons including adverse events and non-adverse events.  
Treatment-emergent adverse events and serious adverse events in cycles 1-12 will be 
summarized descriptively following the methods specified in Section 10.3.2.3.  The 
proportions of treatment discontinuations due to all adverse events, reasons for 
treatment discontinuation due to all adverse events, and dose reductions due to all 
adverse events will be summarized descriptively.   
All EORTC QLQ-C30 and EORTC QLQ-MY20 subscale scores up to cycle 12 or 
disease progression will be summarized descriptively by cycle based on the safety 
analysis set.  The rate of PFS at 1 year will be estimated using the Kaplan-Meier method 
and with CI estimated using the method by Kalbfleisch and Prentice, 1980 with log-log 
transformation.  The response rate and 1-year PFS rate will be summarized descriptively 
by line of prior therapy 1 vs ≥ 2.   
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name: Amgen Inc.  
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Protocol Number:  20170596 
Date:  20 May 2019 
 
Page 17 of 132 
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2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema 
Cycle 2
Safety follow-up
Day 1
30 (+3) days 
after last dose of 
study drug
Screening (up to 21 days)a
Enrollment N = ~75
Cycle12/
EOT
Ten 28-day cycles
K: 70 mg/m2 on days 1, 8, 15
d: 40 mg on days 1, 8, 15
Kd
n = ~25
KRd
n = ~25
KPd
n = ~25
Ten 28-day cycles
K: 56 mg/m2 on days 1, 8, 15
R: 25 mg QD on days 1 to 21
d: 40 mg on days 1, 8, 15
Ten 28-day cycles
K: 56 mg/ m2 on days 1, 8, 15
P: 4 mg QD on Days 1 to 21
d: 40 mg on days 1, 8, 15
Two 28-day cycles
K: 20/56 mg/m2 on
days 1, 2, 8, 9, 15, 16 
d: 20 mg on days 1, 2, 
8, 9, 15, 16, 22, 23
Two 28-day cycles
K: 20/27 mg/m2 on
days 1, 2, 8, 9, 15, 16 
R: 25 mg QD on days 1 
to 21
d: 20 mg on days 1, 2, 
8, 9, 15, 16, 22, 23
Two 28-day cycles
K: 20/27 mg/m2 on days 
1, 2, 8, 9, 15, 16 
P: 4 mg QD on days 1 
to 21
d: 20 mg on days 1, 2, 
8, 9, 15, 16, 22, 23
 
EOT = end of treatment; d = dexamethasone; K = Kyprolis (carfilzomib); P = pomalidomide; QD = once daily; R = lenalidomide 
a All screening assessments except bone marrow aspirate, bone lesion assessment, and plasmacytoma assessment must be completed within 21 days before cycle 1 
day 1.  Bone marrow aspirate, bone lesion assessment, and plasmacytoma assessment must be completed within 28 days of cycle 1 day 1. 
 
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Protocol Number:  20170596 
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Page 18 of 132 
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2.2 
Schedule of Activities 
Table 2-1.  Schedule of Activities 
PROCEDURE 
Screeninga b 
(up to 
21 days 
before 
Day 1) 
Treatment Period 
Safety FUc 
(30 [+3] 
days post 
last dose) Notes 
Cycle 1-2 
Cycle 3-12 
Day 1 
2 
8 
9 15 16 22 23 1 8 15 21 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical 
measurements 
Height, BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BSA should be calculated per Mosteller 
formula and utilized to calculate 
required study drug doses.  BSA should 
be recalculated if weight changes by 
20% or more (gain or loss)  
Weight 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
BSA 
X 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 9.2.1.3 
Substance use  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X X X X X 
 
 
X X X 
 
X 
Checked prior to administration of study 
drug(s) in all cycles.   
ECOG performance status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
At screening and as clinically indicated 
(per Section 12.9) 
Adverse events/serious adverse 
events 
Continuous 
Adverse events are to be captured 
during screening, starting with the 
signing of the informed consent.  
Recommended dyspnea evaluation per 
investigator’s judgment per 
Section 12.9 
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Table 2-1.  Schedule of Activities 
PROCEDURE 
Screeninga b 
(up to 
21 days 
before 
Day 1) 
Treatment Period 
Safety FUc 
(30 [+3] 
days post 
last dose) Notes 
Cycle 1-2 
Cycle 3-12 
Day 1 2 8 9 15 16 22 23 1 8 15 21 
Concomitant therapies review 
Continuous 
 
LABORATORY ASSESSMENTS 
Pregnancy 
test (FCBP 
only)d 
Kd 
Arm 
Urine or serum 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
KPd 
and 
KRd 
Arms 
Serum 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine or serum 
cycle 1 
(predose) 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Within 24 hours prior to dose of 
lenalidomide or pomalidomide for subjects 
in the KRd or KPd arms, respectively 
Urine or serum 
cycle 2 to 12 
(predose; 
regular menses) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Urine or serum 
cycle 2 to 12 
(predose; 
irregular 
menses) 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Hematology 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Hematology and chemistry samples 
from screening may be used for C1D1 if 
taken within 3 days prior to C1D1.  Lab 
results must be evaluated for potential 
dose modification assessment prior to 
dosing (see Section 7.4). Chemistry 
and hematology assessments, other 
than for C1D1, may be taken within 
2 days prior to the scheduled 
assessment. 
Chemistry 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
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Table 2-1.  Schedule of Activities 
PROCEDURE 
Screeninga b 
(up to 
21 days 
before 
Day 1) 
Treatment Period 
Safety FUc 
(30 [+3] 
days post 
last dose) Notes 
Cycle 1-2 
Cycle 3-12 
Day 1 2 8 9 15 16 22 23 1 8 15 21 
Fasting lipid panel  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total cholesterol, HDL, LDL, 
triglycerides (fasting ≥ 12 hours) 
NT-proBNP (or BNP) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
At screening and as clinically indicated 
(see Section 12.9) 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting glucose 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting ≥ 12 hours 
Estimated GFR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estimated GFR calculated using 
CKD-EPI equation (see Section 12.13) 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
For calculation of albumin creatinine 
ratio per exclusion criteria 206, see 
Section 6.2 
DISEASE-SPECIFIC ASSESSMENTS 
LDH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-2 microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Corrected calcium 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPEP/UPEP/SFLC/SIFE/UIFEe 
X 
Xf 
 
 
 
 
 
 
 
X 
 
 
 
 
UPEP requires 24-hour urine collection.  
Evaluated by investigator based on 
IMWG criteria (see Section 12.8) 
Myeloma Response Assessmente 
 
(X)g 
 
X 
Disease assessment to be performed 
every 28 ± 7 days until confirmed PD 
regardless of cycle duration, including 
dose delays.  Disease assessments at 
the safety follow-up visit are not 
required for subjects who discontinue 
early due to confirmed PD or if 
assessments were performed within 
14 days prior to the safety follow-up 
visit. 
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Table 2-1.  Schedule of Activities 
PROCEDURE 
Screeninga b 
(up to 
21 days 
before 
Day 1) 
Treatment Period 
Safety 
FUc (30 
[+3] days 
post last 
dose) 
Notes 
Cycle 1-2 
Cycle 3-12 
Day 1 2 8 9 15 16 22 23 1 
8 15 21 
Bone Lesion Assessmentb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening and will be repeated if 
worsening clinical symptoms suggest PD, 
or as clinically indicated.  (see 
Section 12.8 for IMWG criteria) 
Plasmacytoma evaluationb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 9.2.2.3.  Only required at 
screening in subjects if clinically 
suspected and to confirm response (if 
performed at screening, see Section 12.8 
for IMWG criteria) 
Bone marrow aspirate with FISHb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate is required at 
screening and to confirm a response of 
CR (see Section 12.8 for IMWG criteria).  
FISH is only required at screening. 
CLINICAL OUTCOME ASSESSMENTS 
EORTC QLQ-C30  
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
During treatment period, these 
questionnaires must be completed on 
day 1 of each cycle prior to dosing. 
EORTC QLQ-MY20 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Amgen Satisfaction and 
Convenience Questionnaire 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
During treatment period, these 
questionnaires must be completed on 
day 1 of each cycle prior to dosing, 
starting with C2D1.  Items 8-11 to be 
collected only once at end of treatment or 
at completion of the trial. 
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Page 22 of 132 
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Table 2-1.  Schedule of Activities 
PROCEDURE 
Screeninga b 
(up to 
21 days 
before 
Day 1) 
Treatment Period 
Safety 
FUc (30 
[+3] days 
post last 
dose) 
Notes 
Cycle 1-2 
Cycle 3-12 
Day 1 2 8 9 15 16 22 23 1 
8 15 21 
STUDY TREATMENT  
Kd ARM 
Carfilzomib administrationh 
 
X 
X X X X X 
 
 
X 
X 
X 
 
 
Cycle 1: 20 mg/m2 on days 1 and 2; 
56 mg/m2 on days 8, 9, 15, and 16  
Cycle 2: 56 mg/m2 
Cycles 3-12: 70 mg/m2 
For subjects with baseline hepatic 
function abnormalities (bilirubin or AST 
> ULN), see Section 7.1.1.2.1 for 
modification of the initial dose. 
For cycle 3, for subjects who were 
previously dose reduced, see 
Section 7.1.1.2 for starting dose. 
Dexamethasone administrationh 
 
X 
X X X X X Xi Xi X 
X 
X 
 
 
Cycles 1-2: 20 mg  
Cycles 3-12: 40 mg 
For subjects ≥ 75 years of age, see 
Section 7.4.1.2 for dose modification. 
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Page 23 of 132 
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Table 2-1.  Schedule of Activities 
PROCEDURE 
Screeninga b  
(up to 
21 days 
before Day 1) 
Treatment Period 
Safety FUc 
(30 [+3] 
days post 
last dose) Notes 
Cycle 1-2 
Cycle 3-12 
Day 1 2 8 9 15 16 22 23 1 
8 15 21 
KRd ARM 
Carfilzomib administrationh 
 
X 
X X 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  
Cycle 2: 27 mg/m2  
Cycles 3-12: 56 mg/m2 
For subjects with baseline hepatic 
function abnormalities (bilirubin or AST 
> ULN), see Section 7.1.1.2.1 for 
modification of the initial dose. 
For cycle 3, for subjects who were 
previously dose reduced, see 
Section 7.1.1.2 for starting dose. 
Lenalidomide administration 
 
Days 1 to 21 of each cycle 
 
25 mg 
Dexamethasone administrationh 
 
X 
X X X X X Xi Xi X 
X 
X 
 
 
Cycles 1-2: 20 mg  
Cycles 3-12: 40 mg 
For subjects ≥ 75 years of age, see 
Section 7.4.1.2 for dose modification. 
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Page 24 of 132 
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Table 2-1.  Schedule of Activities 
PROCEDURE 
Screeninga b 
(up to 
21 days 
before Day 1) 
Treatment Period 
Safety FUc 
(30 [+3] 
days post 
last dose) Notes 
Cycle 1-2 
Cycle 3-12 
Day 1 2 8 9 15 16 22 23 1 
8 15 21 
KPd ARM 
Carfilzomib administrationh 
 
X 
X X 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  
Cycle 2: 27 mg/m2  
Cycles 3-12: 56 mg/m2 
For subjects with baseline hepatic 
function abnormalities (bilirubin or AST 
> ULN), see Section 7.1.1.2.1 for 
modification of the initial dose. 
For cycle 3, for subjects who were 
previously dose reduced, see 
Section 7.1.1.2 for starting dose. 
Pomalidomide 
 
Days 1 to 21 of each cycle 
 
4 mg 
Dexamethasone administrationh 
 
X 
X X X X X Xi Xi X 
X 
X 
 
 
Cycles 1-2: 20 mg  
Cycles 3-12: 40 mg 
For subjects ≥ 75 years of age, see 
Section 7.4.1.2 for dose modification. 
Page 7 of 7 
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Page 25 of 132 
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AST = aspartate aminotransferase; BMI = body mass index; BNP = brain natriuretic peptide; BSA = body surface area; CKD-EPI = Chronic Kidney Disease 
Epidemiology Collaboration; CR = complete response; C = cycle; d = dexamethasone; 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; EORTC QLQ-MY20 = EORTC Quality-of-life Questionnaire Multiple Myeloma Module; FCBP = females of childbearing potential; FISH = fluorescence in-situ 
hybridization; FU = follow-up; HbA1c = hemoglobin A1c; GFR = Glomerular Filtration Rate; HDL = high-density lipoprotein; IMWG = International Myeloma Working 
Group; K = Kyprolis (carfilzomib); LDH = lactate dehydrogenase; LDL = low-density lipoprotein; NT-proBNP = N terminal of the prohormone brain natriuretic peptide;  
P = pomalidomide; PD = progressive disease; R = lenalidomide; SFLC = serum free light chain; SIFE = serum immunofixation; SPEP = serum protein electrophoresis; 
UIFE = urine immunofixation; ULN = upper limit of normal; UPEP = urine protein electrophoresis 
(X) = Parentheses indicate that the particular test is situational at that time point, as specified in the respective notes. 
a All screening assessments except bone marrow aspirate, bone lesion assessment, and plasmacytoma assessment must be completed within 21 days before cycle 1 
day 1.  Bone marrow aspirate, bone lesion assessment, and plasmacytoma assessment must be completed within 28 days of cycle 1 day 1. 
b If performed as part of standard of care within 28 days of cycle 1 day 1, then do not repeat at screening unless clinically indicated.    
c Once a subject discontinues from the study drug (see Section 8.1), he/she will have a safety follow-up visit 30 (+3) days after the last dose of study drug(s), unless 
the subject is lost to follow-up, has withdrawn consent, or has died.  After the safety follow-up, subjects who remain on study are required to complete disease 
response assessments and will be followed for subsequent antimyeloma treatment every 28 ± 7 days until up to 12 months from enrollment, death, loss to follow-up, 
withdrawal of consent or PD, whichever occurs first. 
d Additional on-treatment pregnancy testing may be performed at the investigator’s discretion if there is suspicion that a female subject is pregnant or per local laws and 
regulations. 
e Disease assessment should be performed every 28 ± 7 days until confirmed PD regardless of cycle duration, including dose delays.  Cycle 1 disease assessment is 
conducted 28 (± 7) days post cycle 1, day 1.  Subjects who discontinue treatment prior to confirmed PD should continue to complete disease assessments each cycle 
until up to 12 months from enrollment, death, loss to follow-up, withdrawal of consent or PD, whichever occurs first.   
f Unless screening values are within 14 days of cycle 1 day 1, SPEP, UPEP, and SFLC will be repeated on cycle 1 day 1.    
g Cycle 12 disease assessment is conducted 28 (± 7) days post cycle 12, day 1. 
h All 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 
(see Section 7.1.1.2 for additional details). 
i Dexamethasone (if administered orally) may be self-administered at home by the subject on non-clinic days (days 22 and 23 of cycles 1-2).  See Section 7.6 for 
additional details. 
 
 
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Protocol Number:  20170596 
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Page 26 of 132 
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3. 
Introduction 
3.1 
Study Rationale 
Carfilzomib (Kyprolis) with dexamethasone (Kd) and the combination of carfilzomib with 
the immunomodulatory agent (IMiD) lenalidomide and dexamethasone (KRd) 
twice-weekly dose regimens have demonstrated favorable benefit risk profiles as in the 
ENDEAVOR and ASPIRE studies, respectively, and preliminary data for the KPd 
twice-weekly regimen also indicated the favorable benefit risk profile; however, logistical 
challenges of the twice weekly dosing have been reported within the United States (US) 
community practice setting.  Therefore, there is the need to explore a more convenient 
dosing schedule which may lead to better adherence to the treatment, especially in the 
community setting. 
The ENDEAVOR study demonstrated the superiority of the Kd regimen (56 mg/m2  
twice weekly) over bortezomib with dexamethasone (Vd; 1.3 mg/m2 twice weekly).  
Superiority of the Kd regimen was demonstrated in terms of both progression-free 
survival (PFS) (18.7 months vs 9.4 months, hazard ratio [HR] = 0.53) and overall survival 
(OS) (median 47.6 months vs 40.0 months, HR = 0.791, one-sided p = 0.010) 
(Dimopoulos et al, 2016; Dimopoulos et al, 2017).   
Subsequently, the A.R.R.O.W. study results demonstrated that treatment with once 
weekly Kd at the dose of 70 mg/m2 (30 minute infusion) resulted in superior PFS and 
overall response rate (ORR), compared to the twice weekly administration of  
Kd 27 mg/m2 in patients with relapsed and refractory multiple myeloma (RRMM).  The 
safety profile was comparable in the 2 arms.  Based on A.R.R.O.W. data, the Kd once 
weekly dose of 70 mg/m2 was included in the US label. 
Meanwhile, the treatment for RRMM is evolving towards triplet therapies, and triplets 
containing a proteasome inhibitor (PI) and IMiD are among the most efficacious 
therapies.   
The ASPIRE study demonstrated the superiority of the KRd regimen (27 mg/m2) 
twice-weekly) over lenalidomide with dexamethasone.  Superiority of the KRd regimen 
was demonstrated in terms of median PFS (26.3 vs 17.6 months, 
 HR = 0.69), ORR (87.1% vs 66.7%, odds ratio = 3.47) (Stewart et al, 2015), 
health-related quality-of-life (Stewart et al, 2016), as well as 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.   
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Page 27 of 132 
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In addition to the twice weekly triplet dosing regimen (KRd), the once weekly KRd dosing 
regimen has been tested. The ongoing Study CFZ013 evaluates once-weekly KRd in 
patients with relapsed or relapsed and refractory multiple myeloma who have been 
treated with 1 to 3 prior lines of therapy.  As of data cut-off 18 July 2018, efficacy results 
from 56 subjects treated with weekly KRd 56 mg/m2 (n = 10) or KRd 70 mg/m2 (n = 46) 
has shown similar efficacy, as determined by ORR (90.0% versus 89.1%, respectively) 
and similar ORR as previously reported for twice-weekly KRd (27 mg/m2) in the ASPIRE 
study, 87.1% (Biran et al, 2018).  These results complement the significant efficacy 
results of carfilzomib as a triplet therapy. 
The IMiD pomalidomide and dexamethasone (Pd) has been approved for subjects with 
RRMM and has proven efficacy in subjects who were refractory to both bortezomib and 
lenalidomide.  Several phase 2 studies have demonstrated improved efficacy and safety 
of adding carfilzomib twice weekly to Pd (KPd) in advanced RRMM compared to 
historical outcomes with Pd.  The key benefits of carfilzomib, pomalidomide, 
dexamethasone as a triplet-therapy for patients with relapsed and refractory multiple 
myeloma include increases in PFS, OS, and ORR.  The safety profile shows that the 
adverse events observed with the combination KPd are consistent with the product 
labels for carfilzomib and pomalidomide (Sonneveld et al, 2018; Shah et al, 2015). 
These data from the twice weekly KPd regimen provided the rationale to explore a once 
weekly KPd regimen, which may deliver a comparable clinical benefit /risk profile with 
more convenience.  
This study will assess the tolerability and adherence in RRMM subjects at US 
community oncology centers with 3 carfilzomib combinations: Kd, KRd and KPd.  The  
3 regimens will be given for 2 cycles as a twice weekly dosing schedule followed by 
10 cycles of a once weekly dosing schedule. The twice weekly schedule of these  
3 carfilzomib combinations is the originally approved schedule and familiar to the treating 
physicians.  The approval of the once weekly dosing schedule for Kd is relatively new to 
the clinical practice.  To provide a consistent dosing schedule among the different arms, 
in context of this variable carfilzomib dosing, each carfilzomib combination begins with a 
twice weekly schedule and transitions to a once weekly schedule. 
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The purpose of this study is to:  
• 
Describe the safety profile of 3 different weekly carfilzomib based regimens: 
o carfilzomib plus dexamethasone regimen (Kd 56 mg/m2 twice weekly in cycles 
1-2 followed by Kd 70 mg/m2 once weekly in cycles 3-12) );  
o carfilzomib plus lenalidomide and dexamethasone regimen (KRd 27 mg/m2 twice 
weekly in cycles 1-2 followed by KRd 56 mg/m2 once weekly in cycles 3-12);  
o carfilzomib plus pomalidomide and dexamethasone regimen (KPd 27 mg/m2 
twice weekly in cycles 1-2 followed by KPd 56 mg/m2 once weekly in cycles 3-12)  
in subjects with relapsed or refractory multiple myeloma (RRMM) with 1-3 prior 
lines of therapy at study entry.  
• 
Describe subjects’ adherence to these carfilzomib based regimens. 
3.2 
Background 
3.2.1 
Disease 
Multiple myeloma (MM) is a plasma cell disorder representing 1.5% of all cancers and 
up to 13% of all hematological malignancies worldwide (Katzel et al, 2007).  According to 
the American Cancer Society, approximately 30 000 new cases of MM are expected to 
be diagnosed in 2016 (SEER Cancer Statistic Review).  Multiple myeloma is a disease 
of older adults, with a median age at diagnosis of 70 years (Howlader et al, 2013).  
Although MM is usually responsive to cytotoxic therapy, responses are often brief, 
highlighting the need for new therapeutic targets and more successful combination 
therapies.  Over the 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).  The 5-year survival rates have almost doubled, increasing from 
27% to 47% between 1989 and 2010 (Pulte et al, 2014).  Despite improvements in the 
management of the disease, MM still remains a serious illness and most patients 
eventually develop treatment resistance (Barlogie et al, 2006).  In addition, response 
time generally decreases with subsequent number of treatment lines 
(Kumar et al, 2004). 
Treatment of RRMM presents a special therapeutic challenge, due to the heterogeneity 
of disease at relapse and the absence of clear biological based treatment 
recommendations at various time points of disease progression.  The treatment 
landscape is evolving rapidly with increasing recognition of the inherent clonal 
heterogeneity and genomic instability of the plasma cells influencing both inherent and 
acquired therapeutic resistance, the identification of the optimal choice and sequence of 
therapies has become critical.  Several new agents and targets are currently under 
development and show considerable promise.  Besides PI and IMiD, other newer 
treatment approaches have been approved since 2015, including monoclonal antibodies 
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targeting SLAMF7 (ie, elotuzumab) or CD38 (ie, daratuzumab)  
(O’Donnell and Raje, 2017); and more innovative agents are in clinical development. 
The choice of salvage therapy for RRMM patients depends on various factors including 
disease biology, patient’s general condition, as well as the prior treatment and the 
response and long-term toxicity of prior treatment.  The other considerations are 
tolerability and adherence to salvage therapy which will impact the treatment exposure 
hence impact the treatment effects.  Given the various considerations around treatment 
decision, it’s critical to evaluate multiple salvage therapies to provide options meeting the 
different needs of RRMM patients. 
3.2.2 
Amgen Investigational Product Background:  Carfilzomib 
Carfilzomib is a tetrapeptide epoxyketone 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 = 15-30 minutes); < 1% is excreted intact (Kortuem and Stewart, 2013). 
Carfilzomib entered clinical studies in September 2005.  On 20 July 2012, Kyprolis® was 
granted accelerated approval by the US Food and Drug Administration (FDA) for the 
treatment of patients with MM who have received at least 2 prior therapies, including 
bortezomib and an 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 trials:  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.  With the results 
from the A.R.R.O.W. study, the Kd 70 mg/m2 once weekly dosing schedule was 
approved in the US to treat MM.  Carfilzomib for Injection has been approved in 
34 countries/regions worldwide. 
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As of 19 July 2018, approximately 8210 subjects have been enrolled in 116 actively 
enrolling or completed/closed single-group or randomized carfilzomib clinical trials.  It is 
estimated that approximately 88964 patients have been exposed to carfilzomib in the 
post-marketing setting. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of carfilzomib 
is provided in the Carfilzomib Investigator’s Brochure. 
3.2.3 
Benefits of Once-weekly Dosing 
Carfilzomib is FDA approved as a weekly administration in combination with 
dexamethasone (Kyprolis USPI); however, triplet therapies are emerging as SOC for 
RRMM.  Evidence suggests that the convenience afforded by a once-weekly dosing 
schedule can help improve patient adherence to treatment with antimyeloma IV agents.  
The ongoing Study CFZ013 evaluating once-weekly KRd in patients with relapsed or 
relapsed and refractory multiple myeloma has shown similar efficacy as previously 
reported for twice-weekly KRd (27 mg/m2) in the ASPIRE study  
(Biran et al, 2018).  Two studies of a once-weekly versus twice-weekly schedule of 
bortezomib as combination therapy showed consistent findings that patients with 
multiple myeloma treated with a once-weekly dose regimen were more adherent, 
received higher doses, had fewer dose reductions, and were treated for longer durations 
compared with patients treated with a twice-weekly dose regimen (Bringhen et al, 2010; 
Reeder et al, 2010).  Reducing the burden of treatment with once-weekly dosing is also 
expected to improve quality of life in patients with relapsed multiple myeloma, which has 
been shown to be dependent on the ability to maintain a social role and meaningful 
activities (Mortensen and Salomo, 2016). 
A once-weekly dose regimen would substantially reduce the time burden on patients and 
caregivers over twice-weekly dosing.  The total time for a patient to receive IV treatment 
includes transportation time to and from the clinic, wait time, pre-infusion preparation 
time, infusion and post-infusion time, and lost work or leisure time for family members or 
friends who accompany patients to the clinic.  Travel time to the medical facility was 
< 30 minutes for most patients, with 40% of patients traveling over 1 hour, based on a 
study in the United Kingdom and an average of 30 to 35 minutes based on a survey in 
the US (Barrett-Lee et al, 2007; data on file).  Thus, a once-weekly dose regimen would 
represent substantial time-savings for patients and their caregivers. 
In summary, in the setting of RRMM, the ENDEAVOR study demonstrated that the 
labelled dose of twice weekly carfilzomib (56 mg/m2) significantly improved survival.  
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However, real world data discussed above indicates that it is difficult to sustain this level 
of therapy for a prolonged period of time and that once weekly dosing may improve 
treatment adherence and clinical benefit.  Once weekly data from the A.R.R.O.W. and 
CHAMPION 1 trials demonstrated the efficacy and safety of a once weekly dose of 
70 mg/m2 and cross trial comparison between ENDEAVOR and CHAMPION 1 indicate 
there may be no loss of efficacy with weekly dosing (Berenson et al, 2016).  The 
A.R.R.O.W. study results demonstrated that treatment with once weekly Kyprolis and 
dexamethasone at the dose of 70 mg/m2 (30 min infusion) resulted in superior PFS and 
ORR, compared to the twice weekly administration of Kd 27 mg/m2 in patients with 
RRMM.  The safety profile was comparable in the two arms.  Based on A.R.R.O.W. 
data, the Kd once weekly dose of 70 mg/m2 was included in the US label.  Meanwhile, 
other once weekly dosing combination regimens including carfilzomib based triplets are 
being explored and this study is expected to add the data evidence generated from the 
multi-center community setting.  The goal of the study is to demonstrate feasibility and 
adherence of weekly combinations of carfilzomib.  The initial treatment with 2 cycles of 
twice weekly therapy is designed to provide the more familiar labelled treatment for 
subjects with RRMM.   
3.3 
Benefit/Risk Assessment 
The following benefit risk assessment supports the conduct of this clinical trial.  
Reference should be made to the Carfilzomib Investigator’s Brochure for further data on 
carfilzomib. 
3.3.1 
Therapeutic Context 
Multiple myeloma is a clonal neoplastic proliferation of plasma cells, the second most 
common hematologic malignancy, and is responsible for approximately 80 000 annual 
deaths worldwide (1% of cancer deaths).  The 5-year prevalence of MM worldwide was 
estimated at 229 000 persons.  Multiple myeloma is a disease of older adults, with a 
median age at diagnosis of 70 years (Howlader et al, 2013).  While treatment for MM will 
typically induce remission, the disease eventually relapses in most patients.  As patients 
go through cycles of relapse and remission, the duration of remission becomes shorter 
with each successive line of therapy, and eventually becomes nonresponsive to therapy 
(Richardson et al, 2007; Kumar et al, 2004). 
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: 
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control disease to prevent or delay associated complications (such as bone fractures, 
renal insufficiency, and infections), to maintain an acceptable health-related quality of 
life, and to provide relief of pain and other disease-related symptoms.   
3.3.2 
Key Benefits 
Therapy for RRMM has evolved rapidly in the last several years.  Doublet therapy 
combining a PI and steroid remains an important and commonly used option for many 
patients.  The ENDEAVOR trial was a phase 3 head-to-head comparison of Vd and Kd 
in RRMM.  Patients treated with Kd in the ENDEAVOR study had improved PFS 
compared with those treated with Vd: median PFS 18.7 vs 9.4 months (HR = 0.53; 
95% CI 0.44-0.65; p < 0.0001) (Dimopoulos et al, 2016) and improved OS in subjects 
followed for a minimum of 3 years, median OS 47.6 vs 40 months (HR = 0.79, 95% CI, 
0.648-0.964; one-sided p = 0.01) (Dimopoulos et al, 2017).  All patient subgroups 
demonstrated clinical benefit from Kd compared with Vd (Moreau et al, 2015; 
Chng et al, 2017).  The ENDEAVOR study led to expanded approval of carfilzomib in 
patients who had received 1 to 3 lines of prior therapy.  Based on these findings, Kd is 
the only doublet regimen on the NCCN recommended preferred list for RRMM 
(NCCN Multiple Myeloma, 2018).   
The CHAMPION -1 study was conducted to determine the maximum tolerated dose 
(MTD) of carfilzomib administered once weekly in combination with dexamethasone to 
subjects with RRMM.  The MTD was determined to be 70 mg/m2.  The efficacy and 
safety of 70 mg/m2 once-weekly dosing regimen was evaluated in 104 subjects.  Among 
this cohort, 52% of subjects were refractory to bortezomib.  For the overall population, 
the overall response rate (ORR) at 70 mg/m2 was 77% (71% in patients refractory to 
bortezomib) with 13% achieving complete response (CR).  The median PFS was 
12.6 months (Berenson et al, 2016).  The median PFS for the ENDEAVOR 
(56 mg/m2 twice weekly) and CHAMPION-1 (70 mg/m2 once weekly) trials were 
18.7 and 12.6 months, respectively.  However, bortezomib-refractory subjects were not 
eligible in the ENDEAVOR trial.  Among the 50 subjects who were not refractory to 
bortezomib in the CHAMPION-1 trial, the Kaplan-Meier median PFS were 21.0 months 
(no prior bortezomib exposure) and 19.4 months (prior bortezomib exposure but not 
refractory), which compared favorably to the results in the ENDEAVOR study (Amgen 
data on file).   
The MTD defined in the CHAMPION-1 trial was used in the phase 3 A.R.R.O.W. trial, in 
which subjects with RRMM were treated with Kd with carfilzomib dosed either at 
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27 mg/m2 twice-weekly or 70 mg/m2 once-weekly.  The study included 478 subjects with 
RRMM who received 2 or 3 prior lines of therapy, including a PI and an IMiD.  Subjects 
treated with the once-weekly Kd regimen achieved a statistically significant superior PFS 
with a median of 11.2 months compared with 7.6 months for those treated with the 
twice-weekly Kd regimen (HR = 0.69, 95% CI, 0.54-0.88) (A.R.R.O.W. Press 
release, 2017).  The safety profile was comparable in the two arms.  Based on 
A.R.R.O.W. data, the Kd once weekly dose of 70 mg/m2 was included in the US label.  
These results provide additional evidence supporting the efficacy and tolerability of the 
once-weekly Kd regimen.   
Other once weekly dosing combination regimens of carfilzomib are being explored.   
Triplet therapies are emerging as the SOC for RRMM. The combination of a proteasome 
inhibitor (PI) with an immunomodulatory agent (IMiD) and steroid is a commonly used 
and guideline recommended option for patients with RRMM.  Patients refractory to PIs 
and IMiDs have extremely poor prognosis with median OS of approximately 13 months 
and PFS about 5 months (Kumar et al, 2017). Current treatment practices lead to a high 
prevalence of dual, lenalidomide-bortezomib refractory relapses in later lines of therapy.   
The ASPIRE study demonstrated the superiority of the combination of carfilzomib with 
lenalidomide and dexamethasone (KRd; 27 mg/m2 twice-weekly) over lenalidomide with 
dexamethasone.  Superiority of the KRd regimen was demonstrated in terms of median 
PFS (26.3 vs 17.6 months, HR = 0.69), overall response rate (87.1% vs 66.7%, odds 
ratio = 3.47) (Stewart et al, 2015), health-related quality-of-life (Stewart et al, 2016), as 
well as 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.  
Pomalidomide and dexamethasone (Pd) has been approved for subjects with RRMM 
and has proven efficacy in subjects who were refractory to both bortezomib and 
lenalidomide.  Several phase 2 studies have demonstrated improved efficacy and safety 
of adding carfilzomib to Pd (KPd) in advanced RRMM compared to historical outcomes 
with Pd.  The key benefits of carfilzomib, pomalidomide, dexamethasone as a  
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triplet-therapy for patients with relapsed and refractory multiple myeloma include 
increases in PFS, OS, and ORR. 
3.3.3 
Key Risks 
Multiple important identified and potential risks for carfilzomib were identified in the 
pooled safety data from 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.  Where applicable, risk minimization measures specific to a 
particular risk are also provided.  
Additional information regarding important identified risks as well as adverse drug 
reactions for carfilzomib are detailed in the Kyprolis USPI. 
Embryo-fetal toxicity is associated with 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 USPI and REVLIMID Summary of Product 
Characteristics (SmPC) or local prescribing information. 
Embryo-fetal toxicity is associated with pomalidomide treatment. Investigators and 
subjects must comply with the requirements of restricted distribution programs if one is 
present in the local region; (eg, POMALYST REMS program in the United States). 
Additional information regarding risks for pomalidomide are described in Pomalyst USPI 
or local prescribing information. 
3.3.3.1 
Risks 
3.3.3.1.1 
Cardiac Toxicity 
In the pooled data set (n = 2944), the subject incidence of cardiac failure and myocardial 
infarction was 7.2% and 2.0%, respectively.  The subject incidence of serious cardiac 
failure and serious myocardial infarction was 4.1% and 1.3%, respectively.  Fatal 
outcomes have been observed with cardiac failure, myocardial infarction, and cardiac 
arrest.  The risk of cardiac failure is increased in elderly patients (≥ 75 years).  Subjects 
with New York Heart Association (NYHA) Class III and IV heart failure, recent 
myocardial infarction, and conduction abnormalities uncontrolled by medications were 
not eligible for clinical trial and may be at greater risk for cardiac complications.  While 
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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 
Pulmonary Toxicities  
The subject incidence of serious respiratory failure and serious interstitial lung disease 
was < 0.1% and 0.8%, respectively.  Fatal outcomes have been observed with 
respiratory failure and interstitial lung disease.  
3.3.3.1.3 
Pulmonary Hypertension 
The subject incidence of pulmonary hypertension was 1.4% with a subject incidence of 
0.3% for serious events.  Some events have been fatal.   
3.3.3.1.4 
Dyspnea 
The subject incidence of dyspnea was 31.0% with a subject incidence of 2.3% for 
serious events.  The cause of the dyspnea should be investigated promptly and treated 
accordingly (see Section 12.9 for more details).  
3.3.3.1.5 
Hypertension  
The subject incidence of hypertension was 20.3% with a subject incidence of 1% for 
serious events.  Blood pressure is monitored while on study and hypertension should be 
treated as needed.  If the 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.   
3.3.3.1.6 
Acute Renal Failure 
The subject incidence of acute renal failure was 10.8% with a subject incidence of 
5.3% for serious events.  Some events have been fatal.  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 glomerular filtration rate (GFR).  Reduce or stop dose as 
described in the dose modification Section 7.4. 
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3.3.3.1.7 
Tumor Lysis Syndrome 
The subject incidence of tumor lysis syndrome (TLS) was 0.7% with a subject incidence 
of 0.5% for serious events.  Subjects with a high tumor burden should be considered to 
be at greater risk for TLS.  Instructions for ensuring proper hydration prior to cycle 1 and 
in subsequent cycles as needed are provided in Section 7.1.4.3.  Serial monitoring of 
serum electrolytes to monitor for TLS are included in the protocol.  Uric acid lowering 
drugs should be considered in patients at high risk for TLS.  If TLS occurs, the subject 
should be treated promptly, and carfilzomib should be interrupted until the TLS is 
resolved.  
3.3.3.1.8 
Infusion-related Reactions 
The subject incidence of infusion-related reactions was 1.8% with a subject incidence of 
0.3% for serious events.  The dexamethasone that is administered as part of the 
regimen is expected to decrease the incidence and severity of infusion-related reactions.  
3.3.3.1.9 
Hemorrhage and Thrombocytopenia 
The subject incidence of hemorrhage and thrombocytopenia was 19.5% and 33.8%, 
respectively.  The subject incidence of serious hemorrhage and serious 
thrombocytopenia was 2.2% and 1.5%, respectively.  Thrombocytopenia is a significant 
risk factor for hemorrhage events.  Fatal outcomes have been reported for these events.  
Carfilzomib causes thrombocytopenia with platelet nadirs observed between day 8 and 
15 of each 28-day cycle with recovery to baseline platelet count by the start of the next 
cycle.  Serial monitoring of platelets will be performed every 28 days throughout 
treatment period (see Schedule of Activities, Table 2-1).  Dose modification guidance for 
thrombocytopenia (including stopping carfilzomib) is provided in Section 7.4.   
3.3.3.1.10 
Venous Thromboembolism 
The subject incidence of venous thromboembolism was 7.0% with a subject incidence of 
2.4% for serious events.  Fatal outcomes have been reported with deep venous 
thrombosis and pulmonary embolism events.  As described in Section 7.1.4.2, 
thromboprophylaxis should be considered based on an individual benefit-risk 
assessment.   
3.3.3.1.11 
Hepatic Toxicity  
The subject incidence of hepatic toxicity was 1.9% with a subject incidence of 0.7% for 
serious events.  Cases of hepatic failure, including fatal cases, have been reported in 
< 1% of subjects in clinical studies with carfilzomib.  Serial monitoring of liver enzymes is 
conducted every 28 days throughout treatment period (see Schedule of Activities,  
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Table 2-1).  Dose modification guidance for hepatic toxicity (including stopping 
carfilzomib) is provided in Section 7.4.   
3.3.3.1.12 
Thrombotic Microangiopathy 
The subject incidence of thrombotic microangiopathy (TMA) was 0.2% and all events 
were serious.  Fatal outcomes have been reported with TMA.  As described in the dose 
modification Section 7.4, carfilzomib should be held if the diagnosis is suspected.  If the 
diagnosis is excluded, carfilzomib may be restarted based on an individual benefit-risk 
assessment.  The safety of reinitiating carfilzomib in subjects previously experiencing 
TMA (including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome) 
is unknown.  
3.3.3.1.13 
Posterior Reversible Encephalopathy Syndrome  
Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder, which 
can present with seizure, headache, lethargy, confusion, blindness, altered 
consciousness, and other visual and neurological disturbances, along with hypertension; 
the diagnosis is confirmed by neuro-radiological imaging.  The subject incidence of 
PRES was 0.1% and all events were serious.  As described in the dose modification 
Section 7.4, carfilzomib should be held if the diagnosis is suspected.  The safety of 
reinitiating carfilzomib in subjects previously experiencing PRES is unknown. 
3.3.3.1.14 
Herpes Zoster Infections 
Herpes zoster infections is an important potential risk for carfilzomib.  The subject 
incidence of herpes zoster infection was 2.9% but < 0.1% were serious events.  Antiviral 
prophylaxis should be considered in subjects treated with carfilzomib to decrease the 
risk of herpes zoster reactivation.   
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4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
Describe adherence and treatment safety 
across all 12 cycles of carfilzomib based 
regimens in subjects with relapsed or 
refractory multiple myeloma with 1-3 prior 
lines of therapy at study entry. 
• 
proportion of subjects completing 
12 cycles of treatment 
• 
proportion of actual cumulative dose 
received to the full intended cumulative 
dose in cycles 1-12 
• 
relative dose intensity in cycles 1-12  
• 
dose modifications and reasons in 
cycles 1-12  
• 
treatment-emergent adverse events and 
serious adverse events 
Secondary 
Assess subject health-related quality-of--life 
(HRQoL) with the Kd, KRd, and KPd 
regimens. 
• 
European Organization for Research and 
Treatment of Cancer Quality-of-life 
Questionnaire (EORTC QLQ) Core 30 
(C30) and EORTC QLQ Multiple 
Myeloma Module (MY20) scores through 
cycle 12 or up to disease progression  
Assess response to the Kd, KRd, and KPd 
regimens. 
• 
response rate (stringent complete 
response [sCR], complete response 
[CR], very good partial response [VGPR], 
partial response [PR], minimal response 
[MR], stable disease [SD], progressive 
disease [PD], Not evaluable [NE]). 
• 
progression-free survival (PFS) at 1 year 
• 
response rate and PFS by line of prior 
therapy 1 vs ≥ 2 
  
Objectives 
Endpoints 
Exploratory 
4.2 
Hypotheses 
Carfilzomib plus dexamethasone twice weekly with or without daily lenalidomide or 
pomalidomide, followed by carfilzomib plus dexamethasone once weekly with or without 
daily lenalidomide or pomalidomide, is tolerable in subjects with RRMM in a 
community-based setting. 
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5. 
Study Design 
5.1 
Overall Design 
This is a phase 2, multicenter, open-label study in subjects with RRMM in US community 
oncology centers.  Subjects with 1-3 prior lines of therapy at study entry are eligible to be 
screened for participation.  Subjects refractory to their last line of treatment are eligible to 
participate as long as their last line of treatment did not include a PI.  The study will 
consist of a screening period of up to 28 days for bone marrow aspirate, bone lesion 
assessment, and plasmacytoma assessment and up to 21 days for all other 
assessments, up to 12 cycles of treatment, and a 30-day safety follow-up period 
following the last dose of study drug.   
During the treatment period, subjects in the Kd arm will be treated with Kd 20/56 mg/m2 
twice weekly for up to two 28-day cycles followed by Kd 70 mg/m2 once weekly for 
another ten 28-day cycles; subjects in the KRd arm will be treated with KRd 20/27 mg/m2 
twice weekly for up to two 28-day cycles followed by Kd 56 mg/m2 once weekly for 
another ten 28-day cycles; subjects in the KPd arm will be treated with KPd 20/27 mg/m2 
twice weekly for up to two 28-day cycles followed by KPd 56 mg/m2 once weekly for 
another ten 28-day cycles.  After discontinuation of study drugs, subjects will be followed 
for 30 days for safety.   
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
A total of approximately 75 subjects will be enrolled in the study with approximately  
25 subjects in each arm.  
Subjects in this clinical investigation shall be referred to as “subjects”.  A sample size 
of approximately 75 subjects will provide for descriptive statistics to be generated for 
patient safety and treatment adherence.  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 40 investigative sites in the United States will be included in the study.  
Sites that do not enroll subjects within 5 months of site initiation may be closed.  
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5.3 
End of Study 
5.3.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 
The primary completion date is the date when the last subject has completed the 
assessments for the safety follow-up visit. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study 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 study will consist of a screening period (up to 28 days for bone marrow aspirate, 
bone lesion assessment, and plasmacytoma assessment and up to 21 days for all other 
assessments), approximately 12-month treatment period, and a 30 (+3)-day safety 
follow-up.  Therefore, the total study duration for an individual subject is estimated to be 
approximately 14 months.   
5.4 
Justification for Investigational Product Dose 
The dose and dosing frequency of carfilzomib regimens used in this study were selected 
based on data from phase 1/2 and phase 3 studies.   
5.4.1 
Justification for Investigational Product Dose for Kd Arm 
The safety and efficacy of 20/56 mg/m2 twice weekly carfilzomib combined with 
dexamethasone has been defined in a randomized phase 3 trial (ENDEAVOR; 
Dimopoulos et al, 2016).  ENDEAVOR compared carfilzomib administered at 56 mg/m2 
over a 30-min infusion twice per week with dexamethasone against Vd in subjects with 
RRMM who had received between 1 and 3 previous treatments, a similar subject 
population to what is being proposed in this phase 2 trial.  The carfilzomib arm proved 
superior at the first interim analysis for efficacy reducing the risk of progression or death 
by 47% (median PFS [Kd vs Vd]: 18.7 months vs 9.4 months), and at the second interim 
Approved 
 
 


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OS analysis reducing the risk of death by 21% compared to Vd (median OS 47.6 months 
vs 40.0 months, HR = 0.791, one-sided p = 0.010).  Grade 3 or worse adverse events 
were reported in 81% of subjects in the Kd group and 71% of subjects in the Vd group.  
The most frequent grade 3 cardiopulmonary events of interest reported in the Kd and Vd 
groups, respectively, included hypertension 15% vs 3%, pneumonia 9% vs 9%, dyspnea 
6% vs 2%, and congestive heart failure in 6% vs 2%.   
Based on the results of the ENDEAVOR study, the FDA approved carfilzomib in 
combination with dexamethasone for the treatment of patients with RRMM who have 
received 1 to 3 lines of therapy.  The dose of carfilzomib to be used in combination with 
dexamethasone is 56 mg/m2 twice weekly following an initial treatment with 20 mg/m2 on 
the first 2 days of treatment (Kyprolis USPI). 
The safety and efficacy of the 70 mg/m2 dose has been evaluated in the phase 2 
(CHAMPION-1) and phase 3 (A.R.R.O.W.) studies.  Carfilzomib pharmacokinetics in the 
CHAMPION-1 study with the 70 mg/m2 once weekly dose showed higher maximum 
concentration than that with the 56 mg/m2 twice-weekly dose (2390 ng/mL vs 
2079 ng/mL, respectively).  However, the area under the curve was higher with 
56 mg/m2 twice a week (1896 ng•hr/mL vs 1030 ng•hr/mL per week). 
The CHAMPION-1 study, a phase 1/2 trial, provided additional safety data for the 
70 mg/m2 weekly dosing of carfilzomib in combination with dexamethasone.  In that 
study, 104 subjects were treated for a median of 7.7 months at the MTD of 70 mg/m2 
weekly in combination with dexamethasone 40 mg weekly in a similar patient population 
as the proposed study.  At 70 mg/m2, the most common grade ≥ 3 adverse events were 
fatigue (11%) and hypertension (7%).  For specific adverse events of interest, the rates 
of grade ≥ 3 hypertension, dyspnea, cardiac failure, and peripheral neuropathy were 
7%, 5%, 2%, and 1%, respectively.  Discontinuations due to adverse events were 
reported to occur in 12% of subjects.  Discontinuations due to adverse events and the 
incidence of specific cardiovascular events of interest were all lower than that reported in 
the phase 3 ENDEAVOR trial (Berenson et al, 2016).   
The MTD defined in the CHAMPION-1 trial was used in the phase 3 A.R.R.O.W. trial, in 
which subjects with RRMM were treated with Kd with carfilzomib dosed either at 
27 mg/m2 twice-weekly or 70 mg/m2 once-weekly.  The study included 478 subjects with 
RRMM who received 2 or 3 prior lines of therapy, including a PI and an IMiD.  Subjects 
treated with the once-weekly Kd regimen achieved a statistically significant superior PFS 
with a median of 11.2 months compared to 7.6 months for those treated with the 
Approved 
 
 


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twice-weekly Kd regimen (HR = 0.69, 95% CI, 0.54-0.88).  The overall safety profile of 
the once-weekly Kd regimen was comparable to that of the twice-weekly regimen.  The 
most frequently reported treatment-emergent adverse events (greater than or equal to 
20%) in either treatment arm were anemia, diarrhea, fatigue, hypertension, insomnia and 
pyrexia (A.R.R.O.W. Press release, 2017).  With the results from the A.R.R.O.W. study, 
the Kd 70 mg/m2 once weekly dosing schedule was approved in the US, providing the 
US practicing centers one more option to treat MM patients with relapse/refractory 
disease. 
5.4.2 
Justification for Investigational Product Dose for KRd and KPd Arms 
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.  
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).   
Based on evidence from phase 2 studies of KPd, weekly doses up to 70 mg/m2 in 
subjects with first relapse and up to 54 mg/m2 in subjects with advanced myeloma using 
a twice-weekly schedule of carfilzomib have been tolerated (Sonneveld et al, 2018; 
Approved 
 
 


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Shah et al, 2015).  Consistent with the observation from the A.R.R.O.W. study, that 
adjustment from a twice-weekly to a once-weekly schedule was demonstrated to have a 
favorable benefit/risk profile with no new safety issues identified, the CFZ013 trial 
identified 56 to 70 mg/m2 weekly carfilzomib combined with Rd to have an acceptable 
safety profile.  Given these data, this phase 2 study will evaluate the 56 mg/m2 once-
weekly dose schedule for KRd and KPd triplet therapies. 
5.5 
Patient Input on Study Design 
Not applicable.  
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).  This log may be completed and updated via the Interactive Voice/Web 
Response System (IXRS). 
Eligibility criteria will be evaluated during screening.   
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 12.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, will not be provided. 
6.1 
Inclusion Criteria  
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures. 
102 
Males or females ≥ 18 years of age. 
103 
Relapsed MM after last treatment or refractory while receiving non-proteasome 
inhibitor therapy. 
104 
Measurable disease with at least 1 of the following assessed within 21 days prior 
to enrollment: 
• 
immunoglobulin G (IgG)MM: 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. 
105 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 
(Section 12.10)  
Approved 
 
 


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106 
Subjects must have at least partial response (PR) to at least 1 line of prior 
therapy.   
107 
Subjects must have received at least 1 but not more than 3 prior lines of therapy 
for MM (induction therapy followed by stem cell transplant and 
consolidation/maintenance therapy will be considered as 1 line of therapy; 
see Section 12.11).  
109 
Measured creatinine clearance (radionucleotide or 24-hour urine) or calculated 
creatinine clearance per the Chronic Kidney Disease Epidemiology Collaboration 
formula, of ≥ 30mL/min/1.73 m2 within 21 days of enrollment (see Section 12.13). 
Kd Arm 
110 
Prior therapy with a PI is allowed as long as the subject was not removed due to 
toxicity (except for neuropathy, see criterion 213), and if received carfilzomib 
must have achieved at least a PR and have at least a 6-month carfilzomib 
treatment-free interval from last dose received until enrollment.  
KRd Arm 
111 
Prior therapy with a PI or lenalidomide is allowed as long as the subject had at 
least a PR to most recent therapy with PI or lenalidomide, was not removed due 
to toxicity (except for neuropathy, see criterion 213), and if received carfilzomib  
must have at least a 6-month carfilzomib  treatment-free interval from last dose 
received until enrollment. 
KPd Arm 
112 
Prior therapy with a PI is allowed as long as the subject had at least a PR to most 
recent therapy with PI, was not removed due to toxicity (except for neuropathy, 
see criterion 213), and if received carfilzomib must have at least a 6-month 
carfilzomib treatment-free interval from last dose received until enrollment. 
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 
History of plasma cell leukemia. 
206 
Subjects with nephrotic range proteinuria (≥ 3 g albumin for 24 hours urine OR 
≥ 2 g albumin/1 g of creatinine on a random urine specimen). 
207 
Myelodysplastic syndrome. 
248 
Primary amyloidosis (patients with multiple myeloma with asymptomatic 
deposition of amyloid plaques found on biopsy would be eligible if all other 
criteria are met). 
Approved 
 
 


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Other Medical Conditions 
208 
History of other malignancy within the past 3 years, with the following exceptions: 
• 
Malignancy treated with curative intent and with no known active disease 
present for ≥ 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 
• 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ 
• 
Treated medullary or papillary thyroid cancer 
• 
Similar neoplastic conditions with an expectation of > 95% five-year 
disease-free survival 
209 
Known HIV infection, hepatitis C infection (subjects with hepatitis C that achieve 
a sustained virologic response following 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 directed at 
hepatitis B are allowed). 
210 
Active acute or chronic graft-versus-host disease (any grade). 
211 
Acute active infection requiring systemic antibiotics, antifungal, antiviral (except 
antiviral therapy directed at hepatitis B) agents within 14 days prior to enrollment. 
212 
Known cirrhosis. 
213 
Significant neuropathy (grades 3 to 4, or grade 2 with pain) within 14 days prior 
to enrollment. 
214 
Subjects with pleural effusions requiring thoracentesis or ascites requiring 
paracentesis within 14 days prior to enrollment. 
Cardiopulmonary Conditions 
215 
Uncontrolled hypertension, defined as an average systolic blood pressure 
≥ 160 mmHg or diastolic ≥ 100 mmHg (see Section 12.12 for more details).  
Subjects with controlled hypertension are eligible. 
216 
Active congestive heart failure with or without reduced ejection fraction (NYHA 
Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, clinically 
significant electrocardiogram (ECG) abnormalities, screening ECG with corrected 
QT interval (QTc) of > 470 msec, pericardial disease, myocardial infarction within 
4 months prior to enrollment. 
217 
Known chronic obstructive pulmonary disease.   
218 
Known interstitial pneumonitis. 
Approved 
 
 


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Prior/Concomitant Therapy 
219 
Immunotherapy within 21 days prior to enrollment. 
220 
Chemotherapy with approved anticancer therapeutic within 21 days prior to 
enrollment. 
221 
Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 14 days 
prior to enrollment. 
222 
Focal radiation therapy within 7 days prior to enrollment.  Radiation therapy to an 
extended field involving a significant volume of bone marrow within 21 days prior 
to enrollment (ie, prior radiation must have been to less than 30% of the bone 
marrow). 
223 
Major surgery (except kyphoplasty) within 28 days prior to enrollment. 
224 
Autologous or allogeneic stem cell transplant within 90 days prior to enrollment. 
225 
Contraindication to dexamethasone, lenalidomide, or pomalidomide. 
226 
Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize 
carfilzomib). 
227 
Intolerance to intravenous (IV) hydration.  
Prior/Concurrent Clinical Study Experience 
228 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
Organ Function Assessments 
229 
Hepatic dysfunction within 21 days prior to enrollment (see Section 7.1.1.2.1):  
• 
bilirubin ≥ 1.5 times the upper limit of normal (ULN) 
• 
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
≥ 3 times the ULN 
230 
Left ventricular ejection fraction < 40% assessed by transthoracic 
echocardiogram.  
231 
Severe valvular disease assessed by transthoracic echocardiogram.  
232 
Severe right-ventricular dysfunction assessed by transthoracic echocardiogram.  
233 
Right-ventricular systolic pressure > 40 mm Hg assessed by transthoracic 
echocardiogram.  
235 
Absolute neutrophil count (ANC) < 1 x 109/L within 21 days prior to enrollment.  
Screening ANC should be independent of growth factor support for ≥ 1 week. 
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236 
Hemoglobin < 80 g/L within 21 days prior to enrollment.  Use of erythropoietic 
stimulating factors and red blood cell (RBC) transfusions per institutional 
guidelines is allowed, however most recent RBC transfusion may not have been 
done within 7 days prior to obtaining screening hemoglobin. 
237 
Platelet count < 50 x 109/L (≤ 30 x 109/L if myeloma involvement in the bone 
marrow is > 50%) within 21 days prior to enrollment.  Subjects should not have 
received platelet transfusions for at least 1 week prior to obtaining the screening 
platelet count. 
Other Exclusions 
242 
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 study drug(s).  Refer to Section 12.5 for additional contraceptive 
information. 
243 
Male subjects with a pregnant partner who are unwilling to practice abstinence or 
use a condom during treatment and for an additional 90 days after the last dose 
of study drug(s). 
244 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 90 days after the last dose of study drug(s). 
245 
Subject has known hypersensitivity to any of the products or components to be 
administered during dosing, including hypersensitivity to antiviral drugs. 
246 
Subject likely to not be available to complete all protocol required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments [COAs]) to the best of the subject and investigator’s 
knowledge. 
247 
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.  
Kd Arm 
249 
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 
study drug(s). 
250 
Female subjects of childbearing potential unwilling to use 1 highly effective 
method of contraception during treatment and for an additional 30 days after the 
last dose of study drug(s).  Refer to Section 12.5 for additional contraceptive 
information. 
251 
Female subjects of childbearing potential with a positive pregnancy test 
assessed at screening and/or ay 1 by a serum pregnancy test and/or urine 
pregnancy test. 
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KRd and KPd Arms 
252 
Female subjects of childbearing potential unwilling to use 2 methods of 
contraception (1 of which must be highly effective; see Section 12.5) during the 
study and for an additional 30 days after the last dose of study drug. Additionally, 
subjects must be using contraception at least 28 days prior to initiating treatment. 
Refer to Section 12.5 for additional contraceptive information. 
253 
Female subjects of childbearing potential with a positive serum pregnancy test 
assessed within 14 days prior to first dose of study drug or a positive urine 
pregnancy test within 24 hours prior to first dose. In addition, females of 
childbearing potential must agree to pregnancy testing weekly during the first 
4 weeks of pomalidomide or lenalidomide use followed by a pregnancy test every 
4 weeks in females with regular menses or every 2 weeks in females with 
irregular menstrual cycles. 
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 (IRB) 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 must personally sign and date the IRB 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 case report form (CRF). 
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 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.  
6.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
Approved 
 
 


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criteria, and any serious adverse events.  In the event a screen-failure subject 
experiences a serious adverse event, medical history and prior therapies 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 for more detail. 
7. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in  below. 
7.1 
Treatment Procedures 
7.1.1 
Investigational Products 
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 
For all treatment arms, carfilzomib will be administered at 20 mg/m2 on days 1 and 2 of 
the first cycle (see Table 7-1).  For subjects in the Kd arm, carfilzomib will be 
administered at 56 mg/m2 on days 8, 9, 15, and 16 of the first cycle, and then on days 1, 
2, 8, 9, 15, and 16 in cycle 2.  Starting with cycle 3 through cycle 12, carfilzomib will be 
administered at 70 mg/m2 on days 1, 8, and 15 of each 28-day cycle.  For subjects in the 
KRd and KPd arms, carfilzomib will be administered at 27 mg/m2 on days 8, 9, 15, and 
16 of the first cycle, and then on days 1, 2, 8, 9, 15, and 16 in cycle 2.  Starting with 
cycle 3 through cycle 12, carfilzomib will be administered at 56 mg/m2 on days 1, 8, and 
15 of each 28-day cycle. 
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At the time of implementation of protocol amendment 3, subjects previously enrolled 
may have completed more than 2 but less than 6 cycles of twice weekly carfilzomib 
dosing on the Kd arm as per protocol amendment 2.  These subjects should complete 
the dosing regimen as per protocol amendment 2, (ie, 6 cycles of  twice weekly dosing 
for carfilzomib [Kd 56 mg/m2] transitioning to once weekly dosing for carfilzomib  
[Kd 70 mg/m2], starting with cycle 7).  For these subjects, the schedule of activities 
outlined per Table 2-1 for cycles 1 and 2 will continue for cycles 1 through 6.  At the start 
of cycle 7, these subjects will then follow the schedule of activities as outlined per  
Table 2-1 cycles 3 through 12.  In addition, the starting nominal dose of carfilzomib on 
day 1 cycle 7 (which is the initiation of the once weekly carfilzomib dosing for these 
subjects) should be reduced by the same number of dose levels and same percentage 
dose reduction as it was reduced to during cycle 6 (which is the twice weekly carfilzomib 
dosing). Dexamethasone will be administered at a dose of 20 mg once daily on days 1, 
2, 8, 9, 15, 16, 22, and 23 cycles 1 through 6 and at a dose of 40 mg once daily on  
days 1, 8, 15 for the Kd arm for cycles 7 through 12 for these subjects. 
All 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.  The starting dose should 
be modified for chronic mild hepatic insufficiency per Section 7.1.1.2.1.   
Table 7-1.  Carfilzomib Dosage  
Cycle 1 
Cycle 2 
Cycles 3-12 
Kd Arm 
 
 
D1, 2: 20 mg/m2 
D8, 9, 15, 16: 56 mg/m2 
D 1, 2, 8, 9, 15, 16: 56 mg/m2 
D1, 8, 15: 70 mg/m2 
KRd Arm 
 
 
D1, 2: 20 mg/m2 
D8, 9, 15, 16: 27 mg/m2 
D 1, 2, 8, 9, 15, 16: 27 mg/m2 
D1, 8, 15: 56 mg/m2 
KPd Arm 
 
 
D1, 2: 20 mg/m2 
D8, 9, 15, 16: 27 mg/m2 
D 1, 2, 8, 9, 15, 16: 27 mg/m2 
D1, 8, 15: 56 mg/m2 
D = day 
Subjects receiving carfilzomib at doses less than the protocol planned dose (56 mg/m2 
or 27 mg/m2 based on treatment arm) during cycle 2 may have been reduced by 1 or 
more dose levels and/or by 25% for hepatic function abnormalities.  Subjects should 
have the starting nominal dose of carfilzomib (70 mg/m2 or 56 mg/m2 based on treatment 
arm) on day 1 cycle 3 reduced by the same number of dose levels and the same 
Approved 
 
 


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percentage dose reduction as they were reduced during cycle 2, see Table 7-2 for dose 
level reductions. 
Carfilzomib is to be administered as an IV infusion over 30 (± 5) minutes.  Subjects 
should receive 250 mL of normal saline or equivalent IV fluid prior to and after each dose 
during cycle 1.  After cycle 1, at the discretion of treating physician, subjects may receive 
up to but no more than 250 mL of normal saline or equivalent fluid prior to each dose of 
carfilzomib.  For subjects at risk of TLS, see Section 7.1.4.3. 
Mechanical infusion pumps are recommended, but gravity-dependent infusions are 
permitted if the 30-minute infusion duration can be reliably maintained.  Carfilzomib 
infusion must occur at a facility capable of managing hypersensitivity reactions.   
Each subject’s first dose will be calculated based upon baseline BSA per the Mosteller 
formula.  In subjects with BSA of greater than 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 
experiences a change in body weight of ≥ 20% compared to baseline or last calculation 
of BSA, in which case the BSA and dose should be recalculated.  The dose can also be 
modified in response to toxicity following the dose modification guideline tables 
(see Section 7.4). 
The planned dose, dose administered, start date/time, stop date/time, reason for change 
in planned dose or schedule, and package lot number of carfilzomib are to be recorded 
on each subject's CRF. 
7.1.1.2.1 
Starting Dose in Hepatic Insufficiency 
For subjects with mild hepatic insufficiency during screening, the initial dose of 
carfilzomib on days 1 and 2 of cycle 1 should be reduced by 25% to 15 mg/m2.  For 
subjects in the Kd arm, starting on day 8 and for all subsequent doses of carfilzomib 
during cycles 1 and 2, the dose should be 42 mg/m2 (Brown et al, 2017); the dose in 
cycle 3 through 12 should be 53 mg/m2.  For subjects in the KRd and KPd arms, starting 
on day 8 and for all subsequent doses of carfilzomib during cycles 1 and 2, the dose 
should be 20 mg/m2 as per the protocol and doses in cycles 3 through 12 should be 
42 mg/m2. 
If hepatic function returns to normal, the dose in following cycles may be re-escalated to 
the full dose per the protocol.  For dose modification due to subsequent changes in 
hepatic function, refer to Section 7.4.1.1.3 (Table 7-4). 
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Mild and moderate hepatic dysfunction is defined as: 
• 
Mild:  bilirubin > 1.0-1.5 x ULN, or AST > ULN with bilirubin ≤ ULN 
• 
Moderate:  bilirubin > 1.5-3.0 x ULN with any AST 
• 
Grade 3 elevation in ALT and/or AST (> 5x ULN) 
7.1.2 
Non-investigational Products 
7.1.2.1 
Dexamethasone: Dosage, Administration, and Schedule 
For all treatment arms, dexamethasone will be taken orally or by IV infusion at a dose of 
20 mg once-daily on days 1, 2, 8, 9, 15, 16, 22, and 23 of Kd cycles 1-2, and at a dose 
40 mg once-daily on days 1, 8, 15 of Kd cycles 3-12.  All doses should be administered 
on the scheduled days ± 2 days but prior to carfilzomib infusion except for days 22 and 
23 of cycles 1-2.   
Dexamethasone will be administered at least 30 minutes (but no more than 4 hours) 
prior to carfilzomib.  Subjects receiving dexamethasone IV on days 1, 2, 8, 9, 15, and 16, 
may receive the day 22 and day 23 dose orally. 
For subjects ≥ 75 years of age, see Section 7.4.1.2 for dose modification. 
The dose, date, time, and reason for dose change are to be recorded on each subject’s 
CRF. 
Dexamethasone will not be provided or reimbursed by Amgen.  The investigator will be 
responsible for obtaining supplies of dexamethasone.  
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 
for the KRd treatment arm.  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 assigned to the KRd arm of 
this study, and all research subjects enrolled on this study who are assigned to the KRd 
arm, 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. 
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7.1.2.2.2 
Dosage, Administration, and Schedule 
Lenalidomide will be taken once-daily orally at a dose of 25 mg on days 1-21 of each 
28-day cycle.  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 on schedule with the next cycle.  Dose modifications are permitted in response 
to toxicity following the dose modification guideline tables.   
The planned dose, quantity administered, start date, start time, and reason for dose 
change are to be recorded on each subject’s eCRF. 
7.1.2.3 
Pomalidomide 
7.1.2.3.1 
Prescribing Requirements 
Pomalidomide, a non-Amgen non-investigational product, will also be used in this study 
for the KPd treatment arm.  Pomalidomide should be administered in accordance with 
the POMALYST REMS® program of Celgene Corporation 
(http://www.pomalystrems.com/.)  All physicians who prescribe pomalidomide for 
research subjects assigned to the KPd arm of this study, and all research subjects 
enrolled on this study who are assigned to the KPd arm, must be registered in and 
comply with all requirements of the POMALYST 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 pomalidomide. 
7.1.2.3.2 
Dosage, Administration, and Schedule 
Pomalidomide will be taken once-daily orally at a dose of 4 mg on days 1-21 of each 
28-day cycle.  Pomalidomide should be taken at home by the subject at about the same 
time each day.  Pomalidomide 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 on schedule with the next cycle.  Dose modifications are permitted in response 
to toxicity following the dose modification guideline tables. 
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The planned dose, quantity administered, start date, start time, 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 in this study.   
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 
Protocol-required, suggested, or permitted supportive therapies listed below are 
commercially available and will not be provided or reimbursed by Amgen (except if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these protocol-required therapies. 
Additional details regarding these protocol-required therapies are provided in the IPIM.   
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 for 3 days, 2 times a 
day, or per institutional standards), or valacyclovir (eg, 500 mg orally 2 times a day, or 
per institutional standards), dose adjustments for renal function where appropriate, 
initiated within 1 week of the first dose should continue for the duration of treatment with 
carfilzomib. 
7.1.4.2 
Thromboprophylaxis 
It is strongly suggested that all subjects receive an anticoagulant (eg, enteric-coated 
aspirin at standard prophylactic dose or other anticoagulant or antiplatelet medication, 
such as clopidogrel bisulfate, low molecular weight heparin, or warfarin).  In addition, a 
second thromboprophylaxis medication is strongly recommended in subjects with 
elevated risk of thrombosis, based on an individual benefit/risk assessment 
(Li et al, 2017); see Section 12.14 for more details.   
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7.1.4.3 
Tumor Lysis Syndrome Prophylaxis 
An approved uric acid-lowering agent (eg, allopurinol) in subjects at high risk for TLS 
due to high tumor burden may be prescribed at the investigator’s discretion, according to 
the Kyprolis USPI.  Risk factors for TLS include but are not limited to: elevated lactate 
dehydrogenase, beta-2 microglobulin > 5.5 mg/L, elevated uric acid, elevated circulating 
plasma cells, elevated serum creatinine, presence of soft tissue plasmacytomas, or 
international stage III disease. 
Subjects at elevated risk of TLS should be hydrated with 500 mL of normal saline or 
equivalent IV fluid prior to and 250 mL after the first dose of carfilzomib and each 
subsequent dose until the investigator determines that the risk of TLS has resolved or up 
to the end of the first cycle.   
7.1.4.4 
Proton-pump Inhibitor 
Proton-pump inhibitor (omeprazole or equivalent) is required while on dexamethasone.   
7.1.4.5 
Other Permitted Therapies  
The following medications and supportive therapies are examples of support therapies 
that may be used during the study: 
• 
Antifungal prophylaxis:  Fluconazole 200 mg/day (minimum) or equivalent therapy is 
recommended, especially for patients living (coming from) areas known to have high 
incidence of environmental mycoses. 
• 
Prophylaxis for Pneumocystosis jirovenci:  Pneumocystis jirovenci pneumonia 
prophylaxis should be considered, as per institutional guidelines while on 
dexamethasone. 
• 
Bone-preserving therapy: bone preserving therapy (bisphosphonate or other bone 
preserving therapy) is strongly recommended for all subjects with evidence of lytic 
destruction of bone or with osteopenia (Gralow et al, 2013; Terpos et al, 2013).  
Commercially available IV bisphosphonates (pamidronate and zoledronic acid) or 
monoclonal antibodies are preferred when available, used according to the 
manufacturer’s recommendations, as described in the prescribing information, for 
subjects with osteolytic or osteopenic myelomatous bone disease.  Oral 
bisphosphonates may be used as alternatives if IV bisphosphonates are not 
available at the study site.  It is preferred that investigators use the same route of 
bisphosphonate therapy for all subjects at their sites.   
• 
Subjects who are using bone preserving 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 bone preserving therapy at the time of enrollment 
should start as soon as possible during cycle 1 or 2 of treatment.  Investigators 
should not start bone-preserving therapy during the study, unless it has been agreed 
with the sponsor that there is no sign of disease progression. 
• 
Antivirals, antihypertensives, statins, and antibiotics. 
• 
Hyperglycemia medical management. 
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• 
Prevention of constipation (eg, adequate hydration, high-fiber diet, and stool 
softeners, if needed) 
• 
Prophylactic antiemetics, with the exception of corticosteroids.   
• 
Colony-stimulating factors, erythropoietin, and transfusion of platelets and RBC.   
• 
Loperamide is recommended for the treatment of diarrhea, starting at the time of the 
first watery stool.  The loperamide dose and regimen is according to institutional 
guidelines.  Prophylactic loperamide is not recommended. 
• 
Adequate hydration is recommended for prevention of myeloma-related kidney 
disease.   
7.1.5 
Other Treatment Procedures 
No other treatment procedures are required.  Patients may receive surgery or radiation 
therapy as clinically indicated.   
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(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
This includes any investigational/non-investigational product(s) provisioned and/or 
repackaged/modified by Amgen.   
Any product complaint(s) associated with an investigational product(s), 
non-investigational product(s), or device(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 
Concurrent therapy with a marketed or investigational anticancer therapeutic for either a 
palliative or therapeutic intent is excluded.  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 (other than as indicated 
in this protocol).  Higher steroid doses given short term for exacerbations of 
nonmalignant conditions (eg, asthma flare) if medically indicated are permitted.  
Investigational agents are not to be used during the study.  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.  
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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 who meet eligibility criteria will be assigned by the investigator to treatment with 
either Kd, KRd, or KPd; no cross-over will be allowed. 
Investigators are advised to consider the following guidelines when assigning subjects to 
treatment: 
• 
Kd arm:  it is recommended that subjects who are suitable for an IMid free 
doublet regimen are assigned to the Kd arm. 
• 
KRd arm: it is recommended that subjects who are not refractory to lenalidomide 
(lenalidomide sensitive or naïve) and who are suitable for triplet therapy are 
assigned to the KRd arm. 
• 
KPd arm: it is recommended that subjects who are refractory to lenalidomide 
(progressed on or within 60 days of completing this therapy) and who are 
suitable for a triplet therapy are assigned to the KPd arm. 
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment CRF.  
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 
The reason for dose change of carfilzomib is to be recorded on each subject’s CRF. 
Carfilzomib 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.  Carfilzomib dose must be 
modified based on specified toxicities, as indicated in Table 7-3 and Table 7-4.  The 
subject will be considered on protocol treatment while receiving carfilzomib.  Carfilzomib 
(both twice-weekly and once-weekly regimen) must be discontinued permanently if a 
delay of more than 6 weeks is required due to unresolved toxicity. 
If day 1 of a cycle is delayed, 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. 
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If carfilzomib administration does not commence within the allowable window of the 
scheduled administration date, then the dose will be considered a missed dose.  
Administration may resume at the next planned dosing date.  A missed dose will not be 
made up.   
If either carfilzomib or dexamethasone are held for the remainder of the previous cycle 
or the new cycle is delayed due to residual toxicity on the planned day 1 of the next 
cycle, then the new cycle will be started at 1 dose decrement for the drug(s) causing the 
delay.   
For conditions that do not require carfilzomib dose reduction, refer to Section 7.4.1.3. 
7.4.1.1.1 
Dose Reduction Levels 
Dose reduction levels of carfilzomib for toxicity management of individual subjects are 
provided in Table 7-2.  Subjects that require dose reduction may have the dose 
escalated according to specific rules, see Section 7.4.1.1.4.  Subjects should have the 
starting nominal dose of carfilzomib (56 mg/m2 or 70 mg/m2 based on treatment arm) on 
day 1 cycle 3 reduced by the same number of dose levels and the same percentage 
dose reduction as they were reduced during cycle 2, see Table 7-2 for dose level 
reductions.  Subjects who require fifth dose reductions should discontinue carfilzomib.   
Table 7-2.  Dose Decrements for Carfilzomib 
Nominal 
Dosea, b 
(mg/m2) 
First Dose 
Reduction 
Dose -1 
(mg/m2) 
Second Dose 
Reduction 
Dose -2 
(mg/m2) 
Third Dose 
Reduction 
Dose -3 
(mg/m2) 
Fourth Dose 
Reduction 
Dose -4 
(mg/m2) 
20 
15 
11 
Discontinue 
 
27 
20 
15 
11 
Discontinue 
56 
45 
36 
27 
20 
70 
56 
45 
36 
27 
a If dose reduction of carfilzomib is required on Cycle 1 Day 1 or Cycle 1 Day 2 for any reason other than 
mild hepatic insufficiency, the investigator should contact the medical monitor to discuss the situation, 
before any additional doses of carfilzomib are administered. 
b For patients with baseline chronic hepatic impairment (mild), reduce the starting and subsequent doses of 
carfilzomib by 25% (ie, 15 mg/m2 day 1 and 2 of cycle 1 and 42 mg/m2 day 8 cycle 1 and thereafter). 
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7.4.1.1.2 
Guidelines for Hematologic Toxicity 
Guidelines for carfilzomib dose modification in the event of thrombocytopenia and 
neutropenia are summarized in Table 7-3. 
Table 7-3.  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. 
7.4.1.1.3 
Guidelines of Nonhematologic Toxicity 
Guidelines for dose modification in the event of nonhematologic toxicities are 
summarized in Table 7-4. 
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Table 7-4.  Dose Modification Guidelines for Nonhematologic Toxicities 
For grading criteria, see CTCAE grading scale in Section 12.4. 
Symptom/Sign/Investigation 
Recommended Action 
Renal Dysfunctiona: 
Estimated GFR ≥ 15 mL/min/1.73 m2  
Full dose.  
For acute deterioration requiring dialysis, see below. 
Estimated GFR 
< 15 mL/min/1.73 m2  (NCI-CTCAE 
grade 4) 
Hold dose until estimated GFR returns to 
≥ 15 mL/min/1.73 m2, then resume same dose. 
If dialysis is required (regardless of estimated GFR 
levels), 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 (see Section 7.4.1.1.4. for dose 
re-escalation).  Carfilzomib must be administered 
after dialysis. 
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 bilirubin 
(> 3x ULN), ALT and/or AST 
(> 5x ULN) 
Hold carfilzomib until resolution to baseline or 
normal. 
Monitor any abnormality weekly.  Resume carfilzomib 
with a 25% dose reduction for 1 full cycle if 
drug-induced hepatotoxicity is excluded.  If no 
worsening in the total bilirubin, AST or ALT on the 
reduced dose for 1 full cycle, dose may be 
re-escalated, if drug induced hepatotoxicity is 
excluded (see Section 7.4.1.1.4 for dose 
re-escalation instructions). 
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. 
Page 1 of 3 
Footnotes defined on last page of this table.  
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Table 7-4.  Dose Modification Guidelines for Nonhematologic Toxicities 
For grading criteria, see CTCAE grading scale in Section 12.4. 
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.  Once congestive 
heart failure resolves or returns to baseline, treatment 
may continue at 1 dose level reduction.  If no 
resolution after 4 weeks, the subject will be withdrawn 
from all study treatment. 
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. 
Neuropathy (grade 2 with 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 ≥ 3) 
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 Section 12.15) 
< Grade 3 
Continue at same dose if initiation of appropriate 
treatment controls hypertension (see Section 12.12 for 
guidance)  
Grade ≥ 3  
Hold carfilzomib until resolution to normal or baseline.  
Initiate appropriate anti-hypertensive therapy prior to 
resuming carfilzomib at 1 dose decrement (see 
Section 12.12 for guidance). 
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.   
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 at 
prior dose 
Page 2 of 3 
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Table 7-4.  Dose Modification Guidelines for Nonhematologic Toxicities 
For grading criteria, see CTCAE grading scale in Section 12.4. 
Symptom/Sign/Investigation 
Recommended Action 
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; CTCAE = Common Terminology Criteria for Adverse Events; 
DBP = diastolic blood pressure; GFR = Glomerular Filtration Rate; 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 estimated GFR or an absolute fall of ≥ 60 mL/min/1.73 m2, 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 carfilzomib (K), dexamethasone (d), or the combination of Kd to 
the extent possible.  If both carfilzomib and dexamethasone are considered likely to be involved, then 
recommended actions for both should be instituted. 
7.4.1.1.4 
Rules for Re-escalation of Carfilzomib Dose Following Toxicity 
Conditions of carfilzomib-related toxicity that are not permitted for dose re-escalation: 
• 
Pulmonary hypertension 
• 
Non-infectious pulmonary toxicities (per Table 7-4) 
• 
Congestive heart failure (≥ grade 3) 
A reduction in dose level required for any of the adverse events listed above may not be 
re-escalated.  For all other carfilzomib-related toxicities that require dose level reduction, 
if the reduced dose level is tolerated for 1 full cycle, carfilzomib may be re-escalated at 
the treating physician’s discretion up to the maximum dose planned in that cycle 
(56 mg/m2 twice weekly or 70 mg/m2 once weekly).   
7.4.1.2 
Non-Amgen/Amgen Non-investigational Product:  Dexamethasone 
The reason for dose change of dexamethasone is to be recorded on each subject’s 
CRF. 
For conditions that do not require dexamethasone dose reduction, refer to 
Section 7.4.1.1.3. 
For subjects ≥ 75 years of age, the starting dose of dexamethasone should be 20 mg 
weekly, 10 mg administered on days 1, 2, 8, 9, 15, 16, 22, and 23 during cycles 1-2, and 
20 mg administered on the days 1, 8, 15 during cycles 3-12.   
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7.4.1.2.1 
Dose Reduction Levels 
Two dose reduction levels are defined for dexamethasone, as shown in Table 7-5.  Dose 
reductions are permanent and dose must not be increased following a dose reduction. 
Table 7-5.  Dose Decrements for Dexamethasone 
Nominal Dose (mg) 
Reduced Weekly Dexamethasone Doses (mg) 
Dose -1 
Dose -2 
40 
20 
12a 
20 
12 
8 
a If the dose needs to be divided over 2 days, administer 8 mg on the first day and 4 mg on the second day. 
7.4.1.2.2 
Guidelines for Dexamethasone-related Toxicity 
Dexamethasone will be permanently discontinued after 2 dose reductions in the event of 
additional dexamethasone-related toxicities.  At the investigator’s discretion, 
dexamethasone may be tapered prior to complete discontinuation according to 
institutional practice.  The subject may continue on treatment with the other 
protocol-specified drug(s). 
Guidelines for dexamethasone-related toxicities are summarized in Table 7-6.   
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Table 7-6.  Treatment Guidelines for Dexamethasone-related Toxicity 
Symptom 
Findings 
Recommended Action 
Cardiovascular 
Edema > grade 3 (anasarca or 
limiting function and 
unresponsive to therapy) 
Diuretics as needed, and restart 
dexamethasone at 1 dose decrement; if 
edema persists despite above 
measures, decrease dose by another 
dose decrement. 
Discontinue dexamethasone permanently if 
symptoms persist despite second 
reduction. 
Gastrointestinal 
Toxicity 
Dyspepsia, gastric or duodenal 
ulcer, or gastritis grade 1 or 2 
(requiring medical 
management) 
Continue dexamethasone at same dose 
and treat with therapeutic doses of 
histamine 2 (H2) blockers, or proton 
pump inhibitor. 
Consider adding sucralfate or other 
antiulcer treatment as clinically 
indicated. 
If symptoms persist despite above 
measures, decrease dexamethasone 
dose by 1 dose level. 
Dyspepsia, gastric or duodenal 
ulcer, or gastritis ≥ grade 3 
(requiring hospitalization or 
surgery) 
Hold dexamethasone until symptoms 
return to baseline.  
Restart dexamethasone at 1 dose 
decrement along with concurrent 
therapy with H2 blockers, sucralfate, or 
omeprazole. 
If symptoms persist despite above 
measures, discontinue dexamethasone 
permanently. 
Acute pancreatitis 
Discontinue dexamethasone permanently. 
General 
Disorders 
Limb edema > grade 3 (> 30% 
limb discrepancy in volume; 
gross deviation from normal 
anatomic contour; limiting 
self-care activities of daily 
living) 
Hold dexamethasone until symptoms return 
to baseline. 
Diuretics as needed, and restart 
dexamethasone at 1 dose decrement; if 
edema persists despite above 
measures, decrease dose by another 
dose decrement. 
Discontinue dexamethasone permanently if 
symptoms persist despite second 
reduction. 
Psychiatric 
Disorders 
Confusion or mood alteration 
≥ grade 2 (interfering with 
function ± interfering with 
activities of daily living) 
Hold dexamethasone until symptoms return 
to baseline. 
Restart dexamethasone at 1 dose 
decrement. 
If symptoms persist despite above 
measures, reduce by another dose 
decrement. 
Page 1 of 2 
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Table 7-6.  Treatment Guidelines for Dexamethasone-related Toxicity 
Symptom 
Findings 
Recommended Action 
Musculoskeletal 
Muscle weakness ≥ grade 2 
(symptomatic and interfering 
with function ± interfering with 
activities of daily living) 
Decrease dexamethasone by 1 dose 
decrement. 
If weakness persists, decrease dose by 
another dose decrement. 
Discontinue dexamethasone permanently if 
symptoms persist. 
Metabolism and 
Nutrition 
Disorders 
Hyperglycemia ≥ grade 3 
(fasting glucose > 250 mg/dL) 
Treat with insulin or other hypoglycemic 
agents as needed until glucose is 
≤ grade 2 (< 250 mg/dL) then resume 
dexamethasone. 
If uncontrolled despite above measures, 
decrease dose by 1 dose decrement 
until ≤ grade 2 (< 250 mg/dL). 
All Other 
Other toxicity ≥ grade 3 felt 
related to dexamethasone 
Hold dexamethasone dose.  Resume at 
1 dose decrement when toxicity has 
resolved to ≤ grade 2. 
If toxicity recurs, hold dexamethasone dose 
until toxicity has resolved to ≤ grade 2 
and resume dexamethasone dose by 
another dose decrement. 
If toxicity recurs despite 2 dose 
decrements, discontinue 
dexamethasone permanently. 
Page 2 of 2 
7.4.1.3 
Conditions Not Requiring Dose Reduction 
Carfilzomib and dexamethasone 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-gamma-glutamyl transferase elevation 
• 
grade 3 fatigue (unless persisting for > 7 days) 
• 
alopecia 
 
7.4.1.4 
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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7.4.1.5 
Non-Amgen Non-investigational Product:  Pomalidomide 
Pomalidomide 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 pomalidomide for 
additional details. 
The reason for dose change of pomalidomide is to be recorded on each subject’s eCRF. 
7.4.2 
Hepatotoxicity Stopping and Rechallenge Rules 
Hepatotoxicity stopping rules are described in Section 7.4.1.1.3.  
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product 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 site.  Oral medicinal 
products 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 
All therapy administered for treatment of MM prior to screening must be captured on the 
appropriate CRF, regardless of duration of time between prior therapy and screening.   
For prior therapies being taken for MM (eg, chemotherapy), collect therapy name, dose, 
best response, start date and stop date.  Prior lines of MM treatment are defined in 
Section 12.11.   
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. 
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Concomitant therapies are to be collected from 30 days prior to enrollment through the 
end of study. 
For concomitant therapies, collect therapy name, indication, dose, unit, frequency, start 
date and stop date.   
Concomitant medications used prophylactically should be described as such on the 
designated eCRF.  Blood and blood products are not considered concomitant 
medications and must be recorded on the appropriate eCRF.   
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 can decline to continue receiving investigational product and/or other 
protocol-required therapies or procedures at any time during the study but continue 
participation in the study.  If this occurs, the investigator is to discuss with the subject the 
appropriate processes for discontinuation from investigational product or other 
protocol-required therapies and must discuss with the subject the possibilities for 
continuation of the Schedule of Activities (see 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 
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local country’s regulatory mechanism, based on parameters consistent with 
Section 12.3. 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• 
Decision by Sponsor 
• 
Lost to follow-up 
• 
Death 
• 
Ineligibility determined 
• 
Protocol deviation 
• 
Non-compliance  
• 
Adverse event 
• 
Subject request 
• 
Disease progression  
• 
Requirement for alternative therapy 
• 
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.   
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.   
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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 
• 
Disease progression (NOTE: safety follow-up visit is required, and will occur 
30 (+3) days after the last dose of study drug[s])  
8.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
• 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
• 
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. 
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. 
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9.1 
General Study Periods 
9.1.1 
Screening and Enrollment  
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the informed consent form, the site will register the subject in the IXRS and 
screen the subject in order to assess eligibility for participation.  The screening window is 
up to 28 days for bone marrow aspirate, bone lesion assessment, and plasmacytoma 
assessment and up to 21 days for all other assessments. 
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 
(for bone marrow aspirate, bone lesion assessment, and plasmacytoma assessment) or 
a new 21-day (for all other assessments) 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 (for bone marrow aspirate, bone lesion 
assessment, and plasmacytoma assessment) or more than 21 days (for all other 
assessments) 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).  The date of the first dose of 
carfilzomib is defined as day 1.  All subsequent doses and study visits will be scheduled 
based on the day 1 date.  All 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 (see Section 7.1.1.2 for additional details).  Administration of protocol-required 
therapies is to be administered last during each visit that it is required. 
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9.1.3 
Safety Follow-up 
Once a subject discontinues from the study drug (see Section 8.1), he/she will have a 
safety follow-up visit 30 (+3) days after the last dose of study drug(s) unless the subject 
is lost to follow-up, has withdrawn consent, or has died.  After the safety follow-up, 
subjects who remain on study are required to complete disease response assessments 
and will be followed for subsequent antimyeloma treatment every 28 ± 7 days until up to 
12 months from enrollment, death, loss to follow-up, withdrawal of consent or 
progressive disease (PD), whichever occurs first.   
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 must sign and personally date the IRB-approved informed consent before 
any study-specific procedures are performed. 
9.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
9.2.1.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started within 5 years prior to enrollment through signing of the ICF.  Medical history will 
include information on the subject's concurrent medical conditions.  Record all findings 
on the medical history CRF.  The current toxicity grade will be collected for each 
condition that has not resolved.  Cardiovascular risk factors are to be recorded for the 
subject including history of cardiovascular disease (heart attack, stroke, peripheral 
vascular disease), arrhythmias and previous abnormal ECG findings (eg, ventricular 
hypertrophy and/or ischemic changes), hypertension (include treatment history), 
thromboembolism, hyperlipidemia (include statin use), and diabetes.  Family history of 
coronary artery disease in first degree relatives with onset < 65 years of age for female 
relative or < 55 years of age for male relative should also be recorded.   
In addition to the medical history above, multiple myeloma history must date back to the 
original diagnosis.  For subjects who were previously referred to a research site, critical 
referral information will constitute multiple myeloma information from source notes.   
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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 CRF (eg, medical history, event).  A 
complete physical examination includes examination of cardiovascular and respiratory 
systems, abdominal examination, and general neurologic examination.  Clinically 
significant abnormal physical examination findings identified prior to the signing of the 
ICF should be reported as part of medical history, not as adverse events.   
9.2.1.5 
Physical Measurements 
9.2.1.5.1 
Height and Weight 
Height in centimeters is to be measured without shoes.  Weight in kilograms is to be 
measured without shoes.  
9.2.1.5.2 
Body Mass Index  
Body Mass Index (BMI) is to be calculated using the following formula:  
BMI (kg/m2) = weight (kg)/(height [cm]/100)2   
9.2.1.5.3 
Body Surface Area 
Body Surface Area (BSA) is to be calculated using the Mosteller formula:  
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 (smoking and 
tobacco).  
9.2.1.7 
Performance Status  
The subject’s performance status will be assessed using the ECOG PS (Section 12.10).   
9.2.2 
Efficacy Assessments 
Investigators are required to follow International Myeloma Working Group (IMWG) 
criteria for assessment of response and disease progression (see Section 12.8). 
Disease assessments are required during screening to confirm eligibility and for 
determination of disease response (per the Schedule of Activities, Table 2-1).  Per 
IMWG, determination of disease response requires: serum free light chain (SFLC), 
serum and urine protein electrophoresis (SPEP, UPEP, respectively), serum and urine 
immunofixation (SIFE, UIFE, respectively), bone marrow aspirate (for CR confirmation; 
Section 9.2.2.1), corrected calcium, and plasmacytoma evaluation, if present at 
screening (Section 9.2.2.3). 
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Investigators are responsible for the determination of response and disease progression.  
Disease assessments based on local laboratory data will start on day 1 of cycle 1 and 
are performed every 28 (± 7) days regardless of cycle duration, including dose delays 
until confirmed PD or cycle 12.  The cycle 12 disease assessment is conducted 
28 (± 7) days post cycle 12, day 1.   
Subjects who discontinue treatment prior to confirmed PD should continue to complete 
disease assessments until up to 12 months from enrollment, death, loss to follow-up, 
withdrawal of consent or PD, whichever occurs first.   
9.2.2.1 
Bone Marrow Sample Evaluation Including FISH Assessment 
A baseline bone marrow sample evaluation with fluorescence in-situ hybridization (FISH, 
aspirate slides and/or biopsy) will be performed prior to first dose and will be used to 
confirm the diagnosis and quantify the percent (%) of myeloma cell involvement.  Biopsy 
or aspirate slides obtained as standard of care may be used as baseline if performed 
within 28 days of cycle 1 day 1.   
Additional bone marrow biopsy or aspirate should be obtained as clinically indicated to 
confirm a response of CR or stringent CR.   
9.2.2.2 
Bone Lesion Assessment (Skeletal Survey, Computed Tomography, 
or Positron Emission Tomography/Computed Tomography) 
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 (CT) or fluorodeoxyglucose-positron 
emission tomography/computed tomography (PET/CT) may be used in place of skeletal 
survey.  Bone lesion assessment will be conducted at screening and for confirmation of 
PD, if PD is based on bone lesions (see IMWG criteria in Section 12.8).  Bone lesion 
assessments obtained as part of standard of care may be used as baseline if performed 
within 28 days of cycle 1 day 1.  The same method of assessment used at baseline will 
be used throughout the study.  These imaging studies will be read locally. 
9.2.2.3 
Extramedullary Plasmacytoma 
Extramedullary plasmacytoma evaluation will be conducted at screening only if a lesion 
is clinically suspected.  The evaluation may be performed within 28 days of cycle 1 day 1 
if performed as a part of standard of care.  If an extramedullary plasmacytoma is 
detected, evaluation will be repeated to confirm a response of MR or better or to confirm 
PD (see IMWG criteria in Section 12.8).  Assessment of sites of extramedullary disease 
measurable by physical examination may be performed once per cycle.  If assessment 
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can only be performed radiologically, then evaluation of extramedullary plasmacytomas 
should be done to confirm a response or as clinically indicated.  The 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 (Section 12.8).  Bidimensional lesion 
measurements should be performed (see Section 9.2.2.3.1). 
9.2.2.3.1 
Sum of Perpendicular Dimensions 
Response and progression of soft tissue plasmacytomas or progression of bone lesions 
should be determined by the change in the sum of perpendicular dimensions (SPD) 
measured radiographically or by physical examination, as clinically indicated.   
The SPD is defined as the sum of the longest dimension added to the second longest 
dimension that is perpendicular to the longest dimension.  Sum of perpendicular 
dimensions of bone lesions will be measured only for evidence of progression.  The SPD 
for a bone lesion is defined the same as it is for a plasmacytoma.  An increase of 50% or 
more from the nadir in the size of any bone lesion provides evidence for PD, 
see Section 12.8 for more details. 
9.2.2.4 
Progressive Disease Assessment 
Progressive disease (including PD due to development of hypercalcemia attributed 
solely to recurrence/progression of multiple myeloma) will be based on local laboratory 
evaluation.  Confirmation of PD (using 2 consecutive assessments) will be required only 
when it is determined by laboratory evaluations and not if identified via imaging as per 
IMWG criteria.  The assessments outlined in Section 12.8 are required for determination 
of PD.  Subjects should 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 should 
not 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). 
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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 study drug(s) are reported using the Event CRF. 
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 study drug(s) are reported using the Event CRF. 
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 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  Per local requirements in some countries, 
investigators are required to report serious adverse events that they become aware of 
after end of study.  If serious adverse events are reported, the investigator is to report 
them to Amgen within 24 hours following the investigator’s knowledge 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.  
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. 
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9.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
9.2.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Section 12.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
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 CRF. 
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, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB, if appropriate according to local requirements. 
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9.2.3.1.5 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and, if indicated, 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 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 at screening should 
be the same that is used throughout the study and documented on the vital signs CRF.  
Take at least 2 blood pressure measurements spaced 1 to 2 minutes apart and 
additional measurements if the first 2 are quite different (Section 12.15).  Record the 
average blood pressure on the vital signs CRF.   
The temperature location selected for a subject at screening should be the same that is 
used throughout the study and documented on the vital signs CRF.  Record all 
measurements on the vital signs CRF.  
9.2.3.3 
Electrocardiograms (ECGs) 
Electrocardiograms will be required for all subjects at screening. 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  The ECG must 
include the following measurements: heart rate, QRS, QT, QTc, and PR intervals.  The 
PI or designated site physician) will review all ECGs.  The presence of a low voltage 
ECG coded on the ECG output, will be entered on the appropriate eCRF.  Once signed, 
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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.  
9.2.3.4 
Other Safety 
9.2.4 
Echocardiogram 
All subjects will have a baseline transthoracic echocardiogram during screening, 
including assessments of systolic and diastolic left ventricular function and right 
ventricular function, valvular insufficiency, right ventricular systolic pressure, 
intraventricular wall thickness, left and right ventricular wall thickness and left ventricular 
mass index, mitral annular early diastolic velocity, and left atrium value index.  
9.2.5 
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 CRF.  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 Schedule of Activities (Table 2-1).   
9.2.5.1 
Pregnancy Testing 
A serum or urine pregnancy test must be completed at screening. A highly sensitive 
(urine or serum) pregnancy test should be completed within 24 hours of initiation of 
investigational/noninvestigational product for females of childbearing potential (FCBP).   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see Figure 12-2).  Refer to Section 12.5 for contraceptive requirements. 
Additional pregnancy testing must also be performed during treatment, as per the 
Schedule of Activities (Table 2-1) and at the safety follow-up visit.  
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Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
9.2.6 
Clinical Outcome Assessments 
9.2.6.1 
European Organization for Research and Treatment of Cancer 
Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30)  
The European Organization for Research and Treatment of Cancer Quality-of-life 
Questionnaire Core 30 (EORTC QLQ-C30) is a questionnaire developed to assess the 
quality of life of cancer patients (Bjordal et al, 2000).   
EORTC QLQ-C30 includes 30 items grouped into:  
• 
five quality of life categories: physical, social, emotional, cognitive and role 
performance;   
• 
three scales of symptoms: fatigue, pain, and nausea and vomiting;  
• 
a global scale of quality-of-life and individual items related to the symptoms of the 
disease and its treatment; dyspnea, insomnia, loss of appetite, constipation, diarrhea 
and  
• 
an item on economic impact   
The responses to the scale items refer to “last week,” with the exception of the subject’s 
physical performance scale, where the timeframe involved is the present. 
9.2.6.2 
European Organization for Research and Treatment of Cancer 
Quality-of-life Questionnaire Multiple Myeloma Module 
(EORTC QLQ-MY20) 
In addition to the QLQ-C30, a number of disease-specific modules have been produced 
by the EORTC.  This modular approach was adopted by EORTC in recognition of the 
limitations of generic patient-reported outcome instruments to provide an appropriate 
coverage of disease-specific concerns.  Modules specific to tumor site, treatment 
modality, and quality of life have been developed.  These were designed to be 
administered alongside the core questionnaire (QLQ-C30); like the core questionnaire, 
the modules were designed for use in cancer clinical trials.  The MM module 
(the QLQ-MY20) was developed by EORTC in 1999 (Bjordal et al, 2000).  A summary of 
the QLQ-C30 and QLQ-MY20 subscales are provided in Section 12.16.  
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10. 
Statistical Considerations 
10.1 
Sample Size Determination 
The study is descriptive in nature.  Approximately 75 subjects will be enrolled in the 
study with approximately 25 subjects in each treatment arm.   
The sample size is assessed in terms of the expected levels of precision for estimating 
the proportion of subjects completing 12 cycles of treatment, relative dose intensity (%), 
and incidence of adverse events.  
With a sample size of 25 subjects for each treatment arm, assuming 50%, 75%, or 90% 
of subjects will complete 12 cycles of treatment, the expected half-widths of the 95% CI 
for estimating the proportion of subjects completing 12 cycles of treatment are calculated 
as below. 
Sample Size 
95% Confidence Interval Half-width (%) 
50% 
75% 
90% 
25 
20.5 
18.1 
13.5 
In the A.R.R.O.W. trial, the mean (standard deviation) of relative dose intensity of 
carfilzomib is 92.2 (11.2) in Once-weekly subjects. In this study with a sample size of 
25 subjects in each treatment arm, assuming standard deviation ranges from 5% to 
15%, the expected half-widths of the 95% CI for estimating the mean relative dose 
intensity are calculated as below. 
Sample Size 
95% Confidence Interval Half-width (%) 
SD = 5 
SD = 10 
SD = 15 
25 
2.0 
3.9 
5.9 
For subject incidence of adverse events of 1%, 5%, 10%, 50%, 80%, the expected  
half-widths of the 95% confidence interval (CI) for estimating the subject incidences of 
adverse events are calculated as below.  
Sample Size 
95% Confidence Interval Half-width (%) 
1% 
5% 
10% 
50% 
80% 
25 
7.8 
10.8 
13.5 
20.5 
16.9 
 
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10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
Full Analysis Set:  The full analysis set will include all enrolled subjects who received at 
least 1 dose of any study treatment (ie, carfilzomib, dexamethasone. lenalidomide, or 
pomalidomide).   
Safety Analysis Set:  The safety population will include all enrolled subjects who 
received at least 1 dose of any study treatment (ie, carfilzomib, dexamethasone, 
lenalidomide, or pomalidomide).  
The full analysis set will be the same as the safety analysis set for this study.   
10.2.2 
Covariates 
The following covariates will be used to examine primary and secondary endpoints in 
subgroups as appropriate: 
Baseline demographics and characteristics:  
• 
age (as categorical variable: 18 to < 65, 65 to 75, and > 75 years)  
• 
sex (male, female)  
• 
race (white and other categories depending on frequency observed)  
• 
commute distance to treatment center: 0-10, 11-25, > 25 miles 
Baseline organ function and comorbid conditions:  
• 
ECOG performance status (0 or 1)  
• 
estimated GFR (< 50 vs ≥ 50 mL/min/1.73 m2)  
• 
hypertension history (include use of anti-hypertensive medications) (yes, no) 
• 
history of ischemic heart disease (myocardial infarction or coronary artery disease), 
congestive heart failure (NYHA class ≤ 2), stroke, or history of peripheral vascular 
disease (yes, no) 
• 
family history of coronary artery disease in first degree relatives with onset 
< 65 years of age for female relative or < 55 years of age for male relative (yes, no) 
• 
smoking history (yes, no)  
• 
history of hyperlipidemia (yes, no) 
• 
history of diabetes (yes, no) 
• 
history or chronic mild hepatic impairment (yes, no; see Section 7.4.1.1.1) 
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Baseline disease characteristics:  
• 
revised international staging system stage (stage 1 vs stage 2 vs stage 3 vs 
unknown)  
• 
determination of measurable disease at baseline (based on serum or urine 
M-protein, based on SFLC only)  
• 
β2-microglobulin level (< 2.5, ≥ 2.5 and < 5.5, ≥ 5.5 mg/L)  
• 
presence of soft tissue plasmacytoma (yes, no) 
• 
progressive disease on lenalidomide during or within 60 days of discontinuation of 
treatment (yes, no) 
10.2.3 
Subgroups 
The subgroups defined by covariates stated above will be used to examine primary and 
secondary endpoints as appropriate, including examination of safety in subgroups as 
appropriate.  The subgroup analysis will not be carried out if the number of subjects in a 
subgroup for any treatment arm is smaller than 20% of the total number of subjects in 
the treatment arm. 
10.2.4 
Handling of Missing and Incomplete Data 
Subjects may have missing data points for a variety of reasons.  The procedures 
outlined below describing what will be done when data are missing may be refined 
during the blind review of the data. 
Incomplete adverse event start dates, concomitant medications start or stop dates, and 
death date will be imputed and the detailed rules will be specified in statistical analysis 
plan (SAP).  
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 
Data Review Team 
A Data Review Team (DRT) will review safety data for the KPd treatment arm on an 
ongoing basis.  A DRT is a group, internal to Amgen but external to the relevant 
carfilzomib product team, that reviews accumulating data from the ongoing clinical trial to 
ensure no avoidable increased risk for harm to subjects.  The DRT includes a clinician, a 
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safety physician, and a biostatistician.  Membership procedures and meeting timing will 
be described in detail in the study DRT charter. 
10.3.1.2 
Final Analysis 
The final analysis will occur after all subjects have completed therapy, disease 
assessments and safety follow-up.   
10.3.2 
Methods of Analyses 
10.3.2.1 
General Considerations 
In principle, summary statistics including non-missing sample size (n) mean, standard 
deviation, median, minimum and maximum quartiles, will be provided for continuous 
variables.  Frequency and percentage will be summarized for binary and categorical 
variables.  Proportions and the corresponding 95% confidence intervals will be based on 
normal approximations unless otherwise specified.  The Clopper-Pearson method of 
exact binomial confidence intervals will be used to calculate the confidence intervals as 
appropriate.  
Details of all the analyses will be provided in the statistical analysis plan, which will be 
developed and finalized before database lock.  To preserve study integrity, the final 
analysis will be conducted and reported following the end of study, as defined in 
Section 5.3.1.   
10.3.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
Unless otherwise specified, the following analyses will be based on the 
safety analysis set.  The analyses will be carried out for subjects on the 
Kd, KRd, and KPd regimens, respectively. 
All EORTC QLQ-C30 and EORTC QLQ-MY20 subscale scores up to 
cycle 12 or disease progression will be summarized descriptively by cycle.   
The rate of PFS at 1 year will be estimated using the Kaplan-Meier method 
and with CI estimated using the method by Kalbfleisch and Prentice, 1980 
with log-log transformation. 
The response rate and 1-year PFS rate will be summarized descriptively 
by line of prior therapy 1 vs ≥ 2. 
Exploratory 
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10.3.2.3 
Safety Analyses 
10.3.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Unless otherwise specified, following analyses will be based on the safety 
analysis set.  The analyses will be carried out for subjects on the Kd, KRd, 
and KPd regimens, respectively. 
The proportion of subjects completing 12 cycles of Kd, KRd, and KPd 
treatment will be calculated based on the safety analysis set. 
The proportion of actual cumulative dose received to the full intended 
cumulative dose in cycles 1-12 will be summarized descriptively.  The full 
intended cumulative dose is defined as all therapy specified per 
Sections 7.1.1.2 and 7.1.2 without consideration for dose modification or 
skipped doses.  Relative dose intensity in cycles 1-12 will be summarized 
descriptively.  Dose modifications including dose reduction, dose withheld, 
and dose delay in cycles 1-12 will be summarized along with reasons 
including adverse events and non-adverse events.  Treatment-emergent 
adverse events and serious adverse events in cycles 1-12 will be 
summarized descriptively following the methods specified in 
Section 10.3.2.3. 
Secondary 
Not applicable 
Exploratory 
Not applicable 
 
10.3.2.3.2 
Adverse Events  
Subject 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 significant treatment emergent adverse events will also be 
provided.   
10.3.2.3.3 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics over time.  
Post dose shifts in grades of safety laboratory values relative to baseline will be 
tabulated.   
10.3.2.3.4 
Vital Signs 
The analyses of vital signs will include summary statistics over time.   
10.3.2.3.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics over time.   
10.3.2.3.6 
Electrocardiogram 
The ECG measurements from this clinical study will be performed as per standard of 
care for routine monitoring, rather than for purposes of assessment of potential QTc 
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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 trials.   
10.3.2.3.7 
Exposure to Investigational Product 
The number of days on investigational product, the daily dose, the total dose of 
investigational product, and the proportion of subjects receiving each dose level will be 
summarized using descriptive statistics.  
10.3.2.3.8 
Exposure to Other Protocol-required Therapy 
Descriptive statistics will be produced to describe the exposure to other 
protocol-required therapies, if relevant.  
10.3.2.3.9 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term as coded by the World Health Organization Drug (WHODRUG) 
dictionary.   
10.3.2.4 
Other Analyses 
The descriptive summary of cardiopulmonary events by baseline covariates to be 
specified in the SAP may be performed. 
The descriptive summary of cardiovascular reasons for screen failure will be captured for 
exclusion criteria 230-234 (Section 6.2) from the IXRS system.  The specific analyses 
will be specified in the SAP. 
The use of the dyspnea guidance instructions will be summarized by correlating the 
dates of reporting of dyspnea adverse events with dates of collection of brain natriuretic 
peptide (BNP) or N terminal of the prohormone brain natriuretic peptide BNP 
(NT-ProBNP), serum creatinine, echocardiograms, and evaluations for infection or 
pulmonary disorders as detailed in Section 12.9.  The proportion of subjects in whom 
dyspnea is reported as an adverse event and undergo each evaluation and the results of 
these evaluations will be summarized descriptively.  The specific analyses will be 
described in the SAP.   
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11. 
References 
Barrett-Lee P, Bloomfield D, Dougherty L, et al.  An audit to determine the time taken to 
administer intravenous bisphosphonate infusions in patients diagnosed with metastatic 
breast cancer to bone in a hospital setting.  Curr Med Res Opin.  2007;23:1575-1582. 
Barlogie B, Tricot G, Anaissie E, et al.  Thalidomide and hematopoietic-cell 
transplantation for multiple myeloma.  N Engl J Med.  2006;354(10):1021–1030. 
Berenson JR, Cartmell A, Bessudo A, et al.  CHAMPION-1: a phase 1/2 study of 
once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple 
myeloma.  Blood.  2016;127:3360-3368.   
Bjordal K, de Graeff A, Fayers PM, et al.  A 12 country field study of the EORTC 
QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC 
QLQ-H&N35) in head and neck patients.  EORTC Quality of Life Group.  Eur J Cancer.  
2000;36:1796-1807. 
Biran N, Siegel DSD, Berdeja JG, et al.  Weekly carfilzomib, lenalidomide, and 
dexamethasone (KRd) in relapsed or refractory multiple myeloma (RRMM): A phase 1b 
study [abstract].  J Clin Oncol.  2018;36. Abstract 8022. 
Bringhen S, Larocca A, Rossi D, et al.  Efficacy and safety of once-weekly bortezomib in 
multiple myeloma patients.  Blood.  2010;116(23):4745-4753. 
Brown J, Plummer R, Bauer TM, et al.  Pharmacokinetics of carfilzomib in patients with 
advanced malignancies and varying degrees of hepatic impairment: an open-label, 
single-arm, phase 1 study.  Exp Hematol Oncol.  2017;6:27.   
Chanan-Khan AA, Giralt S.  Importance of achieving a complete response in multiple 
myeloma, and the impact of novel agents.  J Clin Oncol.  2010;28(15):2612-2624. 
Carfilzomib Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
Chng WJ, Goldschmidt H, Dimopoulos M.  Carfilzomib–dexamethasone vs 
bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic 
risk in the phase 3 study ENDEAVOR.  Leukemia 2017;31:1368–1374.   
Dimopoulos, Moreau, Palumbo, et al.  Carfilzomib and dexamethasone versus 
bortezomib and dexamethasone for patients with relapsed or refractory multiple 
myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study.  Lancet 
Oncol.  2016;17:27-38.   
Dimopoulos M, Goldschmidt H, Niesvizky R.  Carfilzomib or bortezomib in relapsed or 
refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an 
open-label, randomised, phase 3 trial.  Lancet Oncol.  2017;18:1327-1337.   
Durie BG, Harousseau JL, Miguel JS, et al.  International uniform response criteria for 
multiple myeloma.  Leukemia.  2006;20(9):1467-1473.  
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.   
Howlader N, Noone AM, Krapcho M, et al.  SEER Cancer Statistics Review, 1975-2010, 
National Cancer Institute. 2013.  Available from http://seer.cancer.gov/csr/1975_2010/ 
Hoy SM.  Carfilzomib Triple Combination Therapy:  A Review in Relapsed Multiple 
Myeloma.  Target Oncol.  2016;11:2552-2562.  
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Page 87 of 132 
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James P, 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.   
Kalbfleisch JD and Prentice RL.  The Statistical Analysis of Failure Time Data, New 
York:  John Wiley & Sons; 1980. 
Katzel JA, Hari P, Vesole DH.  Multiple myeloma: charging toward a bright future.  
CA Cancer J Clin. 2007;57(5):301–318. 
Kortuem KM, Stewart AK.  Carfilzomib.  Blood.  2013;121(6):893–897. 
Kumar SK, Dimopoulos MA, Kastritis E, et al.  Natural history of relapsed myeloma, 
refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG 
study.  Leukemia.  2017; 31, 2443–2448. 
Kumar S, Paiva B, Anderson KC, et al.  International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple 
myeloma.  Lancet Oncol.  2016;17(8):328-346. 
Kumar SK, Lee JH, Lahuerta JJ, et al.  International Myeloma Working Group.  Risk of 
progression and survival in multiple myeloma relapsing after therapy with IMiDs and 
bortezomib: a multicenter international myeloma working group study.  Leukemia.  
2012;26(1):149–157.   
Kumar SK, Therneau TM, Gertz MA, et al.  Clinical course of patients with relapsed 
multiple myeloma.  Mayo Clin Proc.  2004;79(7):867–874.  
Kyprolis® (carfizomib for injection) United States Prescribing Information.  Thousand 
Oaks CA:  Amgen, Inc; September 2018.  https://www.pi.amgen.com/~/media/amgen 
/repositorysites/pi-amgen-com/kyprolis/kyprolis_pi.pdf.  Accessed 12 February 2019. 
Levey AS, Stevens LA, Schmid CH, et al.  A new equation to estimate glomerular 
filtration rate.  Ann Intern Med.  2009;150(9):604-612. 
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.  
Moreau P, Joshua D, Chng WJ.  Impact of Prior Treatment on Patients with Relapsed 
Multiple Myeloma Treated with Carfilzomib and Dexamethasone Vs Bortezomib and 
Dexamethasone in a Subgroup Analysis of the Phase 3 Endeavor Study 
(NCT01568866).  Blood.  2015;126:729.   
Mortensen GL, Salomo M.  Quality of life in patients with multiple myeloma:  a qualitative 
study.  J Cancer Sci Ther.  2016;8:289-293. 
National Comprehensive Cancer Network.  NCCN Clinical Practice Guidelines in 
Oncology:  Multiple Myeloma, V. 2.2018.  J Natl Compr Canc Netw.  2018 
https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. 
O’Donnell EK and Raje NS.  New monoclonal antibodies on the horizon in multiple 
myeloma.  Ther Adv Hematol.  2017;8(2):41-53. 
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the Eastern 
Cooperative Oncology Group.  Am J Clin Oncol.  1982;5(6):649–655. 
Phase 3 A.R.R.O.W. Study Of Once-Weekly KYPROLIS® (Carfilzomib) Regimen Meets 
Primary Endpoint Of Progression-Free Survival In Relapsed And Refractory Multiple 
Myeloma Patients [press-release].  Thousand Oaks, CA.  PRNewswire.  
23 October 2017.  PRNewswire 
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Pomalyst® (pomalidomide) United States Prescribing Information. Summit NJ: Celgene 
Corporation; May 2018.  https://media.celgene.com/content/uploads/pomalyst-pi.pdf.  
Accessed 11 December 2018. 
Pulte D, Redaniel MT, Brenner H, Jansen L, Jeffreys M.  Recent improvement in survival 
of patients with multiple myeloma: variation by ethnicity.  Leuk Lymphoma. 
2014;55(5):1083–1089. 
Rajkumar SV, Richardson P, San Miguel JF.  Guidelines for determination of the number 
of prior lines of therapy in multiple myeloma.  Blood.  2015;126:921-922.  
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. 
Richardson P, Mitsiades C, Schlossman R, et al.  The treatment of relapsed and 
refractory multiple myeloma.  Hematology Am Soc Hematol Educ Program.  
2007:317-223. 
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.  https://media.celgene.com/content/uploads/revlimid-
pi.pdf.  Accessed 11 December 2018. 
San Miguel J, Weisel K, Moreau P, et al.  Pomalidomide plus low-dose dexamethasone 
versus high-dose dexamethasone alone for patients with relapsed and refractory 
multiple myeloma (MM-003): a randomized, open-label, phase 3 trial.  Lancet Oncol.  
2013;14(11):1055-1066. 
SEER Cancer Statistics Review, 1975–2004.  National Cancer Institute.  Bethesda, MD:  
National Cancer Institute; 2003. 
Shah JJ, Stadtmauer EA, Abonour R, et al. Carfilzomib, pomalidomide, and 
dexamethasone for relapsed or refractory myeloma.  Blood.  2015;126(20):2284-2290. 
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. 
Smith TJ, Bohlke K, Lyman GH, et al.  Recommendations for the Use of WBC Growth 
Factors:  American Society of Clinical Oncology Clinical Practice Guideline Update.  J 
Clin Oncol 2015;33:3199-3212. 
Sonneveld P, Zweegman S, Cavo M, et al.  Carfilzomib, Pomalidomide, and 
Dexamethasone (KPd) in Patients with Multiple Myeloma Refractory to Bortezomib and 
Lenalidomide.  The EMN011 Trial.  Blood.  2018;132:801. 
Stewart AK, Dimopoulos MA, Masszi T, et al.  Health-Related Quality-of-Life Results 
From the Open-Label, Randomized, Phase III ASPIRE Trial Evaluating Carfilzomib, 
Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone in 
Patients With Relapsed Multiple Myeloma.  J Clin Oncol.  2016;34:3921-3930. 
Stewart AK, Rajkumar SV, Dimopoulos MA, et al.  Carfilzomib, lenalidomide, and 
dexamethasone for relapsed multiple myeloma.  N Engl J Med.  2015;372:142-152. 
Streiff MB, Bockenstedt PL, Cataland SR, et al.  Venous thromboembolic disease.  
Clinical Practice Guidelines in Oncology.  J Natl Compr Canc Netw.  2011;9:714-777. 
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Terpos E, Morgan G, Dimopoulos MA, et al.  International Myeloma Working Group 
recommendations for the treatment of multiple myeloma-related bone disease.  J Clin 
Oncol.  2013;31(18):2347-2357. 
Approved 
 
 


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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 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BNP 
brain natriuretic peptide 
BSA 
body surface area 
CFR 
US Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COA 
Clinical Outcome Assessment 
CR 
complete response 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT 
computed tomography 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
electronic data capture 
eCRF 
electronic case report form 
End of Treatment 
defined as the last day the subject receives protocol-specified 
treatment for an individual subject 
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 
EORTC QLQ-MY20 
European Organization for Research and Treatment of Cancer 
Quality-of-life Questionnaire Multiple Myeloma Module 
FCBP 
females of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate  
HR 
hazard ratio 
HRQoL 
health-related quality-of-life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
Ig 
immunoglobulin 
IMiD 
immunomodulatory drug 
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Abbreviation or Term 
Definition/Explanation 
IMWG 
International Myeloma Working Group 
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 
IV 
intravenous 
K 
Kyprolis 
Kd 
carfilzomib with dexamethasone regimen 
Kd56 
Kd 56 mg/m2 twice weekly 
Kd70 
Kd 70 mg/m2 once weekly 
KPd 
carfilzomib with pomalidomide and dexamethasone regimen 
KPd27 
KPd 27 mg/m2 twice weekly 
KPd56 
KPd 56 mg/m2 once weekly 
KRd 
carfilzomib with lenalidomide and dexamethasone regimen 
KRd27 
KRd 27 mg/m2 twice weekly 
KRd56 
KRd 56 mg/m2 once weekly 
MM 
multiple myeloma 
MR 
minimal response 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PET/CT 
positron emission tomography/computed tomography 
PFS 
progression-free survival 
PI 
proteasome inhibitor 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
RBC 
red blood cell 
RRMM 
relapsed or refractory multiple myeloma 
SAP 
Statistical Analysis Plan 
sCR 
stringent complete response 
SFLC 
serum free light chain 
SIFE 
serum immunofixation 
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Abbreviation or Term 
Definition/Explanation 
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 trial 
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 
sum of perpendicular dimensions 
SPEP 
serum protein electrophoresis 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TLS 
tumor lysis syndrome 
TMA 
thrombotic microangiopathy 
UIFE 
urine immunofixation 
UPEP 
urine protein electrophoresis 
ULN 
upper limit of normal 
US 
United States 
Vd 
bortezomib with dexamethasone regimen 
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 a local laboratory.  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 6.1 to Section 6.2. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 12-1.  Analyte Listing 
Screening only  
Chemistry 
Hematology 
Other Labs 
β-2 microglobulin 
Bone marrow 
aspirate with FISH 
Creatinine  
Glucose (fasting) 
HbA1c 
LDH 
Lipid panel (fasting): 
•Total cholesterol 
•HDL 
•LDL 
•triglycerides 
NT-proBNP (or BNP)a 
SFLC 
SIFE 
SPEP 
UIFE 
UPEP 
Uric acid 
Urine albumin 
Urine creatinine 
Albumin 
ALP 
ALT (SGPT) 
AST (SGOT) 
Bicarbonate  
BUN or Urea 
Calcium 
Chloride 
Creatinine 
Glucose 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total protein 
Hemoglobin 
Hematocrit 
Platelets 
RBC 
WBC 
Differential 
• Bands/stabs 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
• Neutrophils 
Serum or Urine 
Pregnancy 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BNP = brain natriuretic peptide; BUN = blood urea nitrogen; FISH = fluorescence in-situ hybridization; 
HbA1c = hemoglobin A1c; HDL = high-density lipoproteins; LDH = lactate dehydrogenase; 
LDL = low-density lipoproteins; NT-proBNP = N-terminal of the prohormone brain natriuretic peptide; 
RBC = red blood cells; SFLC = serum free light chain; SGOT = serum glutamic oxaloacetic transaminase; 
SGPT = serum glutamate-pyruvate transaminase; SIFE = serum immunofixation electrophoresis; 
SPEP = serum protein electrophoresis; UIFE = urine immunofixation electrophoresis;  
UPEP = urine protein electrophoresis; WBC = white blood cells. 
a Either NT-proBNP or BNP may be used per investigator’s discretion. 
Approved 
 
 


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12.3 
Appendix 3.  Study Governance Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
• 
Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
• 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board (IRB) by the investigator and reviewed and approved by 
the IRB.  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 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 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 annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB 
• 
Obtaining annual IRB approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB continuance of approval must be 
sent to Amgen 
• 
Notifying the IRB of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance 
with local procedures 
• 
Overall conduct of the study at the site and adherence to requirements of Title 21 
of the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB, and all 
other applicable local regulations 
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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 (Amgen Inc.) and the local IRB. 
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 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 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 or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
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The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  Subject 
withdrawal of consent or discontinuation from study treatment and/or procedures must 
also be documented in the subject’s medical records; refer to Section 8. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject.  
If a potential subject is illiterate or visually impaired, 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.   
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. 
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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 direct access to review the subject’s original medical 
records for verification of study-related procedures and data.  Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are 
important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
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 
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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 
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 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.  
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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 Quality, 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. 
Amgen (or designee) will perform Self-Evident Corrections to obvious data errors in the 
clinical trial database.  Self-Evident Corrections will be documented in the CRF Standard 
Instructions and the CRF Specific Instructions, both of these will be available through the 
electronic data capture (EDC) system.  Examples of obvious data errors that may be 
corrected by Amgen (or designee) include deletion of obvious duplicate data (ie, the 
same results sent twice with the same date with different visit) and updating a specific 
response if the confirming datum is provided in the “other, specify” field (eg, for race, 
reason for ending study). 
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. 
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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/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 clinical outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
• 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB and 
Amgen 
• 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
• 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
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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 in writing of the study’s completion or early termination and send a copy of 
the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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12.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
• 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
• 
Note:  An adverse event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a treatment, combination product, medical device or procedure. 
Events Meeting the Adverse Event Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram, radiological scans, vital signs measurements), 
including those that worsen from baseline, that are considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported regardless of 
sequelae. 
• 
For situations when an adverse event or serious adverse event is due to multiple myeloma 
report all known signs and symptoms.  Death due to disease progression in the absence of 
signs and symptoms should be reported as the primary tumor type (eg, metastatic 
pancreatic cancer).  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.  
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. 
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Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, meets 
at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalization are an adverse event.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  When in 
doubt as to whether “hospitalization” occurred or was necessary, the adverse event is to be 
considered serious.  Hospitalization for elective treatment of a pre-existing condition that 
did not worsen from baseline is not considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.  This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse event 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the other outcomes 
listed in the above definition.  These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
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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). 
• 
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 grade defined below); 
o 
Assessment of relatedness to carfilzomib; and 
o 
Action taken. 
• 
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 sponsor in lieu of completion of the Event CRF page. 
• 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the medical 
records.  In this case, all subject identifiers, with the exception of the subject number, will 
be blinded on the copies of the medical records before submission to Amgen. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious adverse 
event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and serious 
adverse event reported during the study.  The assessment of severity will be based on:  
The Common Terminology Criteria for Adverse Events, version 4.03 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 procedure and each occurrence of 
each adverse event/serious adverse event. 
• 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
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• 
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. 
• 
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. 
• 
New or updated information will be recorded in the originally completed Event CRF. 
• 
The investigator will submit any updated serious adverse event data to Amgen within 
24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
• 
The primary mechanism for reporting serious adverse event will be the electronic data 
capture (EDC) system via the Safety Report Form.  
• 
If the EDC system is unavailable for more than 24 hours, then the site will report the 
information to Amgen using an electronic Serious Adverse Contingency Report Form 
(see Figure 12-1) within 24 hours of the investigator’s knowledge of the event. 
• 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
• 
After the study is completed at a given site, the EDC system will be taken off-line to prevent 
the entry of new data or changes to existing data. 
• 
If a site receives a report of a new serious adverse event from a study subject or receives 
updated data on a previously reported serious adverse event after the EDC has been taken 
off-line, then the site can report this information on a paper Serious Adverse Event Report 
Form (see Figure 12-1). 
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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 
 
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12.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for male and female of childbearing potential 
are outlined in Section 6.2. 
Male and female subjects of childbearing potential must receive pregnancy prevention 
counseling and be advised of the risk to the fetus if they become pregnant or father a 
child during treatment and for 30 days (for female subjects) and 90 days (for male 
subjects) after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and/or for an increased length of time.  In addition, male 
subjects may also be required to use contraception for an increased length of time.  The 
investigator must discuss these contraceptive changes with the subject. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
• 
Premenopausal female with 1 of the following: 
− 
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 
• 
Postmenopausal female 
− 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
− 
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.   
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Contraception Methods for Female Subjects 
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 trial and the preferred 
and usual lifestyle of the subject) 
Contraception Methods for Male Subjects  
• 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject)  
• 
Use a condom during treatment and for an additional 90 days after the last dose of 
protocol-required therapies 
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 must not donate sperm during treatment and for an additional 90 days after the 
last dose of carfilzomib. 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 
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Unacceptable Methods of Birth Control for Male and Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• 
Withdrawal (coitus interruptus) 
• 
Spermicides only 
• 
Lactational amenorrhea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
• 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 30 days after the last 
dose of protocol-required therapies. 
• 
Information will be recorded on the Pregnancy Notification Worksheet  
(see Figure 12-2).  The worksheet must be submitted to Amgen Global Patient 
Safety within 24 hours of learning of a subject’s pregnancy.  (Note:  Sites are not 
required to provide any information on the Pregnancy Notification Worksheet that 
violates the country or regions local privacy laws). 
• 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant 
health information and complete the pregnancy questionnaire for any female subject 
who becomes pregnant while taking protocol-required therapies through 30 days 
after the last dose of the study drug.  This information will be forwarded to Amgen 
Global Patient Safety.  Generally, infant follow-up will be conducted up to 12 months 
after the birth of the child (if applicable). 
• 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
• 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
• 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
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• 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 12.4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
• 
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 or Were Pregnant at the Time of 
Enrollment 
• 
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 Worksheet.  The worksheet (see 
Figure 12-2) must be submitted to Amgen Global Patient Safety within 24 hours of 
the site’s awareness of the pregnancy.  (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Worksheet that violates the country or 
regions local privacy laws). 
• 
The investigator will attempt to obtain a signed authorization for release of 
pregnancy and infant health information directly from the pregnant female partner to 
obtain additional pregnancy information. 
• 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
• 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
• 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
• 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 30 days after the last dose of 
protocol-required therapies. 
• 
Information will be recorded on the Lactation Notification Worksheet (see below) 
and submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
• 
Study treatment will be discontinued if female subject breastfeeds during the study. 
• 
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 Worksheet 
 
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12.6 
Appendix 6.  Sample Storage and Destruction 
Not applicable. 
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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 7.4.1.1.3. 
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12.8 
Appendix 8.  International Uniform Response Criteria for Multiple 
Myeloma 
Summary of International Myeloma Working Group Uniform Response Criteria 
(IMWG-URC). 
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 and 
• 
Normal SFLC ratio and 
• 
Absence of clonal plasma cells in bone marrow biopsy by 
immunohistochemistry (κ/λ ratio ≤ 4:1 or ≥ 1:2 for κ and λ patients, 
respectively, after counting ≥ 100 plasma cells) 
CR 
• 
Negative immunofixation on the serum and urine and 
• 
Disappearance of any soft tissue plasmacytomas and 
• 
< 5% plasma cells in bone marrow 
• 
In patients with measurable disease only by SFLC, normal SFLC ratio 
(0.26 to 1.65) 
VGPR 
• 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or 
• 
≥ 90% reduction in serum M-component with urine M-component 
< 100 mg per 24 hours (requires a 24-hour urine collection) 
• 
In patients with measurable disease only by SFLC, a decrease ≥ 90% in 
the difference between involved and uninvolved FLC levels 
PR 
• 
≥ 50% reduction of serum M-protein and reduction in 24-hour urinary 
M-protein by ≥ 90% or to < 200 mg per 24 hours (if both are measurable 
at baseline) 
• 
In patients 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. 
• 
If the serum and urine M-protein are not measurable, and SFLC assay is 
also not measurable, ≥ 50% reduction in bone marrow plasma cells is 
required in place of M-protein, provided baseline percentage was ≥ 30%. 
• 
In addition to the above criteria, if present at baseline, ≥ 50% reduction in 
the size of soft tissue plasmacytomas is also required. 
MR 
• 
≥ 25% but ≤ 49% reduction of serum M-protein and reduction in 24-hour 
urinary M-protein by 50% to 89%.  In addition to the above listed criteria, 
if present a baseline a ≥ 50% reduction in the size (SPD) of soft tissue 
plasmacytoma is required 
Page 1 of 2 
Footnotes defined on next page 
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Response 
Subcategory 
Multiple Myeloma Response Criteria 
Stable Disease 
• 
Not meeting criteria for CR, VGPR, PR, or PD 
PD 
• 
Increase of 25% from lowest response value in any of the following: 
− 
Serum M-component (absolute increase must be ≥ 0.5 g/dL)  
− 
Serum M-protein increase ≥ 1 g/dL, if the lowest M component was 
≥ 5 g/dL 
− 
Urine M-component (absolute increase must be ≥ 200 mg per 
24 hours)  
− 
In patients without measurable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels (absolute 
increase must be > 10 mg/dL) 
− 
In patients without measurable serum and urine M-protein levels and 
without measurable disease by FLC levels, bone marrow PC 
percentage (absolute percentage must be ≥ 10%) 
• 
Definite development of new bone lesions or soft tissue plasmacytomas 
or definite increase in size of existing bone lesions or soft tissue 
plasmacytomas, ≥ 50% increase from nadir in SPD of > 1 lesion, or 
≥ 50% increase in the longest diameter of a previous lesion that is 
> 1 cm in short axis.  Plasmacytoma measurements should be taken 
from the CT portion of the PET/CT, or MRI scans, or dedicated CT scans 
where applicable.  For patients with only skin involvement, skin lesions 
should be measured with a ruler.  Measurement of tumor size will be 
determined by the SPD. 
• 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL 
or 2.75 mmol/L) attributed solely to the plasma cell proliferative disorder. 
Page 2 of 2 
CR = complete response; CT = computed tomography; MR = minimal response; MRI = magnetic resonance 
imaging; PD = progressive disease; PET/CT = positron emission tomography/computed tomography; 
PR = partial response; sCR = stringent complete response; SFLC = serum free light chain; SPD = sum of 
the products of the maximal perpendicular diameters of measured lesions; VGPR = very good partial 
response. 
All response categories (complete response [CR], stringent complete response [sCR], 
very good partial response [VGPR], partial response [PR]) require 2 consecutive 
assessments made at any time 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. 
For sCR: presence/absence of clonal cells in bone marrow is based upon the 
normalization of kappa lambda ratio.  “Measurable” disease is defined by at least one of 
serum protein electrophoresis (SPEP) ≥ 1.0 g/dL, urine protein electrophoresis 
(UPEP) ≥ 200 mg per 24 hours, or in subjects without detectable serum or urine 
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M-protein, serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an 
abnormal kappa lambda ratio.   
Determination of progressive disease (PD) while on study requires 2 consecutive 
assessments made at any time before classification of PD and/or the institution of new 
therapy.  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 definite increase in the size is defined as a ≥ 50% increase from 
nadir as measured serially by the sum of the products of the maximal perpendicular 
diameter (SPD) of the measurable lesion or a ≥ 50% increase in the longest diameter of 
a previous lesion with ≥ 1 cm short axis.  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.  Plasmacytomas of lesser size will be considered non-measurable.  The 
requirement for bi-directional measurements applies only to plasmacytomas.  The 
plasmacytoma specifications for PD are based on the sponsor’s interpretation of the 
IMWG-URC and practical considerations for study execution.  
For defining nadir, in the case where a value is felt to be a spurious result per 
physician/Independent Review Committee discretion (eg, a possible laboratory error), 
that value will not be considered when determining the lowest value. 
(Sources:  Durie et al, 2006; Kumar et al, 2016; Rajkumar et al, 2011) 
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12.9 
Appendix 9.  Guidance for Dyspnea Adverse Events 
If a subject reports dyspnea, it is recommended that subject be evaluated clinically for 
fluid overload.  If clinical fluid overload is present (eg, > 5% weight gain, peripheral 
edema, jugular venous distension) obtain an N terminal of the prohormone brain 
natriuretic peptide (NT-Pro-BNP) or brain natriuretic peptide (BNP) (use same test as 
was used at baseline evaluation) and serum creatinine.  If the NT-Pro-BNP (or BNP) is 
elevated or higher than baseline, obtain an echocardiogram within 72 hours of onset of 
dyspnea or as soon as possible.  In the absence of clinical evidence of fluid overload or 
if otherwise clinically indicated, it is recommended to evaluate for the present of 
infection, pulmonary disease (including pulmonary embolus), or significant reduction in 
renal function. 
DYSPNEA 
Clinical fluid overload 
 
 
YES 
 
 
 
 
 
 
 
NO 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Elevated              NO 
 
 
 
 
 
 
 
 
 
 
 
YES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infection 
Pulmonary Disease 
Reduction in Renal 
Function 
NT-Pro-BNP or BNP   
Echocardiogram 
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12.10 
Appendix 10.  Eastern Cooperative Oncology Performance Status 
GRADE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (eg, light house work, office work) 
2 
Ambulatory and capable of all self care but unable to carry out any work activities.  
Up and about more than 50% of waking hours 
3 
Capable of only limited self care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self care.  Totally confined to bed or 
chair 
5 
Dead 
Source:  Oken et al, 1982. 
Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair 
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12.11 
Appendix 11.  Guidelines for Documenting Prior Treatment 
Patients must have documented relapse after at least 1, but no more than 3 prior 
treatment regimens or lines of therapy for multiple myeloma.  When documenting prior 
treatments for multiple myeloma, the following guidelines should be used  
(Rajkumar et al, 2015): 
• 
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 patient 
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 off 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 patient was not removed from carfilzomib therapy due to 
toxicity must also be available.  For patients with prior therapy with carfilzomib, the 
start of the 6-month treatment-free interval is when carfilzomib is discontinued even if 
other portions of the regimen are continued. 
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12.12 
Appendix 12.  2014 Antihypertensive Management by Joint National 
Committee 8 (JNC8) 
 
2014 Hypertension Guideline Management Algorithm (James et al, 2014) 
ACEI = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel 
blocker; DBP = diastolic blood pressure; SBP = systolic blood pressure. 
a ACEIs and ARBs should not be used in combination. 
b If blood pressure fails to be maintained at goal, reenter the algorithm where appropriate based on the 
current individual therapeutic plan. 
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12.13 
Appendix 13.  Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) Equation 
Table 12-2.  CKD-EPI Equation for Estimating Glomerular Filtration Rate (GFR) 
Expressed for Specified Race, Sex, and Serum Creatinine in mg/dL 
Race 
Sex 
Serum Creatinine, 
Scr (mg/dL) 
Equation (age in years for ≥ 18) 
Black 
Female 
≤ 0.7 
GFR = 166 × (Scr/0.7)-0.329 × (0.993)Age 
Black 
Female 
> 0.7 
GFR = 166 × (Scr/0.7)-1.209 × (0.993)Age 
Black 
Male 
≤ 0.9 
GFR = 163 × (Scr/0.9)-0.411 × (0.993)Age 
Black 
Male 
> 0.9 
GFR = 163 × (Scr/0.9)-1.209 × (0.993)Age 
White or other 
Female 
≤ 0.7 
GFR = 144 × (Scr/0.7)-0.329 × (0.993)Age 
White or other 
Female 
> 0.7 
GFR = 144 × (Scr/0.7)-1.209 × (0.993)Age 
White or other 
Male 
≤ 0.9 
GFR = 141 × (Scr/0.9)-0.411 × (0.993)Age 
White or other 
Male 
> 0.9 
GFR = 141 × (Scr/0.9)-1.209 × (0.993)Age 
Source:  Levey et al, 2009. 
CKD-EPI equation expressed as a single equation (Levey et al, 2009): 
GFR = 141 x min (Scr /κ, 1)α x max(Scr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 
[if black] 
where: 
• 
Scr is serum creatinine in mg/dL 
• 
κ is 0.7 for females and 0.9 for males 
• 
α is -0.329 for females and -0.411 for males 
• 
min indicates the minimum of Scr /κ or 1, and 
• 
max indicates the maximum of Scr /κ or 1. 
Approved 
 
 


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12.14 
Appendix 14.  Venous Thromboembolic Disease (VTE) Risk 
Assessment and Prophylaxis for Multiple Myeloma 
 
Source:  Streiff et al, 2011. 
Approved 
 
 


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12.15 
Appendix 15.  2013 European Society of Hypertension/European 
Society of Cardiology Office Blood Pressure Measurement 
 
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12.16 
Appendix 16.  Overview of QLQ-C30 and QLQ-MY20 Scales 
 
Source:  Bjordal et al, 2000. 
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Approved 
 
 


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Amendment 4 
Protocol Title:  An Open Label Phase 2 Study of Carfilzomib Combinations 
(Carfilzomib Plus Dexamethasone, Carfilzomib Plus Lenalidomide and 
Dexamethasone, and Carfilzomib Plus Pomalidomide and Dexamethasone), To 
Assess Tolerability and Adherence in Subjects With Relapsed or Refractory 
Multiple Myeloma at US Community Oncology Centers 
 
Amgen Protocol Number 20170596 
 
 
Amendment 4 Date: 
20 May 2019 
Rationale: 
• 
Protocol amendment 4 has been issued to address carfilzomib dosing errors 
within the Schedule of Activity during Cycle 1 for the Kd and KRd regimens.  An 
error in the dose of carfilzomib during cycle 3 through 12 for subjects with mild 
hepatic insufficiency has also been corrected. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20170596 
Date:  20 May 2019 
Page 2 of 6 
CONFIDENTIAL 
 
 
Description of Changes: 
Section:  Global 
Change:  Header has been updated to reflect the date of Amendment 4. 
Section:  Title Page; Protocol Date 
Add:  Protocol Amendment 4  20 May 2019 
Section:  Investigator’s Agreement 
Replace:   
I have read the attached protocol entitled An Open-label Phase 2 Study of Carfilzomib 
Plus Dexamethasone To Assess Tolerability and Adherence in Subjects With Relapsed 
or Refractory Multiple Myeloma at US Community Oncology Centers, dated 25 February 
2019, and agree to abide by all provisions set forth therein. 
With:   
I have read the attached protocol entitled An Open-label Phase 2 Study of Carfilzomib 
Combinations (Carfilzomib Plus Dexamethasone, Carfilzomib Plus Lenalidomide and 
Dexamethasone, and Carfilzomib Plus Pomalidomide and Dexamethasone), To Assess 
Tolerability and Adherence in Subjects With Relapsed or Refractory Multiple Myeloma at 
US Community Oncology Centers, dated  
29 March 201920 May 2019, and agree to abide by all provisions set forth therein..
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20170596 
Date:  20 May 2019 
Page 3 of 6 
CONFIDENTIAL 
 
 
Section:  Table 2-1 Schedule of Activities 
Replace:  
PROCEDURE 
Screeninga b 
(up to 
21 days 
before 
Day 1) 
Treatment Period 
 
 
Cycle 1-2 
Cycle 3-12 
Day 1 2 8 9 15 16 22 23 1 
8 15 21 
STUDY TREATMENT  
Kd ARM 
Carfilzomib administrationh 
 
X 
X X 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  
Cycle 2: 56 mg/m2 
Cycles 3-12: 70 mg/m2 
For subjects with baseline hepatic 
function abnormalities (bilirubin or AST 
> ULN), see Section 7.1.1.2.1 for 
modification of the initial dose. 
For cycle 3, for subjects who were 
previously dose reduced, see 
Section 7.1.1.2 for starting dose. 
 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20170596 
Date:  20 May 2019 
Page 4 of 6 
CONFIDENTIAL 
 
 
With:  
PROCEDURE 
Screeninga b 
(up to 
21 days 
before 
Day 1) 
Treatment Period 
Safety 
FUc (30 
[+3] days 
post last 
dose) 
Notes 
Cycle 1-2 
Cycle 3-12 
Day 1 2 8 9 15 16 22 23 1 
8 15 21 
STUDY TREATMENT  
Kd ARM 
Carfilzomib administrationh 
 
X 
X X X X X 
Wi
th  
 
X 
X 
X 
 
 
Cycle 1: 20 mg/m2 on days 1 and 2; 
2756 mg/m2 on days 8, 9, 15, and 16  
Cycle 2: 56 mg/m2 
Cycles 3-12: 70 mg/m2 
For subjects with baseline hepatic 
function abnormalities (bilirubin or AST 
> ULN), see Section 7.1.1.2.1 for 
modification of the initial dose. 
For cycle 3, for subjects who were 
previously dose reduced, see 
Section 7.1.1.2 for starting dose. 
 
 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20170596 
Date:  20 May 2019 
Page 5 of 6 
CONFIDENTIAL 
 
 
Replace: 
KRd ARM 
Carfilzomib administrationh 
 
X 
X X X X X 
 
 
X 
X 
X 
 
 
Cycle 1: 20 mg/m2 on days 1 and 2; 
56 mg/m2 on days 8, 9, 15, and 16  
Cycle 2: 27 mg/m2  
Cycles 3-12: 56 mg/m2 
For subjects with baseline hepatic 
function abnormalities (bilirubin or AST 
> ULN), see Section 7.1.1.2.1 for 
modification of the initial dose. 
For cycle 3, for subjects who were 
previously dose reduced, see 
Section 7.1.1.2 for starting dose. 
With: 
KRd ARM 
Carfilzomib administrationh 
 
X 
X X X X X 
 
 
X 
X 
X 
 
 
Cycle 1: 20 mg/m2 on days 1 and 2; 
5627 mg/m2 on days 8, 9, 15, and 16  
Cycle 2: 27 mg/m2  
Cycles 3-12: 56 mg/m2 
For subjects with baseline hepatic 
function abnormalities (bilirubin or AST 
> ULN), see Section 7.1.1.2.1 for 
modification of the initial dose. 
For cycle 3, for subjects who were 
previously dose reduced, see 
Section 7.1.1.2 for starting dose. 
 
 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20170596 
Date:  20 May 2019 
Page 6 of 6 
CONFIDENTIAL 
 
 
Section:  7.1.1.2.1 Starting Dose in Hepatic Insufficiency 
Replace:   
For subjects with mild hepatic insufficiency during screening, the initial dose of 
carfilzomib on days 1 and 2 of cycle 1 should be reduced by 25% to 15 mg/m2.  For 
subjects in the Kd arm, starting on day 8 and for all subsequent doses of carfilzomib 
during cycles 1 and 2, the dose should be 42 mg/m2 (Brown et al, 2017); the dose in 
cycle 3 through 12 should be 52 mg/m2.   
With:   
For subjects with mild hepatic insufficiency during screening, the initial dose of 
carfilzomib on days 1 and 2 of cycle 1 should be reduced by 25% to 15 mg/m2.  For 
subjects in the Kd arm, starting on day 8 and for all subsequent doses of carfilzomib 
during cycles 1 and 2, the dose should be 42 mg/m2 (Brown et al, 2017); the dose in 
cycle 3 through 12 should be 5253 mg/m2.   
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20170596 
Date:  29 March 2019 
Page 1 of 53 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  An Open Label Phase 2 Study of Carfilzomib Combinations 
(Carfilzomib Plus Dexamethasone, Carfilzomib Plus Lenalidomide and 
Dexamethasone, and Carfilzomib Plus Pomalidomide and Dexamethasone), To 
Assess Tolerability and Adherence in Subjects With Relapsed or Refractory 
Multiple Myeloma at US Community Oncology Centers 
 
Amgen Protocol Number 20170596 
 
 
Amendment Date: 
29 March 2019 
Rationale: 
• 
With the results from the A.R.R.O.W. study, the Kd 70mg/m2 once weekly dosing 
schedule was approved in the US, providing the US practicing centers one more 
option to treat relapse or refractory multiple myeloma (RRMM) patients with more 
convenience.  In the light of A.R.R.O.W. approval, and based on the feedback 
from investigators, the protocol amendment increased the cycles of Kd once 
weekly dosing schedule while keeping the total treatment cycles.  The initial 
treatment with 2 cycles of twice weekly therapy is designed to provide the more 
familiar labelled treatment for subjects with RRMM. 
• 
Triplet therapy are emerging as standard of care for RRMM patients.  The 
ASPIRE study demonstrated the superiority of the combination of carfilzomib with 
lenalidomide and dexamethasone (KRd; 27 mg/m2 twice-weekly) over 
lenalidomide with dexamethasone.  However, despite the favorable benefit-risk 
profile of the KRd regimen, 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 ongoing Study CFZ013 
evaluates once-weekly KRd in patients with RRMM and newly diagnosed 
multiple myeloma.  Available efficacy results have shown similar efficacy to the 
effect previously reported for twice-weekly KRd (27 mg/m2) in the ASPIRE study 
(Biran et al, 2018).  Hence, to better reflect the clinical practice, and to 
investigate a more convenient KRd once weekly dosing schedule in the 
community setting, the protocol amendment is adding a KRd arm, starting with 
2 cycles of the approved twice weekly dosing schedule followed by 10 cycles of 
the investigational once weekly dosing schedule. 
• 
Pomalidomide and dexamethasone (Pd) has been approved for subjects with 
RRMM.  Several phase 2 studies have demonstrated improved efficacy of adding 
carfilzomib to Pd (KPd) in patients with RRMM compared to historical data for Pd 
with safety consistent with carfilzomibs known profile.  Based on the phase 2 
studies, the protocol amendment is adding a KPd arm and will further investigate 
the once weekly KPd dosing regimen.  Considering the safety data on KPd is 
limited compared to other Kyprolis containing regimens, a Data Review Team will 
be implemented to review the safety data. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20170596 
Date:  05 October 2018 
Page 1 of 23 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  An Open-label Phase 2 Study of Carfilzomib Plus Dexamethasone 
To Assess Tolerability and Adherence in Subjects With Relapsed or Refractory 
Multiple Myeloma at US Community Oncology Centers 
 
Amgen Protocol Number (Carfilzomib) 20170596 
Amendment Date: 
05 October 2018 
Rationale: 
This protocol is being amended to: 
 
Add clarifying language to the dose intensity parts of the primary and secondary 
endpoints and statistical analyses 
 
Update the wording of several eligibility criteria including measureable disease to 
align with the CANDOR study, and cardiac and graft versus host disease exclusion 
criteria 
Approved 
 
 


Product:  Carfilzomib
Protocol Number:  20170596
Date:  06 March 2018
Page 1 of 8
CONFIDENTIAL
Amendment 1
Protocol Title:  An Open label Phase 2 Study of Carfilzomib Plus Dexamethasone 
To Assess Tolerability and Adherence in Subjects With Relapsed or Refractory 
Multiple Myeloma at US Community Oncology Centers
Amgen Protocol Number Carfilzomib 20170596
Amendment Date:  06 March 2018
Rationale:
This protocol is being amended for the following reasons:

Update the study phase from phase 4 to phase 2 as determined by Amgen Clinical 
Study Team in alignment with definition of a phase 2 study.

Provide additional rationale for once weekly dosing in response to request from US 
Central IRB.

Update the protocol to remove biospecimen destruction language in order to 
maintain consistency in the protocol as no samples are collected. 

Update sample size justification to state that study is descriptive to address request 
from US Central IRB. 

Remove references to legally authorized representatives in order to maintain 
consistency in the protocol and address US Central IRB concerns. 

Update schedule of activities and analyte table by addition of a screening urinalysis 
to support exclusion criteria requiring albumin/creatinine ratio.

Update schedule of activities by addition of myeloma response assessment and 
footnote to maintain consistency with the protocol.

Update study assessments and procedures section with additional instruction for 
echocardiogram data to align with data required to confirm eligibility.

Update instructions for the subject satisfaction and convenience questionnaire to 
clarify when the end of treatment items are completed.

Make minor corrections and clarifications throughout the document, including 
administrative, typographical, and formatting errors.
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20170596 
Date:  26 January 2018 
Page 1 of 1 
CONFIDENTIAL 
 
Superseding Original Protocol 
Protocol Title:  An Open Label Phase 4 Study of Carfilzomib Plus Dexamethasone 
To Assess Tolerability and Adherence in Subjects With Relapsed or Refractory 
Multiple Myeloma at US Community Oncology Centers 
 
Amgen Protocol Number Carfilzomib 20170596  
 
 
Superseding Original Protocol Date: 
26 January 2018 
Rationale: 
A formatting mistake was identified in the original protocol: in Table 2-1 (Schedule of 
Activities): the header row was missing from the second and third pages of the table.  In 
the superseding version, this formatting mistake was fixed.   
Approved 
 
 

SAP_001.pdf: 
Product:  Carfilzomib  
Protocol Number:  20170596 
Date:  08 June 2018 
Page 1 of 27 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
An Open-label Phase 2 Study of Carfilzomib Plus 
Dexamethasone to Assess Tolerability and 
Adherence in Subjects with Relapsed or Refractory 
Multiple Myeloma at US Community Oncology 
Centers 
Short Protocol Title: 
A Study of Carfilzomib Plus Dexamethasone in 
Subjects with Relapsed or Refractory Multiple 
Myeloma at US Community Oncology Centers 
Protocol Number: 
20170596 
NCT Number: 
Not available for the first version. 
Authors: 
,  
Biostatistician,  
PAREXEL International. 
,  
Biostatistics Manager,  
GBS, Center for Design and Analysis, Amgen Inc. 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive, Thousand Oaks, CA 
91320, United States 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
08 June 2018 
NCT Number: NCT03512353
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


Product:  Carfilzomib  
Protocol Number:  20170596 
Date:  08 June 2018 
Page 2 of 27 
CONFIDENTIAL 
Table of Contents 
Table of Contents ................................................................................................... 2 
1.
Introduction ............................................................................................................. 6
2.
Objectives, Endpoints and Hypotheses ................................................................... 6 
2.1 
Objectives and Endpoints ............................................................................ 6 
2.2 
Hypotheses and/or Estimations ................................................................... 7 
3.
Study Overview ...................................................................................................... 7 
3.1 
Study Design ............................................................................................... 7 
3.2 
Sample Size ................................................................................................ 8 
3.3 
Adaptive Design .......................................................................................... 8 
4.
Covariates and Subgroups ..................................................................................... 8 
4.1 
Planned Covariates ..................................................................................... 8 
4.2 
Subgroups ................................................................................................... 8 
5.
Definitions ............................................................................................................... 9
6.
Analysis Sets ........................................................................................................ 13 
6.1 
Full Analysis Set........................................................................................ 13 
6.2 
Safety Analysis Set ................................................................................... 13 
6.3 
Interim Analyses Set(s) ............................................................................. 14 
7.
Planned Analyses ................................................................................................. 14 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 14 
7.2 
Primary Analysis ....................................................................................... 14 
7.3 
Final Analysis ............................................................................................ 14 
8.
Data Screening and Acceptance ........................................................................... 14 
8.1 
General Principles ..................................................................................... 14 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 14 
8.3 
Handling of Missing and Incomplete Data ................................................. 14 
8.4 
Detection of Bias ....................................................................................... 14 
8.5 
Outliers ..................................................................................................... 14 
8.6 
Distributional Characteristics ..................................................................... 15 
8.7 
Validation of Statistical Analyses ............................................................... 15 
9.
Statistical Methods of Analysis.............................................................................. 15 
9.1 
General Considerations ............................................................................. 15 
9.2 
Subject Accountability ............................................................................... 15 
9.3 
Important Protocol Deviations ................................................................... 16 
9.4 
Demographic and Baseline Characteristics ............................................... 16 
9.5 
Efficacy Analyses ...................................................................................... 17 


Product:  Carfilzomib  
Protocol Number:  20170596 
Date:  08 June 2018 
Page 3 of 27 
CONFIDENTIAL 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 17 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 17 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 18 
9.6 
Safety Analyses ........................................................................................ 18 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 18 
9.6.2 
Analyses of Secondary Safety Endpoint(s) ................................ 18 
9.6.3 
Adverse Events and Disease-related Events ............................. 19 
9.6.4 
Laboratory Test Results ............................................................ 19 
9.6.5 
Vital Signs ................................................................................. 20 
9.6.6 
Physical Measurements ............................................................ 20 
9.6.7 
Electrocardiogram ..................................................................... 20 
9.6.8 
Exposure to Investigational Product .......................................... 20 
9.6.9 
Exposure to Other Protocol-Specified Treatment ....................... 20 
9.6.10 
Exposure to Concomitant Medication ........................................ 20 
9.6.11 
Other Analyses .......................................................................... 21 
10.
Changes from Protocol-specified Analyses ........................................................... 21 
11.
Literature Citations / References ........................................................................... 22 
12.
Appendices ........................................................................................................... 23
Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs ........................................................ 24 
Appendix B.  Reference Values/Toxicity Grades ................................................... 26 
Appendix C.  Concomitant Medications ................................................................ 27 
List of Tables 
Table 5-1 Conventions for Censoring for PD dates ........................................................ 13 


Product:  Carfilzomib  
Protocol Number:  20170596 
Date:  08 June 2018 
Page 4 of 27 
CONFIDENTIAL 
List of Abbreviations and Definition of Terms 
Term or Abbreviation 
Description 
ACE 
Angiotensin-Converting Enzyme 
AE(s) 
Adverse Event(s) 
BNP 
Brain Natriuretic Peptide 
BSA 
Body Surface Area 
CDM 
Clinical Data Management 
CI 
Confidence Interval 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organization for Research and Treatment of Cancer 
EuroQOL 
European Quality of Life 
EQ-5D-5L 
European Quality of Life-5 Dimensions 
EOI 
Event of Interest 
EOT 
End of Treatment 
GFR 
Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
GSO-DM 
Global Study Operations-Data Management 
HRQoL 
Health-related quality-of-life 
IMWG-URC 
International Myeloma Working Group-Uniform Response Criteria 
IP 
Investigational Product 
IPD 
Important Protocol Deviation 
ISS 
International Staging System 
IXRS 
Interactive Voice/Web Response System 
Kd 
Carfilzomib and Dexamethasone 
Kd56 
Kd 56 mg/m2 twice weekly 
Kd70 
Kd 70 mg/m2 once weekly 
KM 
Kaplan-Meier 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 


Product:  Carfilzomib  
Protocol Number:  20170596 
Date:  08 June 2018 
Page 5 of 27 
CONFIDENTIAL  
 
 
Term or Abbreviation 
Description 
MR 
Minimal Response 
MRI 
Magnetic Resonance Imaging 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NE 
Not Evaluable 
NT-ProBNP 
N Terminal of the Prohormone Brain Natriuretic Peptide 
NYHA 
New York Heart Association 
ORR  
Overall Response Rate 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS  
Progression-free Survival 
PO 
Orally 
PR 
Partial Response 
QLQ-C30 
Quality of Life Core Module 
QLQ MY20 
Quality of Life Multiple Myeloma Module 20 
QTc 
corrected QT-interval 
RDI 
Relative Dose Intensity 
RRMM 
Relapsed or Refractory Multiple Myeloma 
SAE(s) 
Serious Adverse Event(s) 
SAP 
Statistical Analysis Plan 
sCR 
Stringent Complete Response 
SD 
Stable Disease 
SFLC 
Serum Free Light Chain 
SMQ 
Standardized MedDRA Queries 
VGPR 
Very Good Partial Response 
VQ Scan 
Pulmonary Ventilation/Perfusion Scan 
WHO DRUG 
World Health Organization Drug dictionary 


Product:  Carfilzomib  
Protocol Number:  20170596 
Date:  08 June 2018 
Page 6 of 27 
CONFIDENTIAL  
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20170596, AMG 981 
dated 06 Mar 2018. The scope of this plan includes the final analysis that is 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 
Describe tolerability and treatment safety 
of a Kd regimen (Kd 56 mg/m2 [Kd56] 
twice weekly for cycles 1-6 followed by 
Kd 70 mg/m2 [Kd70] once weekly for 
cycles 7-12) in subjects with relapsed or 
refractory multiple myeloma with 1-3 prior 
lines of therapy at study entry. 
• 
Proportion of subjects completing 
12 cycles of treatment 
• 
Dose intensity defined as total actual 
dose divided by planned dose 
through cycle 12 or up to disease 
progression 
• 
Treatment-emergent adverse events 
and serious adverse events 
Secondary 
Describe treatment adherence by the Kd 
regimen (Kd56 twice weekly and Kd70 
once weekly). 
• 
Dose intensity in cycles 1-6 and 
cycles 7-12 defined as total actual 
dose divided by planned dose 
through cycle 6 or 12 or up to 
disease progression 
• 
Dose reductions in cycles 1-6 and 
cycles 7-12 
•  Treatment discontinuation for all 
reasons in cycles 1-6 and cycles 7-12 
Assess subject health-related 
quality-of-life (HRQoL) with Kd56 twice 
weekly and Kd70 once weekly. 
• 
European Organization for Research 
and Treatment of Cancer 
Quality-of-life Questionnaire (EORTC 
QLQ) Core 30 (C30) and EORTC 
QLQ Multiple Myeloma Module 
(MY20) scores through cycle 12 or up 
to disease progression  
• 
EORTC QLQ-C30 and EORTC 
QLQ-MY20 scores for cycles 1-6 and 
cycles 7-12 in subjects completing 
12 cycles of treatment  


Product:  Carfilzomib  
Protocol Number:  20170596 
Date:  08 June 2018 
Page 7 of 27 
CONFIDENTIAL  
 
 
Objectives 
Endpoints 
Assess response to the Kd regimen. 
• 
Response rate (minimal response 
[MR], partial response [PR], very 
good partial response [VGPR], 
complete response [CR], and 
stringent complete response [sCR]). 
• 
Landmark response rate (MR, PR, 
VGPR, CR and sCR) after 6 and 
12 cycles.  
• 
Progression-free survival (PFS) at 
1 year 
• 
Response rate and PFS by line of 
prior therapy 1 vs ≥ 2 
 
Exploratory 
2.2 
Hypotheses and/or Estimations 
Carfilzomib plus dexamethasone twice weekly followed by carfilzomib plus 
dexamethasone once weekly is tolerable in subjects with RRMM in a community-based 
setting. 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 2, multicenter, open-label study in subjects with RRMM in US community 
oncology centers.  Subjects with 1-3 prior lines of therapy at study entry are eligible to be 
screened for participation.  Subjects refractory to their last line of treatment are eligible to 
participate as long as their last line of treatment did not include an IP.  The study will 
consist of a screening period of up to 28 days, up to 12 cycles of treatment, and a 
30-day safety follow-up period following the last dose of study drug.   
During the treatment period, all subjects will be treated with Kd 20/56 mg/m2 twice 
weekly for up to six 28-day cycles followed by up to Kd 70 mg/m2 once weekly for 
another six 28-day cycles.  After discontinuation of study drugs, subjects will be followed 
for 30 days for adverse events.   


Product:  Carfilzomib  
Protocol Number:  20170596 
Date:  08 June 2018 
Page 8 of 27 
CONFIDENTIAL  
 
 
3.2 
Sample Size 
The study is descriptive in nature. Approximately 75 subjects will be enrolled in the 
study.  A sample size of 75 will provide an estimate for the percent of subjects 
completing 12 cycles of Kd treatment with an expected precision (half-width of the 
95% CI) of 11.3%, assuming an expected proportion of 50%.  The expected precision 
will be 9.8% for an expected proportion of 75%. 
3.3 
Adaptive Design 
Not applicable. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Not applicable. 
4.2 
Subgroups 
Proportion of subjects completing 12 cycles of treatment, proportion of subjects 
completing 6 cycles of treatment, relative dose intensity, causes of discontinuation, 
overall response rate, greater than or equal to grade 3 non-hematology AEs, 
cardiovascular AEs by Standardized MedDRA Queries (SMQ) narrow term will be 
examined in subgroups. If the numbers of subjects in certain category of subgroups are 
less than 10% of total sample size, relevant subgroups may be rationally combined or 
subgroup analysis may not be carried forward. 
Proportion of subjects completing 12 cycles of treatment, proportion of subjects 
completing 6 cycles of treatment, relative dose intensity and causes of discontinuation 
will be analyzed in the following subgroup: 
• 
commute distance to treatment center: 0-10, 11-25, > 25 miles 
Overall response rate, greater than or equal to grade 3 non-hematology AEs, 
cardiovascular AEs by SMQ narrow search will be analyzed in the following subgroup:   
• 
hypertension history (include use of anti-hypertensive medications) (yes, no) 
• 
history of ischemic heart disease (myocardial infarction or coronary artery 
disease), congestive heart failure (NYHA class ≤ 2), stroke, or history of 
peripheral vascular disease (yes, no) 
• 
family history of coronary artery disease in first degree relatives with onset 
< 65 years of age for female relative or < 55 years of age for male relative 
(yes, no) 
• 
smoking history (yes, no)  
• 
history of hyperlipidemia (yes, no) 


Product:  Carfilzomib  
Protocol Number:  20170596 
Date:  08 June 2018 
Page 9 of 27 
CONFIDENTIAL  
 
 
• 
history of diabetes (yes, no) 
• 
revised international staging system stage (stage 1 vs stage 2 vs stage 3 vs 
unknown)  
• 
progressive disease on lenalidomide during or within 60 days of treatment 
(yes, no) 
5. 
Definitions 
Study Treatment 
Study treatment of this study includes carfilzomib and dexamethasone. 
First Dose Date 
The first dose date is the date on which a subject is administered the first dose of any 
study treatment. 
Last Dose Date 
The last dose date is the date on which a subject is administered the last dose of any 
study treatment.   
End of Study Date for a Subject 
The end of study date is the date recorded on the End of Study page for an enrolled 
subject. 
Baseline  
When analyzing progression-free survival time (PFS), baseline will be defined as the day 
of enrollment. When analyzing all other analysis endpoints for subjects who received 
study treatment, baseline is the closest recorded measurement prior to the first dose of 
any study treatment. If a subject doesn't receive any study treatment, baseline is defined 
as the latest measurement on or prior to enrollment date. If multiple valid records are 
observed at the same date and time, the average of these values will be used.  
Study Day 1  
The first day of study treatment administration or the enrollment date for subjects who 
are not administered any dose of study treatment.  
Study Day 
The number of days from the study day 1 to a date of interest, inclusive:  
Study day n = (date of interest – date of study day 1) + 1. 


Product:  Carfilzomib  
Protocol Number:  20170596 
Date:  08 June 2018 
Page 10 of 27 
CONFIDENTIAL  
 
 
Unless otherwise specified, the timing of all study-related events, assessments, and 
interventions will be calculated relative to study day 1.  Study day −1 will be the day 
before study day 1, and in general for assessments prior to study day 1, study day is 
defined as: 
Study Day n = (date of interest – date of Study day 1) 
Relative Dose Intensity (%) 
Relative Dose Intensity (%) of carfilzomib/dexamethasone is defined as  
Relative Dose Intensity =  100 x Actual Dose Intensity
Intended Dose Intensity 
Actual dose intensity is the actual cumulative dose (mg/m2 for carfilzomib, mg for 
dexamethasone) divided by the duration of exposure (week). Intended dose intensity is 
the planned cumulative dose (mg/m2 for carfilzomib, mg for dexamethasone) divided by 
the protocol specified treatment duration (week). Specifically,  
• 
Actual cumulative dose is the sum of actual doses that a subject received. For 
carfilzomib, it is the sum of received doses (mg) divided by baseline BSA (m2). If 
BSA is > 2.2 m2, then 2.2 will be used in the calculation. For dexamethasone, it is 
the sum of received doses (mg). 
• 
Duration of exposure (week) is calculated as (Last Dose Date – First Dose Date 
+ Interval (days) to next planned treatment) / 7. Depending on the cycle and day 
of the last infusion, Interval (days) to next planned treatment is specified in 
following table: 
Last Cycle 
Cycle Day of the Last 
Administration 
Interval (days) to Next 
Planned Carfilzomib 
Administration  
Interval (days) to Next 
Planned 
Dexamethasone 
Administration 
1 - 6 
Day 1 or Day 8 
7 
7 
 
Day 2 or Day 9 
6 
6 
 
Day 15 
14 
7 
 
Day 16 
13 
6 
 
Day 22 
- 
7 
 
Day 23 
- 
6 
7-12 
Day 1 or Day 8 
7 
7 
 
Day 15 
14 
14 


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• 
Planned cumulative dose (mg/m2 for carfilzomib, mg for dexamethasone) is the 
sum of protocol specified doses of the subject. Protocol specified doses are 
summarized in following table: 
Cycle  
Cycle Day 
Carfilzomib 
Dose (mg/m2)  
Dexamethasone 
Dose (mg) 
1 
1, 2 
20 
20 
1 
8, 9, 15, 16 
56 
20 
1 
22, 23 
- 
20 
2 – 6 
1, 2, 8, 9, 15, 16 
56 
20 
2 – 6 
22, 23 
- 
20 
7 – 12 
1, 8, 15 
70 
40 
• 
Number of protocol specified treatment weeks is calculated as 4 x number of 
completed cycles + the number of weeks in the last cycle according to following 
table. 
Last Cycle Day of the 
last Infusion 
Number of weeks for carfilzomib 
Number of weeks for 
dexamethasone 
Day 1 or Day 2 
1 
1 
Day 8 or Day 9 
2 
2 
Day 15 or Day 16 
4 
3 
Day 22 or Day 23 
- 
4 
Dose Reduction 
The occurrence that actual dose a patient received in one treatment administration is 
less than the protocol specified dose. 
Best Overall Response 
Response category will be assessed by investigator according to International Myeloma 
Working Group Uniform Response Criteria (IMWG-URC) per standard procedure. Best 
overall response will be derived for multiple myeloma disease assessments based on the 
International Myeloma Working Group Uniform Response Criteria (IMWG-URC). Best 
overall response will be decided in the following order of confirmed responses: stringent 
complete response (sCR), complete response (CR), very good partial response (VGPR), 
partial response (PR), MR, SD, PD starting from the best to the worst. Determine stable 
disease (SD) as best overall response requires a duration of at least 6 weeks. If a 
subject’s best overall response is none of above, the patient’s best overall response is 
not evaluable (NE).  
Overall Response Rate 
Overall response rate is the proportion of subjects whose best overall response is sCR, 
CR, VGPR, or PR. 


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Progression-free survival (PFS) 
 
PFS is defined as the time (months) from First Dose Date until the earliest date of 
disease progression or death due to any cause, whichever occurs first. 
PFS = (PD / death date – first dose date +1)/30.4 
Progression-free survival will be right-censored for subjects who met one of the following 
conditions: 1) no baseline disease assessments, 2) non-protocol anti-myeloma therapy 
started before documentation of disease progression or death, 3) death or disease 
progression immediately after more than 1 consecutively missed disease assessment 
visit, or 4) alive and does not have documentation of disease progression before a data 
analysis cutoff date. These conventions are based on the May 2007 FDA Guidance for 
Industry, ‘Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics’ 
(https://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf), The censoring 
rules for the primary analysis of PFS are described in Table 5-1. Additionally, if the last 
disease assessment date is after the date that triggers the analysis, the subject will be 
censored at the analysis trigger date. 


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Table 5-1 Conventions for Censoring for PD dates 
Situation 
Date of Progression or 
Censoring 
Outcome 
No baseline disease assessments Date of first dose 
Censored 
New anti-myeloma therapy started 
before documentation of PD 
or death 
Date of last disease assessment 
prior to start of new 
anti-myeloma therapy 
Censored 
Death or PD immediately after 
more than 1 consecutively 
missed disease assessment visit 
Date of last disease assessment 
visit without documentation of PD 
that is before the first missed visit 
Censored 
Alive and without PD 
documentation (including lost to 
follow-up without PD) 
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 disease 
assessment 
Date of death 
Progressed 
Treatment-emergent Adverse Event  
AEs starting on or after first dose of investigational product as indicated by field "Did 
event start before first dose of investigational product?" in Events page and up to 
30 days, inclusive, after the last dose of study treatment.  
6. 
Analysis Sets 
6.1 
Full Analysis Set 
The full analysis set will include all enrolled subjects who received at least 1 dose of any 
study treatment (ie, carfilzomib or dexamethasone). 
6.2 
Safety Analysis Set 
The safety analysis set is the same as full analysis set. 


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6.3 
Interim Analyses Set(s) 
Not Applicable. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Not Applicable. 
7.2 
Primary Analysis 
Not Applicable. 
7.3 
Final Analysis 
The final analysis will occur after all subjects have completed therapy, disease 
assessment and safety follow-up. 
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. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
8.3 
Handling of Missing and Incomplete Data 
The 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 
and concomitant medications are described in Appendix A. 
8.4 
Detection of Bias 
Not Applicable. 
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. 


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8.6 
Distributional Characteristics 
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.   
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 
In general, safety analysis set will be utilized to generate summary statistics for different 
dosing regimen, including Kyprolis in combination with dexamethasone (Kd) 56 mg/m2 
[Kd56] twice weekly and Kd 70 mg/m2 [Kd70] weekly. 
Continuous variables will be summarized by the non-missing sample size (n), mean, 
standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by the n and percentage in each category. Time to event endpoints will be 
summarized with Kaplan-Meier (KM) curves (Kaplan and Meier, 1958), KM proportions 
at select time points, KM quartiles (when estimable), the number of subjects with events, 
the number of subjects censored, and censoring reasons. Point estimates for efficacy 
endpoints will be accompanied by 2-sided 95% confidence intervals including estimates 
of KM quartiles (Klein and Moeschberger, 1997), KM proportions (Kalbfleisch and 
Prentice, 1980), and binomial proportions (Clopper CJ and Pearson, 1934). 
9.2 
Subject Accountability 
The number and percent of subjects who were screened, enrolled, and received study 
treatment will be summarized. The number and percent of subjects who discontinued 
study treatment and study will also be tabulated, along with the reason for 


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discontinuation. Key study dates for the first subject enrolled, last subject enrolled, and 
data cut-off date for analysis will be presented. 
9.3 
 Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. 
9.4 
Demographic and Baseline Characteristics 
Descriptive statistics for demographic and baseline characteristics will be summarized. 
Baseline demographics and characteristics:  
• 
age (as categorical variable: 18 to < 65, 65 to 75, and > 75 years)  
• 
sex (male, female)  
• 
race (white and other categories depending on frequency observed)  
• 
commute distance to treatment center: 0-10, 11-25, > 25 miles 
Baseline organ function and comorbid conditions:  
• 
ECOG performance status (0 or 1)  
• 
estimated GFR (< 50 vs ≥ 50 mL/min/1.73 m2)  
• 
hypertension history (include use of anti-hypertensive medications) (yes, no) 
• 
history of ischemic heart disease (myocardial infarction or coronary artery disease), 
congestive heart failure (NYHA class ≤ 2), stroke, or history of peripheral vascular 
disease (yes, no) 
• 
family history of coronary artery disease in first degree relatives with onset 
< 65 years of age for female relative or < 55 years of age for male relative (yes, no) 
• 
smoking history (yes, no)  
• 
history of hyperlipidemia (yes, no) 
• 
history of diabetes (yes, no) 
• 
history or chronic mild hepatic impairment (yes, no) 
Baseline disease characteristics:  
• 
revised international staging system stage (stage 1 vs stage 2 vs stage 3 vs 
unknown)  
• 
determination of measurable disease at baseline (based on serum or urine 
M-protein, based on SFLC only)  
• 
β2-microglobulin level (< 2.5, ≥ 2.5 and < 5.5, ≥ 5.5 mg/L)  


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• 
presence of soft tissue plasmacytoma (yes, no) 
• 
progressive disease on lenalidomide during or within 60 days of treatment (yes, no) 
• 
progressive disease on lenalidomide in combination with dexamethasone during or 
within 60 days of treatment (yes/no) 
9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
Not applicable. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
European Organization for Research and Treatment of Cancer Quality of life 
Questionnaire (EORTC QLQ) Core 30 (C30) and EORTC QLQ Multiple Myeloma 
Module (MY20) scores will be administered and collected prior to study treatment on 
Day 1 of each cycle. Actual values and changes from baseline of QLQ-C30 and 
QLQ-MY20 scores will be summarized for each cycle with non-missing sample size (n), 
mean, standard deviation, median, minimum, and maximum. The summary statistics will 
be tabulated separately for following groups: subjects who ended treatment due to 
disease progression before the end of Cycle 6, subjects who ended treatment due to 
disease progression after the end of Cycle 6 but before the end of Cycle 12, subjects 
who have completed all 12 cycles, subjects who ended treatment with reasons other 
than “Disease progression” before the end of Cycle 12. For subjects who have 
completed all 12 cycles of treatment, the overall QLQ-C30 and QLQ-MY20 scores will be 
summarized by Cycle 1-6 versus Cycle 7-12. 
Best overall response rates (minimal response [MR], partial response [PR], very good 
partial response [VGPR], complete response [CR], and stringent complete response 
[sCR]) will be summarized descriptively at the end of study, end of Cycle 6 and end of 
Cycle 12 respectively. Overall response rate will also be summarized descriptively with 
95 % CI estimated using the Clopper-Pearson method at the end of study, end of Cycle 
6 and end of Cycle 12 respectively. The rate of PFS at 1 year will be estimated using the 
Kaplan-Meier method and with 95% CI estimated by Greenwood’s formula (Kalbfleisch 
and Prentice, 1980) with log-log transformation and will be summarized by number of 
prior lines (1 vs ≥2).  Similarly, the best overall response and overall response rate will 
also be summarized by number of prior lines (1 vs ≥2).  
All secondary efficacy endpoints will be based on full analysis set. 


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9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
The proportion of subjects completing 12 cycles of Kd treatment will be calculated and 
the associated 95% CI will be estimated using the Clopper-Pearson method. Per 
protocol, dose intensity is defined as total actual dose divided by planned dose through 
cycle 12 or up to disease progression. In this SAP, duration of exposure/protocol 
specified treatment weeks will be taken into consideration when summarizing dose 
intensity data. Specifically, relative dose intensity as defined in section 5, number of 
cycles received, duration of treatment, number of administrations and actual cumulative 
dose will be summarized descriptively for Cycle 1-12 and tabulated separately, with the 
same four groups as described in section 9.5.2.  
Number and proportion of subjects who had dose modifications (dose reductions, 
missed dose, etc), and reasons of dose modifications will be summarized for Cycle 1-12, 
tabulated by the same four groups as described in section 9.5.2. In addition, summary 
statistics of the difference between protocol specified dose and actual dose received will 
be provided and tabulated by reasons. 
Treatment-emergent adverse events and serious adverse events will be summarized 
descriptively following methods specified in section 9.6.3. The profile plot for each 
subject, which includes both actual dose received and treatment-emergent adverse 
events and serious adverse events during the study will be provided. All analyses of 
primary safety endpoints will be based on the safety analysis set.  
9.6.2 
Analyses of Secondary Safety Endpoint(s) 
Relative dose intensity, number of cycles received, duration of treatment, number of 
administrations and actual cumulative dose in Cycle 1-6 and Cycle 7-12 will be 
summarized respectively, with the same four groups as described in section 9.5.2. 
Number and proportion of subjects who had dose modifications, and reasons of dose 
modifications will be summarized for Cycle 1-6, and Cycle 7-12 respectively. In addition, 
treatment discontinuation along with reasons will be summarized descriptively for 
Cycle 1-6 and Cycle 7-12. Summary statistics of the difference between protocol 
specified dose and actual dose received will be provided and tabulated by reasons for 


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Cycle 1-6 and Cycle 7-12 respectively. All analyses of secondary safety endpoints will 
be based on the safety analysis set.  
9.6.3 
Adverse Events and Disease-related Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 21.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. 
Treatment-emergent adverse events are events starting on or after first dose of 
investigational product and up to 30 days, inclusive, after the last dose of study 
treatment.  
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, serious adverse events, and adverse events leading to dose 
modifications, withdrawal of investigational product, fatal adverse events, and adverse 
events of interest when defined.  
Subject incidence of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to dose modifications, withdrawal of investigational product, and 
fatal adverse events will be tabulated by system organ class and preferred term in 
alphabetical order.   
Subject incidence of events of interest (standardized MedDRA queries and/or Amgen 
customized queries) will also be summarized according to their categories and preferred 
term. 
In addition, summaries of treatment-emergent and serious adverse events occurring in 
at least 5% of the subjects by preferred term in any treatment arm will be provided in 
descending order of frequency.   
Summaries of treatment-emergent and serious adverse events will be tabulated by 
system organ class, preferred term, and grade. 
9.6.4 
Laboratory Test Results 
For hematology, chemistry, and other laboratory values, descriptive statistics for the 
actual value at each visit and the change from baseline at each post-baseline visit during 
the study period will be summarized. Subjects with missing data for baseline and/or a 
scheduled visit will not contribute to the summary table which summarizes the change 
from baseline to that scheduled visit. Numeric values of each laboratory parameter will 


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be converted to grades according to NCI CTCAE (v4.03) and grade shit from baseline 
will be summarized.    
9.6.5 
Vital Signs 
The analyses of vital signs, including systolic/diastolic blood pressure, heart rate, 
respiratory rate and temperature, will be summarized descriptively by scheduled time 
point for actual value and change from baseline.   
9.6.6 
Physical Measurements 
Any clinically significant abnormal values noted on the physical examination will be 
reported by the investigator as AEs.  No summary of the physical examination data will 
be provided. 
9.6.7 
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 QT interval corrected (QTc) effect.  Because these evaluations 
may not necessarily be performed under the rigorous conditions expected to lead to 
meaningful evaluation of QTc data; neither summaries nor statistical analyses will be 
provided, and these data would not be expected to be useful for meta-analysis with data 
from other trials.  
9.6.8 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to carfilzomib as 
described in section 9.6.1 and 9.6.2.  
9.6.9 
Exposure to Other Protocol-Specified Treatment 
Descriptive statistics will be produced to describe the exposure to non-Amgen 
non-investigational products (dexamethasone). The number of cycles received, duration 
of treatment, number of administrations, cumulative dose, number and proportion of 
subjects with dose modifications, reasons for modification will be summarized 
descriptively. 
9.6.10 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving therapies of interest will be 
summarized by preferred term or category by dosing regimen period and overall as 


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coded by the World Health Organization Drug (WHO DRUG) dictionary.  See Appendix 
Appendix C for a list of selected medications and their groupings.  
9.6.11 
Other Analyses 
Cardiovascular events may be summarized by risk group defined by ABC score 
(Bulter 2008).The information of cardiovascular reasons for screen failure will be 
captured for exclusion criteria from the IXRS system. If warranted by the completeness 
of information, the proportion of failure reasons may be summarized.  
The use of the dyspnea guidance instructions may be summarized by correlating the 
dates of reporting of dyspnea adverse events with dates of collection of brain natriuretic 
peptide (BNP) or N terminal of the prohormone brain natriuretic peptide BNP 
(NT-ProBNP), serum creatinine, echocardiograms, and evaluations for infection or 
pulmonary disorders as detailed in protocol Section 12.9. The proportion of subjects in 
whom dyspnea is reported as an adverse event and undergo each evaluation and the 
results of these evaluations may be summarized descriptively. 
10. 
Changes from Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 


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11. 
Literature Citations / References 
BladÉ, J., et al. (1998). Criteria for Evaluating Disease Response and Progression in 
Patients with Multiple Myeloma Treated by High-dose Therapy and Haemopoietic Stem 
Cell Transplantation. British Journal of Haematology 102(5): 1115-1123. 
Butler J, Kalogeropoulos A, et al. (2008). Incident Heart Failure Prediction in the Elderly: 
The Health ABC Heart Failure Score. Circ Heart Fail. 1 (2): 125-133. 
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial.  Biometrica.  1934(26):404-413. 
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. 
Kalbfleisch JD, Prentice RL.  The Statistical Analysis of Failure Time Data, New York: 
John Wiley & Sons, 1980. 
Kaplan, E. L.; Meier, P. (1958). Nonparametric Estimation from Incomplete 
Observations. J. Amer. Statist. Assn. 53 (282): 457–481. JSTOR 2281868 
Klein JP, Moeschbeger ML.  Survival Analysis:  Techniques for Censored and Truncated 
Data, New York:  Springer-Verlag, 1997. 
Kyle, R. A. and S. V. Rajkumar (2009). Criteria for Diagnosis, Staging, Risk Stratification 
and Response Assessment of Multiple Myeloma." Leukemia: Official Journal of the 
Leukemia Society of America, Leukemia Research Fund, U.K 23(1): 3-9.  
Rajkumar SV, et al. Consensus Recommendations for the Uniform Reporting of Clinical 
Trials: Report of the International Myeloma Workshop Consensus Panel 1. Blood 
117:4691-4695.2011 
Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple 
myeloma. Lancet Oncol. 2016;17(8):328-346. 


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12. 
Appendices 


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Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs 
The handing of incomplete and partial dates for adverse events and concomitant 
medications are described below: 
Imputation rules for partial or missing AE start dates: 
1) If AE start date is partial with missing day, but year and month are the same as the 
first dose date, then impute it with the first dose date. 
2) If AE start date is partial with missing day, and year or month is not the same as the 
first dose date, then impute it with day 1 of the month. 
3) If AE start date is partial with missing month and day, but year is the same as the 
first dose date, then impute it with the first dose date. 
4)   If AE start date is partial with missing month and day, and year is not the same as 
the first dose date, then impute it with January 1st of the year.  
 
5)   If AE start date is completely missing, then impute it with the first dose date. 
Note: Imputation rules for partial or missing concomitant medication start date will be 
utilizing above algorithm by replacing “AE start date” with “Concomitant medication start 
date”.  
Imputation Rules for Incomplete/Missing Death Dates: 
• 
If death year and month are available but day is missing: 
 
• 
If mmyyyy for last contact date = mmyyyy for death date, set death date 
to the day after the last contact date. 
• 
If mmyyyy for last contact date < mmyyyy for death date, set death date 
to the first day of the death month. 
• 
If mmyyyy for last contact date > mmyyyy for death date, data error 
and do not impute. 
• 
If both month and day are missing for death date or a death date is totally 
missing, do not impute. 
Imputation Rules for date of initial diagnosis: 
• If the day is missing and month and year < month and year of enrollment then 
impute 15 for the day. 


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• Else if the day is missing and month and year = month and year of enrollment 
then impute day with 15 unless the day of enrollment is < 15 then impute date of 
enrollment.  
• If the day and month are missing and year = year of enrollment then impute July 
1st. 
• Else if the day and month are missing and year = year of enrollment then impute 
July 1st unless the day of enrollment is < July 1st then impute January 1st. 


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Appendix B.  Reference Values/Toxicity Grades 
Laboratory Values 
Safety laboratory values below a distinct limit (eg. detection limit, documented as 
“< [limit]”) will be substituted by half of the limit and values above a distinct limit 
(documented as “> [limit]”) will be substituted by the limit itself for all analyses. A Grade 
will be assigned to each laboratory based on CTCAE version 4.0 [v4.03: June 14, 2010]. 
Depending on the toxicity definition, the same result may be assigned to two grading for 
deviations towards higher or lower values. Values not meeting any of the criteria will be 
assigned a grade 0. 


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Appendix C.  Concomitant Medications 
The following therapies of interest will be summarized. The list may be updated upon 
clinical discretion.   
 
Anti-hypertensives; 
Angiotensin-Converting Enzyme (ACE); 
Calcium Chanel Blockers; 
Cardiac Enzymes; 
Diuretics;  
Other cardiac medications for pulmonary hypertension: treprostinil, iloprost, bosentan, 
macitentan, ambrisentan, sildenafil, tadalafil, adempas;  
Anticoagulants: aspirin, warfarin, low molectular weight heparin, other platelet inhibitors 
such as plavix.   
 
Procedures including dialysis, CT’s, MRI’s, PET scans, VQ scans, pulmonary function 
tests, lung biopsy, cardiac procedures ECHO, heart catheterization, stress tests.