Clinical trial NCT03934684
Conditions: Relapsed Refractory Multiple Myeloma
Sponsor: Amgen
Start date: 2019-09-16; Completion date: 2025-06-27
Enrollment: 101 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To characterize safety associated with the use of Kyprolis under the locally approved label.

Detailed description:
Kyprolis® (K; carfilzomib) was approved in India on 17 January 2017 as a prescription medication in combination with dexamethasone (Kd) or with lenalidomide (Revlimid®) plus dexamethasone (KRd) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) following 1 to 3 prior lines of therapy.

This non-comparative, interventional phase 4 study is designed to fulfil the post-marketing requirement to assess safety, tolerability, and efficacy of Kyprolis on Indian subjects with RRMM as per the locally approved label.

Arms: arm 1: Drug: Carfilzomib + Dexamethasone

* Carfilzomib 20 mg/m2 on days 1 and 2, and if tolerated, escalated to a target dose of 56 mg/m2 starting on day 8 of cycle 1 and thereafter.
* Dexamethasone 20 mg taken by mouth or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. An individual subject will receive study treatment for a maximum of 3 years if the subject has not yet experienced disease progression arm 2: Drug: Carfilzomib + Lenalidomide + Dexamethasone

* Carfilzomib is 20 mg/m2 on days 1 and 2, and if tolerated, escalated to a target dose of 27 mg/m2 starting on day 8 of cycle 1 and thereafter. From cycle 13, the day 8 and day 9 doses of Carfilzomib will be omitted.
* Lenalidomide 25 mg is taken orally on days 1 to 21.
* Dexamethasone 40 mg on days 1, 8, 15, and 22 of the 28-day cycles. An individual subject will receive study treatment for a maximum of 18 months consistent with the approved use in this combination.
Interventions: intervention 1: Drug: Carfilzomib + Dexamethasone intervention 2: Drug: Carfilzomib + Lenalidomide + Dexamethasone
Intervention descriptions: intervention 1: Drug: Carfilzomib + Dexamethasone

* Carfilzomib will be administered as a 30-minute infusion.
* Dexamethasone will be taken by mouth or intravenously. intervention 2: Drug: Carfilzomib + Lenalidomide + Dexamethasone

* Carfilzomib will be administered as a 10 minute infusion.
* Lenalidomide will be taken orally.
* Dexamethasone will be taken by mouth or intravenously.

Protocol documents:
Prot_000.pdf: 
Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 1 of 92 
 
 
CONFIDENTIAL  
 
Title Page 
Protocol Title: 
Post-marketing Phase 4 Study to Evaluate 
Safety, Tolerability, and Efficacy of Kyprolis® 
(Carfilzomib) in Indian Patients With Relapsed or 
Refractory Multiple Myeloma:  A Prospective, 
Open-label, Non-comparative, Multicenter Study 
Short Protocol Title: 
Phase 4 Study to Evaluate Safety, Tolerability, 
and Efficacy of Kyprolis (Carfilzomib) in 
Relapsed or Refractory Multiple Myeloma 
Protocol Number: 
20160372 
Investigational Product: 
Carfilzomib 
Trade Name: 
Kyprolis 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
Telephone Number: 
+1-805-447-1000 
Key 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
Telephone Number: 
 
Email Address: 
 
EudraCT Number: 
Not Applicable 
NCT Number: 
NCT03934684 
Protocol Date: 
Document Version 
Date 
Original 
09 June 2017 
Amendment 1 
08 October 2019 
Superseding 
Amendment 1 
29 October 2019 
Version/Date: 
Data Element 
Standards Version 
Date 
5.0 
20 March 2015 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 2 of 92 
 
 
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:  Amgen’s general number in the US, 
1-805-447-1000. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
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CONFIDENTIAL  
 
Investigator's Agreement: 
I have read the attached protocol entitled Post-marketing Phase 4 Study to Evaluate 
Safety, Tolerability, and Efficacy of Kyprolis® (Carfilzomib) in Indian Patients With 
Relapsed or Refractory Multiple Myeloma:  A Prospective, Open-label, Non-comparative, 
Multicenter Study, dated 29 October 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 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:  20160372 
Date:  29 October 2019 
Page 4 of 92 
CONFIDENTIAL 
Table of Contents 
Table of Contents ................................................................................................... 4
1.
Protocol Synopsis ................................................................................................... 9
2.
Study Schema and Schedule of Activities ............................................................. 13
2.1
Study Schema ........................................................................................... 13
2.2
Schedule of Activities ................................................................................ 14
3.
Introduction ........................................................................................................... 18
3.1
Study Rationale ......................................................................................... 18
3.2
Background ............................................................................................... 18
3.2.1
Disease ..................................................................................... 18
3.2.2
Amgen Investigational Product Background:  Kyprolis ............... 19
3.2.2.1
Kyprolis Background (Non-clinical) .......................... 19
3.2.2.2
Kyprolis Background (Clinical) ................................. 19
3.2.3
Non-Amgen Investigational Product Background: 
Lenalidomide and Dexamethasone ........................................... 20
3.2.3.1
Lenalidomide ........................................................... 20
3.2.3.2
Dexamethasone ...................................................... 20
4.
Objectives, Endpoints and Hypotheses ................................................................. 21
4.1
Objectives and Endpoints .......................................................................... 21
4.2
Hypotheses ............................................................................................... 21
5.
Study Design ........................................................................................................ 22
5.1
Overall Design .......................................................................................... 22
5.2
Number of Subjects ................................................................................... 22
5.2.1
Replacement of Subjects ........................................................... 22
5.2.2
Number of Sites ......................................................................... 23
5.3
End of Study ............................................................................................. 23
5.3.1
End of Study Definition .............................................................. 23
5.3.2
Study Duration for Subjects ....................................................... 23
5.4
Justification for Investigational Product Dose ............................................ 23
6.
Study Population .................................................................................................. 24
6.1
Inclusion Criteria ....................................................................................... 24
6.2
Exclusion Criteria ...................................................................................... 25
6.3
Subject Enrollment .................................................................................... 27
6.4
Screen Failures ......................................................................................... 28
7.
Treatments ........................................................................................................... 28
7.1
Treatment Procedures............................................................................... 29
7.1.1
Investigational Products ............................................................ 29
7.1.2
General Dosing Instructions ...................................................... 29
Approved 
 
 


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CONFIDENTIAL  
 
7.1.2.1 
Kyprolis in Combination With 
Lenalidomide and Dexamethasone (KRd) ............... 30 
7.1.2.2 
Kyprolis in Combination With 
Dexamethasone (Kd) .............................................. 31 
7.1.2.3 
Intravenous Prehydration ........................................ 32 
7.1.3 
Non-investigational Products ..................................................... 32 
7.1.4 
Medical Devices ........................................................................ 33 
7.1.5 
Other Protocol-required Therapies ............................................ 33 
7.1.5.1 
Antiviral Prophylaxis ................................................ 33 
7.1.5.2 
Proton-pump Inhibitor .............................................. 33 
7.1.5.3 
Prophylaxis for Hepatitis B Virus ............................. 33 
7.1.5.4 
Supportive Therapies .............................................. 33 
7.1.6 
Other Treatment Procedures ..................................................... 33 
7.1.7 
Product Complaints ................................................................... 34 
7.1.8 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 34 
7.2 
Method of Treatment Assignment ............................................................. 34 
7.3 
Blinding ..................................................................................................... 34 
7.4 
Dose Modification ...................................................................................... 35 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 35 
7.4.1.1 
Amgen Investigational Product:  Kyprolis ................ 35 
7.4.1.2 
Non-Amgen Non-investigational Product:  
Lenalidomide and Dexamethasone ......................... 35 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 35 
7.6 
Treatment Compliance .............................................................................. 35 
7.7 
Treatment of Overdose ............................................................................. 36 
7.8 
Prior and Concomitant Treatment ............................................................. 36 
7.8.1 
Prior Treatment ......................................................................... 36 
7.8.2 
Concomitant Treatment ............................................................. 36 
8. 
Discontinuation Criteria ......................................................................................... 36 
8.1 
Discontinuation of Study Treatment........................................................... 37 
8.2 
Discontinuation From the Study ................................................................ 37 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 38 
8.2.2 
Reasons for Removal From Study ............................................. 38 
8.3 
Lost to Follow-up ....................................................................................... 38 
9. 
Study Assessments and Procedures .................................................................... 38 
9.1 
General Study Periods .............................................................................. 39 
9.1.1 
Screening, Enrollment and/or Randomization ............................ 39 
9.1.2 
Treatment Period ....................................................................... 39 
9.1.3 
End of Study .............................................................................. 40 
Approved 
 
 


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CONFIDENTIAL  
 
9.2 
Description of General Study Assessments and Procedures ..................... 40 
9.2.1 
General Assessments ............................................................... 40 
9.2.1.1 
Informed Consent .................................................... 40 
9.2.1.2 
Demographics ......................................................... 40 
9.2.1.3 
Medical History ........................................................ 40 
9.2.1.4 
Physical Examination .............................................. 40 
9.2.1.5 
Physical Measurements .......................................... 41 
9.2.1.6 
Performance Status................................................. 41 
9.2.2 
Efficacy Assessments ................................................................ 41 
9.2.3 
Safety Assessments .................................................................. 41 
9.2.3.1 
Adverse Events ....................................................... 41 
9.2.3.2 
Vital Signs ............................................................... 44 
9.2.3.3 
Electrocardiograms (ECGs) ..................................... 44 
9.2.3.4 
Other Safety ............................................................ 44 
9.2.4 
Clinical Laboratory Assessments ............................................... 45 
9.2.4.1 
Pregnancy Testing .................................................. 46 
10. 
Statistical Considerations ...................................................................................... 46 
10.1 
Sample Size Determination ....................................................................... 46 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 46 
10.2.1 
Analysis Sets ............................................................................. 46 
10.2.2 
Covariates ................................................................................. 46 
10.2.3 
Subgroups ................................................................................. 46 
10.2.4 
Handling of Missing and Incomplete Data .................................. 47 
10.3 
Statistical Analyses ................................................................................... 47 
10.3.1 
Planned Analyses ...................................................................... 47 
10.3.1.1 
Primary Analysis ..................................................... 47 
10.3.1.2 
Final Analysis .......................................................... 47 
10.3.2 
Methods of Analyses ................................................................. 47 
10.3.2.1 
General Considerations ........................................... 47 
10.3.2.2 
Efficacy Analyses .................................................... 48 
10.3.2.3 
Safety Analyses ...................................................... 49 
11. 
References ........................................................................................................... 52 
12. 
Appendices ........................................................................................................... 53 
Appendix 1.  List of Abbreviations and Definitions of Terms .................................. 54 
Appendix 2.  Clinical Laboratory Tests .................................................................. 57 
Appendix 3.  Study Governance Considerations ................................................... 59 
Data Monitoring Committee(s) ................................................................... 59 
Regulatory and Ethical Considerations ...................................................... 59 
Informed Consent Process ........................................................................ 60 
Data Protection/Subject Confidentiality ..................................................... 61 
Publication Policy ...................................................................................... 62 
Approved 
 
 


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CONFIDENTIAL 
Investigator Signatory Obligations ............................................................. 63
Data Quality Assurance ............................................................................. 63
Source Documents .................................................................................... 64
Study and Site Closure.............................................................................. 65
Compensation ........................................................................................... 65
Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting ......................................................... 66
Definition of Adverse Event ....................................................................... 66
Definition of Serious Adverse Event .......................................................... 67
Recording Adverse Events and Serious Adverse Events .......................... 68
Evaluating Adverse Events and Serious Adverse Events .......................... 68
Reporting of Serious Adverse Event .......................................................... 70
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information ................................................................................. 74
Definition of Females of Childbearing Potential ......................................... 74
Contraception Methods for Female Subjects ............................................. 75
Contraception Methods for Male Subjects ................................................. 75
Collection of Pregnancy Information .......................................................... 76
Collection of Lactation Information ............................................................ 77
Appendix 6.  Sample Storage and Destruction ...................................................... 84
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments ............................................................................ 85
Appendix 8.  2013 ESH/ESC Office Blood Pressure Measurement ...................... 86
Appendix 9.  Guidelines for Documenting Prior Treatment .................................... 87
Appendix 10.  ECOG Performance Scale ............................................................. 88
Appendix 11.  International Uniform Response Criteria for Multiple 
Myeloma ................................................................................................... 89
Appendix 12.  Corticosteroid Dose Equivalents .................................................... 92
List of Tables 
Table 2-1.  Schedule of Activities ................................................................................... 14
Table 7-1.  Study Treatments ........................................................................................ 29
Table 7-2.  Kyprolis (10-minute Infusion) Dosing in Combination With 
Lenalidomide and Dexamethasone (Triplet Combination) ....................... 31
Table 7-3.  Kyprolis (30-minute Infusion) Dosing in Combination With 
Dexamethasone (Double Combination) .................................................. 32
Table 12-1.  Analyte Listing ........................................................................................... 58
Table 12-2.  Lenalidomide:  Contraceptive Guidelines and Collection of 
Pregnancy and Lactation Information ..................................................... 78 
Approved 
 
 


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CONFIDENTIAL  
 
List of Figures 
Figure 2-1.  Study Schema ............................................................................................ 13 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form ....................................................................................................... 71 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet ...................................... 82 
Approved 
 
 


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CONFIDENTIAL 
1.
Protocol Synopsis
Protocol Title:  Post-marketing Phase 4 Study to Evaluate Safety, Tolerability, and
Efficacy of Kyprolis® (Carfilzomib) in Indian Patients With Relapsed or Refractory
Multiple Myeloma:  A Prospective, Open-label, Non-comparative, Multicenter Study
Short Protocol Title:  Phase 4 Study to Evaluate Safety, Tolerability, and Efficacy of 
Kyprolis (Carfilzomib) in Relapsed or Refractory Multiple Myeloma 
Study Phase:  4 
Indication:  Relapsed Refractory Multiple Myeloma 
Rationale 
Kyprolis® (K; carfilzomib) was approved in India on 17 January 2017 as a prescription 
medication in combination with dexamethasone (Kd) or with lenalidomide (Revlimid®) 
plus dexamethasone (KRd) for the treatment of patients with relapsed or refractory 
multiple myeloma (RRMM) following 1 to 3 prior lines of therapy. 
This non-comparative, interventional phase 4 study is designed to fulfill the 
post-marketing requirement to assess safety, tolerability, and efficacy of Kyprolis on 
Indian subjects with RRMM as per the locally approved label. 
Objective(s)/Endpoint(s) 
Objectives 
Endpoints 
Primary 
To characterize safety associated with the use 
of Kyprolis under the locally approved label 
The subject incidence, severity, and outcome 
of treatment-emergent adverse events using 
National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI 
CTCAE) v.4.03 including clinically significant 
laboratory parameter changes over time 
Approved 
 
 


Product:  Carfilzomib 
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Date:  29 October 2019 
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CONFIDENTIAL 
Objectives 
Endpoints 
Secondary 
To characterize efficacy of Kyprolis when 
administered under the locally approved label 
Progression free survival (PFS), overall 
response rate (ORR), clinical benefit rate 
(CBR), time to response (TTR), and duration 
of response (DOR) will be evaluated by the 
investigator as per local standard procedure 
using International Myeloma Working 
Group-Uniform Response Criteria 
(IMWG-URC). 

PFS is defined as the time from first dose
of study treatment until the earliest date of
disease progression or death due to any
cause

ORR is defined as the proportion of
subjects with either a best overall
response of stringent complete response
(sCR), complete response (CR), very
good partial response (VGPR), or partial
response (PR)

CBR is defined as the proportion of 
subjects with either a best overall 
response of sCR, CR, VGPR, PR, and 
minimal response (MR) 

TTR is calculated only for subjects who
achieve a best overall response of PR or
better and is defined as the time from first
dose of study treatment to the earliest
date a response of PR or better is first
achieved and subsequently confirmed

DOR is defined as the time from initial
response (sCR, CR, VGPR, or PR) to
date of disease progression
Hypotheses 
This phase 4 study is descriptive in nature.  There is no hypothesis to be tested.  The 
study will provide descriptive data on the safety profile associated with the use of 
Kyprolis under the locally approved label as well as its efficacy in terms of PFS, ORR, 
CBR, TTR, and DOR. 
Overall Design 
This open-label, multicenter, non-comparative phase 4 study of Kyprolis is part of 
Amgen’s post-marketing requirement to the Indian Regulatory Authority.  The study 
population consists of approximately 100 subjects with RRMM and for whom Kyprolis is 
indicated in accordance with the approved prescribing information in India. 
Approved 
 
 


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Date:  29 October 2019 
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CONFIDENTIAL  
 
A subject will be considered on study treatment while receiving Kyprolis.  If Kyprolis is 
discontinued, lenalidomide and/or dexamethasone may be continued outside of the 
study.  No crossover between the treatments will be allowed. 
Number of Subjects 
Approximately 100 subjects with previously treated RRMM will be enrolled. 
Summary of Subject Eligibility Criteria 
The key inclusion criteria include: 
 
documented RRMM after last treatment 
 
eligible to receive Kyprolis per the locally approved label 
 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 
 
adequate organ and bone marrow function within 28 days prior to treatment 
The key exclusion criteria include:  
 
active congestive heart failure, clinically significant echocardiogram (ECHO) 
abnormalities, screening electrocardiogram (ECG) with corrected QT interval (QTc) 
of > 470 msec, pericardial disease, or myocardial infarction within 4 months prior to 
enrollment 
 
uncontrolled hypertension 
 
infiltrative pulmonary disease and/or known pulmonary hypertension 
 
prior treatment with Kyprolis (carfilzomib) 
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.2. 
Treatments 
Subjects will receive Kyprolis according to the locally approved label either as triplet 
(KRd) or doublet (Kd) combination, assigned by the investigator based on clinical 
evaluation and before the decision to include the patient in this study. 
For the triplet combination with lenalidomide and dexamethasone, Kyprolis will be 
administered as an infusion over approximately 10 minutes on days 1, 2, 8, 9, 15, and 
16 of repeated 28-day treatment cycles.  The recommended starting dose of Kyprolis is 
20 mg/m2 on days 1 and 2, and if tolerated, escalated to a target dose of 27 mg/m2 
starting on day 8 of cycle 1 and thereafter.  From cycle 13, the day 8 and day 9 doses of 
Kyprolis will be omitted.  After cycle 18, Kyprolis will be discontinued.  Lenalidomide 
25 mg is taken orally on days 1 to 21 and dexamethasone 40 mg by mouth or 
intravenously on days 1, 8, 15, and 22 of the 28-day cycles. 
Approved 
 
 


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Date:  29 October 2019 
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CONFIDENTIAL 
For the doublet combination with dexamethasone, Kyprolis should be administered as a 
30-minute infusion on days 1, 2, 8, 9, 15, and 16 of repeated 28-day treatment cycles.
The recommended starting dose of Kyprolis is 20 mg/m2 on days 1 and 2, and if
tolerated, escalated to a target dose of 56 mg/m2 starting on day 8 of cycle 1 and
thereafter.  Dexamethasone 20 mg is taken by mouth or intravenously on days 1, 2, 8, 9,
15, 16, 22, and 23 of each 28-day cycle.
Procedures
Informed consent must be obtained before starting any screening procedure.  The 
following procedures will occur per the Schedule of Assessments:  demographics, 
medical/surgical history, physical measurements, vital signs, ECG, ECOG performance 
status, ECHO/multigated acquisition (MUGA) scan, review of adverse event/serious 
adverse event, concomitant medications, and review of disease status.  Laboratory 
assessments will include pregnancy testing, coagulation tests, hematology, chemistry 
tests, and other analytes specified in Table 12-1. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Table 2-1. 
Statistical Considerations 
The primary analysis of safety and efficacy will be performed on the Safety Analysis Set. 
The Safety Analysis Set will include all subjects who received at least 1 dose of the 
investigational product.  The primary analysis will occur when the last subject enrolled 
has had the opportunity to receive the study treatment for at least 9 months. 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class, preferred term, and severity grade.  The safety laboratory endpoints, vital 
signs, physical measurements, and ECG measurements will also be analyzed.  
Descriptive statistics will be produced to describe the exposure to investigational product 
(Kyprolis) and non-Amgen non-investigational products (dexamethasone and/or 
lenalidomide). 
Secondary efficacy endpoints include PFS, ORR, CBR, TTR, and DOR.  Progression 
free survival will be summarized descriptively using with the Kaplan-Meier (KM) method.  
The point estimates of ORR and CBR will be summarized along with exact binomial 
95% confidence intervals.  TTR and DOR are calculated only for the responders, and will 
be summarized descriptively.  KM method will be used to analyze DOR. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name:  Amgen Inc. 
Approved 
 
 


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CONFIDENTIAL 
2.
Study Schema and Schedule of Activities
2.1
Study Schema
Figure 2-1.  Study Schema
RRMM
1-3 prior 
lines
N ~ 100
KRd (Triplet)a, b
K at 20/27 mg/m2
R 25 mg 
d 40 mg
Kd (Duplet)b, c
K at 20/56 mg/m2
d 20 mg
28-day cycles
0
4
8
12
16
20 
Primary Endpoint:
Safety
(subject incidence, severity, 
and outcome of TEAE)
Key Secondary Endpoints:
PFS
ORR
CBR
TTR
DOR
CBR = clinical benefit rate; D = day; d = dexamethasone; DOR = duration of response; DP = disease progression; K = Kyprolis; ORR = overall response rate; 
PFS = progression free survival; R = Revlimid (lenalidomide); RRMM = relapsed or refractory multiple myeloma; TEAE = treatment-emergent adverse events; TTR = time to 
response; TX = treatment.
a KRd:  K is administered by 10-minute infusion on  D 1, 2, 8, 9, 15, 16 of repeated 28-day cycles. From cycle 13, omit the D 8 and D 9 doses of Kyprolis. Discontinue 
Kyprolis after cycle 18.  Revlimid 25 mg is taken orally on days 1-21 and dexamethasone 40 mg by mouth or intravenously on D 1, 8, 15, and 22 of the 28-day cycles.
b For patients with mild or moderate hepatic impairment, reduce the dose of Kyprolis by 25% (ie, 15 mg/m2 day 1 and 2 of cycle 1 for KRd and Kd, 20 mg/m2 day 8 cycle 1 
and thereafter for KRd and 42 mg/m2 day 8 cycle 1 and thereafter for Kd.
c Kd:  K is administered by 30 min infusion on D 1, 2, 8, 9, 15, 16 of repeated 28-day cycles until disease progression or unacceptable toxicity occurs. Dexamethasone 20 
mg is taken by mouth or intravenously on D 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle.
d Treat until disease progression or a maximum of 3 years.
months 
30 
D
A
Y
P
O
S
T  
T
X 
V
I
S
I
T
DPd
18 
cycles
Approved


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CONFIDENTIAL  
 
2.2 
Schedule of Activities 
Table 2-1.  Schedule of Activities 
Procedure 
SCRa 
Treatment Period Days (All Cycles) 
End of 
Study 
Visitb 
Notes 
1 
2 
8 
9 
15 
16 
22 
General and Safety Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
Including multiple myeloma history 
Physical measurements:  height 
X 
 
 
 
 
 
 
 
 
 
Physical measurements:  
weight, BSA 
X 
X 
 
 
 
 
 
 
 
BSA should be calculated per institutional standard and 
utilized to calculate required study drug doses.  BSA 
should be recalculated if there is  20% change in body 
weight. 
Physical examination 
X 
X 
 
 
 
 
 
 
X 
C1D1:  Screening exam may be used if within 7 days prior 
to C1D1. 
ECG 
X 
 
 
 
 
 
 
 
X 
 
Vital signs:  Kd arm (all cycles) 
and KRd arm (cycles 1-12) 
X 
X 
X 
X 
X 
X 
X 
 
X 
Checked prior to administration of study drug in all cycles. 
Vital signs:  KRd arm (cycle 13+) 
 
X 
X 
 
 
X 
X 
 
X 
Checked prior to administration of study drug in all cycles. 
ECOG performance status 
X 
 
 
 
 
 
 
 
X 
 
Page 1 of 3 
Footnotes and abbreviation definitions are after last page of table. 
 
Approved 
 
 


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CONFIDENTIAL 
Table 2-1.  Schedule of Activities 
Procedure 
SCRa 
Treatment Period Days (All Cycles) 
End of 
Study 
Visitb 
Notes 
1 
2 
8 
9 
15 
16 
22 
ECHO/MUGA scan 
X 
X 
Repeated ECHO every 6 months ( 2 weeks) from 
C1D1 until end of study visit, or if clinically indicated.  
An ECHO must be performed within 72 hours of the 
onset of a suspected cardiac failure event. 
Review of AE/SAE 
Continually 
Concomitant medications 
Continually 
Will be collected from 30 days prior to signing of informed 
consent to 30 days after last dose of study treatment. 
Review of disease status 
Performed per local standards 
Disease status will be evaluated by the investigator using 
IMWG-URC starting from screening until EOT. 
Laboratory Assessments 
Serum or urine pregnancy test 
(FCBP)c 
X 
X 
X 
Must be confirmed negative at screening, on day 1 of 
each cycle prior to dosing, and at end of study visit. 
Additional serum or urine 
pregnancy test (KRd-treated 
FCBP only)d:  Cycle 1 
Xe 
X 
X 
X 
Weekly pregnancy tests required during cycle 1. 
See Table 12-2 for additional information on 
lenalidomide-specific pregnancy testing requirements. 
Coagulation tests 
X 
Hematology 
X 
X 
(X) 
(X) 
C1D1:  Results from screening may be used if taken 
within 14 days prior to C1D1. 
(X):  Day 8 and 15 samples only collected during cycle 1. 
Chemistry 
X 
X 
(X) 
(X) 
NTproBNP 
X 
Page 2 of 3 
Footnotes and abbreviation definitions are after last page of table. 
 
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Table 2-1.  Schedule of Activities 
Procedure 
SCRa 
Treatment Period Days (All Cycles) 
End of 
Study 
Visitb 
Notes 
1 
2 
8 
9 
15 
16 
22 
Hepatitis B Virus (HBV) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local serology testing for HBsAg, anti-HBs, and 
anti-HBc.  Testing is required: 
 
For subjects with a prior history of HBV 
infection at screening and HBV DNA testing 
every 12 weeks  2 weeks through end of 
study visit. 
 
For all other subjects at screening unless 
obtained within 6 months of screening and 
there was no change in the subject’s risk 
factors within these 
6 months.  
 
For subjects positive at screening, who 
become positive for serology during 
treatment, or who are at risk of becoming 
positive, HBV DNA testing will be performed 
every 12 weeks  2 weeks (and as clinically 
indicated) through end of study visit.   
A specialist should be consulted for all subjects who 
test positive for HBV serology. Subjects who have 
received Hepatitis B vaccination with only anti-HBs 
positivity and no clinical signs of hepatitis do not 
require HBV DNA monitoring. 
See Section 9.2.3.4.2 
Page 3 of 3 
AE = adverse events; BNP = b-type natriuretic peptide; BSA = body surface area; CXDX = cycle X day X; ECG = electrocardiogram; ECHO = echocardiogram; 
ECOG = Eastern Cooperative Oncology Group; FCBP = female of child bearing potential; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface 
antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; IMWG-URC = International Myeloma Working Group-Uniform Response Criteria; 
MUGA = multigated acquisition scan; NTproBNP = N-terminal pro b-type natriuretic peptide; SAE = serious adverse event; SCR = screening. 
a Screening:  up to 28 days before enrollment 
 
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b End of study visit is 30 days (+ 3) after last dose of Kyprolis 
c 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. 
d The subject may not receive lenalidomide until the investigator has verified that the results of these pregnancy tests are negative. 
e KRd-treated FCBP must have 2 negative pregnancy tests (combined sensitivity of at least 50 mIU/mL) prior to starting lenalidomide.  The first pregnancy test must be 
performed within 10 to 14 days prior to the start of lenalidomide and the second pregnancy test must be performed within 24 hours prior to the start of lenalidomide. 
If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study discontinuation, and at 
days 14 and 28 following discontinuation from the study. 
 
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3.
Introduction
3.1 
Study Rationale
Kyprolis® (K; carfilzomib) was approved in India on 17 January 2017 as a prescription
medication in combination with dexamethasone (Kd) or with lenalidomide (Revlimid®)
plus dexamethasone (KRd) for the treatment of patients with relapsed or refractory
multiple myeloma (RRMM) following 1 to 3 prior lines of therapy and as single agent for
the treatment of patients with RRMM who have received 1 or more lines of therapy.
This non-comparative, interventional phase 4 study is designed to fulfil the 
post-marketing requirement to assess safety, tolerability, and efficacy of Kyprolis on 
Indian subjects with RRMM as per the locally approved label.  
3.2 
Background 
3.2.1 
Disease 
Multiple myeloma, a clonal neoplastic proliferation of plasma cells, is the second most 
common hematologic malignancy and is responsible for approximately 80 000 annual 
deaths worldwide (1% of cancer deaths) (Ferlay et al, 2015).  In 2012, the estimated 
incidence of multiple myeloma in India was 6955, which represents 0.7% of all cancers.  
The 5 year prevalence of multiple myeloma was estimated at 11 886 persons; 
(WHO Fact Sheet).  Multiple myeloma is a disease of older adults, with a median age at 
diagnosis of 70 years (Howlader et al, 2013).
While treatment for multiple myeloma will typically induce remission, multiple myeloma 
eventually relapses in most patients.  Remissions are increasingly transient with 
successive lines of therapy, with disease eventually becoming refractory (nonresponsive 
to the most recent therapy or progression within 60 days of discontinuation from the 
most recent therapy), and most patients ultimately die of myeloma-related complications 
(Richardson et al, 2007; Kumar et al, 2004). 
The primary goal of treatment for relapsed and refractory multiple myeloma is to achieve 
the longest progression-free survival (PFS) and subsequently overall survival (OS).  In 
this setting, the depth of response is an important prognostic factor and associated with 
OS (Chanan-Khan and Giralt, 2010; Richardson et al, 2007).  Additional goals are to 
control disease activity to prevent or delay progression and its associated complications 
(such as bone fractures, renal insufficiency, and infections), to maintain an acceptable 
health-related quality of life (HRQoL), and to provide relief of pain and other 
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disease-related symptoms.  These goals must be achieved by using regimens with an 
acceptable tolerability. 
3.2.2 
Amgen Investigational Product Background:  Kyprolis 
3.2.2.1 
Kyprolis Background (Non-clinical) 
Kyprolis is a tetrapeptide epoxyketone based inhibitor of the 20S proteasome.  Kyprolis, 
showed less off target activity when measured against a broad panel of proteases 
including metallo-, aspartyl-, and serine proteases compared to bortezomib; bortezomib 
showed off target inhibitory activity in the nanomolar range against several serine 
proteases (Arastu-Kapur et al, 2009).  This selectivity may be responsible for the 
reductions in myelosuppression and neuropathy observed in studies comparing Kyprolis 
with bortezomib. 
Incubation of hematologic tumor cell lines with Kyprolis for as little as 1 hour led to rapid 
inhibition of proteasome activity followed by accumulation of polyubiquitinated proteins 
and induction of apoptotic cell death (Suzuki et al, 2011; Kuhn et al, 2007). 
Kyprolis has also been administered to rats and monkeys for 6 and 9 months, 
respectively (twice weekly for 3 weeks on a 28-day cycle).  Kyprolis was well tolerated at 
doses resulting in more than 80% proteasome inhibition, with no behavioral or 
histological evidence of peripheral neuropathy (PN) and no neutropenia 
(Carfilzomib Investigator's Brochure). 
3.2.2.2 
Kyprolis Background (Clinical) 
Kyprolis entered clinical studies in September 2005.  On 20 July 2012, Kyprolis 
(Carfilzomib for Injection) was approved under the United States Food and Drug 
Administration’s (US FDA) accelerated approval program for the treatment of patients 
with multiple myeloma who have received at least 2 prior therapies, including bortezomib 
and an immunomodulatory agent (IMiD).  This initial approval was based upon overall 
response rate (ORR) in a heavily pretreated population studied in the phase 2 
PX-171-003-A1 study.  Subsequent full approval in the US and globally were based on 
2 large open-label phase 3 trials:  PX 171-009 ASPIRE and 2011-003 ENDEAVOR. 
Following these approvals, Kyprolis is indicated for use in combination with either 
lenalidomide (Revlimid) and dexamethasone (20/27 mg/m2 K) or dexamethasone alone 
(20/56 mg/m2 K) for the treatment of RRMM following 1 to 3 prior lines of therapy.  In 
various countries, Kyprolis is also approved as a single agent (20/27 mg/m2 or 
20/56 mg/m2) for subjects with RRMM who have received at least 1 prior treatment 
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regimen.  The exact indication wording varies by region.  Additional data on clinical 
background is summarized in the Investigator’s Brochure. 
As of 19 January 2017, an estimated 3504 subjects (2911 subject-years) have been 
exposed to Kyprolis in clinical trials conducted by Amgen since the beginning of the 
development program.  An estimated 51 275 patients (19 760 patient-years) have been 
cumulatively exposed to the product in the marketed setting. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of Kyprolis is 
provided in the Investigator’s Brochure. 
3.2.3 
Non-Amgen Investigational Product Background:  Lenalidomide and 
Dexamethasone 
3.2.3.1 
Lenalidomide 
Lenalidomide, a thalidomide analogue is commercially available in 5, 10, 15, or 25 mg 
capsules for oral administration and will not be supplied by Amgen.  Details regarding 
the description, supply, and storage instructions for lenalidomide are found in the 
Prescribing Information.  Sites are advised to refer to the prescribing information for 
information that is specific to the brand or formulation of the drug product in use. 
3.2.3.2 
Dexamethasone 
Dexamethasone is commercially available and will not be supplied by Amgen.  Details 
regarding the description, supply, and storage instructions for dexamethasone are found 
in the prescribing information.  Sites are advised to refer to the prescribing information 
for information that is specific to the brand or formulation of the drug product in use. 
Refer to the regional manufacturer package insert for additional information. 
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4.
Objectives, Endpoints and Hypotheses
4.1 
Objectives and Endpoints
Objectives 
Endpoints 
Primary 
To characterize safety associated with the use 
of Kyprolis under the locally approved label 
The subject incidence, severity, and outcome 
of treatment-emergent adverse events using 
National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI 
CTCAE) v.4.03 including clinically significant 
laboratory parameter changes over time 
Secondary 
To characterize efficacy of Kyprolis when 
administered under the locally approved label 
Progression free survival (PFS), overall 
response rate (ORR), clinical benefit rate 
(CBR), time to response (TTR), and duration 
of response (DOR) will be evaluated by the 
investigator as per local standard procedure 
using International Myeloma Working 
Group-Uniform Response Criteria 
(IMWG-URC). 

PFS is defined as the time from first dose
of study treatment until the earliest date of
disease progression or death due to any
cause

ORR is defined as the proportion of
subjects with either a best overall
response of stringent complete response
(sCR), complete response (CR), very
good partial response (VGPR), or partial
response (PR)

CBR is defined as the proportion of
subjects with either a best overall
response of sCR, CR, VGPR, PR, and
minimal response (MR)

TTR is calculated only for subjects who
achieve a best overall response of PR or
better and is defined as the time from first
dose of study treatment to the earliest
date a response of PR or better is first
achieved and subsequently confirmed

DOR is defined as the time from initial
response (sCR, CR, VGPR, or PR) to
date of disease progression
4.2 
Hypotheses 
This phase 4 study is descriptive in nature.  There is no hypothesis to be tested.  The 
study will provide descriptive data on the safety profile associated with the use of 
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CONFIDENTIAL   
 
Kyprolis under the locally approved label as well as its efficacy in terms of PFS, ORR, 
CBR, TTR, and DOR. 
5. 
Study Design 
5.1 
Overall Design 
This open-label, multicenter, non-comparative phase 4 study of Kyprolis is part of 
Amgen’s post-marketing requirement to the Indian Regulatory Authority.  The study 
population consists of approximately 100 subjects with RRMM and for whom Kyprolis is 
indicated in accordance with the approved prescribing information in India.  The sample 
size of 100 is as directed by the regulatory authority. 
The assignment of subjects to protocol treatment will be decided by the investigator 
based on clinical evaluation and before the decision to include the subject in this study. 
A subject will be considered on study treatment while receiving Kyprolis.  If Kyprolis is 
discontinued, lenalidomide and/or dexamethasone may be continued outside of the 
study.  No crossover between the treatments will be allowed. 
Safety assessments include the collection of adverse events and serious adverse events 
until the last follow-up visit.  In addition, laboratory tests will be performed according to 
the assessment schedule outlined in Table 2-1. 
All subjects will be evaluated by the investigator for multiple myeloma disease response 
based on local standard procedures. 
Following disease progression or discontinuation of study treatment, all subjects will 
have 1 final assessment that occurs 30 days (+ 3 days) after the last dose of Kyprolis. 
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
Approximately 100 subjects with previously treated RRMM will be enrolled.  
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 10.1. 
5.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
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5.2.2 
Number of Sites 
Approximately 15 investigative sites in India will be included in the study.  Sites that do 
not enroll subjects within 5 months of site initiation may be closed. 
5.3 
End of Study 
5.3.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject 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.  Primary completion 
is planned to occur when the last subject has had the opportunity to receive the study 
treatment for at least 9 months. 
The primary completion date is the date when data for the primary endpoint are last 
collected for the purposes of conducting the primary analysis. 
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).  This study will conclude when all subjects discontinue study treatment 
or have received study treatment for a maximum of 3 years, whichever occurs first. 
5.3.2 
Study Duration for Subjects 
Total study duration for an individual subject may vary by the assigned study treatment. 
For subjects receiving KRd the total study duration is estimated to be approximately 
20 months.  For subjects receiving Kd, the total study duration is estimated to be 
approximately 23 months. 
5.4 
Justification for Investigational Product Dose 
The study is being conducted as a post authorization safety study as mandated by the 
Indian Regulatory Authority.  The doses chosen are the approved doses in the local 
Kyprolis Prescribing Information. 
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CONFIDENTIAL   
 
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, enrolled into study, reason for ineligibility, or refusal to participate). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Appendix 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 
Documented RRMM after last treatment.  Refractory is defined as meeting 1 or 
more of the following: 
 
Nonresponsive to most recent therapy (stable disease [SD] or progressive 
disease [PD]) while on treatment, or 
 
Disease progression within 60 days of discontinuation from the most recent 
therapy 
102 
Eligible to receive Kyprolis per the locally approved label 
103 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 
104 
Adequate hepatic function within 28 days prior to enrollment: 
 
bilirubin < 1.5 times the upper limit of normal (ULN) 
 
aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) < 2.5 times the ULN 
105 
Absolute neutrophil count (ANC) ≥ 1.0 x 109/L within 28 days prior to enrollment.  
(Screening ANC should be independent of granulocyte- and granulocyte 
macrophage-colony stimulating factor support for at least 1 week and of 
pegylated granulocyte stimulating factor for ≥ 2 weeks). 
106 
Hemoglobin ≥ 80 g/L within 28 days prior to enrollment.  Subjects should not 
have received red blood cell (RBC) transfusions for at least 7 days prior to 
obtaining the screening hemoglobin. 
107 
Platelet count ≥ 75 x 109/L (≥ 50 x 109/L if myeloma involvement in the bone 
marrow is ≥ 50%) within 28 days prior to enrollment.  Subjects should not have 
received platelet transfusions for at least 7 days prior to obtaining the screening 
platelet count. 
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108 
Adequate renal function within 28 days prior to enrollment (either measured or 
calculated using a standard formula such as the Cockcroft and Gault):  

Calculated or measured creatinine clearance (CrCl) of ≥ 50 mL/min for
subjects receiving KRd

Calculated or measured CrCl of ≥ 15 mL/min for subjects receiving Kd
109 
Left ventricular ejection fraction ≥ 40% as assessed by transthoracic 
echocardiogram (TTE) or multigated acquisition scan (MUGA) 
110 
Females of childbearing potential (FCBP) must have a negative serum 
pregnancy test within the 10 to 14 days prior to enrollment and a negative urine 
pregnancy test within the 24 hours prior to day 1 of each cycle prior to dosing. 
111 
Subject or legally acceptable representative has provided informed 
consent/assent prior to initiation of any study specific activities/procedures 
6.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply. 
201 
Waldenström macroglobulinemia 
202 
Plasma cell leukemia (> 2.0 x 109/L circulating plasma cells by standard 
differentials) 
203 
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes) 
204 
Myelodysplastic syndrome 
205 
Primary amyloidosis (subjects with multiple myeloma with asymptomatic 
deposition of amyloid plaques found on biopsy would be eligible if all other 
criteria are met) 
206 
History of other malignancy within the past 5 years, with the following 
exception[s]: 

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
207 
Known immediate or delayed hypersensitivity reaction to Captisol (a cyclodextrin 
derivative used to solubilize Kyprolis) 
208 
Contraindication to any of the required concomitant drugs or supportive 
treatments, including hypersensitivity to antiviral drugs 
209 
Intolerance to hydration 
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210 
Active congestive heart failure (New York Heart Association [NYHA] Class III to 
IV), symptomatic ischemia, uncontrolled arrhythmias, clinically significant 
echocardiogram (ECHO) abnormalities, screening ECG with corrected QT 
interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction within 
4 months prior to enrollment 
211 
Infiltrative pulmonary disease and/or known pulmonary hypertension 
212 
Active infection within 14 days prior to enrollment requiring systemic antibiotics, 
antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents. 
Such infections must be fully resolved prior to initiating study treatment 
213 
Pleural effusions requiring thoracentesis within 14 days prior to enrollment. 
214 
Ascites requiring paracentesis within 14 days prior to enrollment. 
215 
Uncontrolled hypertension, defined as an average systolic blood pressure 
> 159 mmHg or diastolic > 99 mm/Hg despite optimal treatment (measured
following European Society of Hypertension/European Society of Cardiology
[ESH/ESC] 2013 guidelines [Appendix 8])
233 
Active hepatitis B virus (HBV) infection.  Subjects with positive hepatitis B 
surface antigen (HBsAg) or core antibody (anti-HBc) that achieve sustained 
virologic response with antiviral therapy directed at hepatitis B are allowed.  
Subjects with known history or resolved infection (negative for HBsAg but 
positive for antibodies to surface antigen, and/or core antigen) must be 
screened with HBV DNA levels.  EXCEPTION:  Subjects with serologic 
findings suggestive of HBV vaccination (hepatitis B surface antibody 
[anti-HBs] positivity as the only serologic marker) AND a known history of 
prior HBV vaccination, do not need to be tested for HBV DNA. 
216 
Known human immunodeficiency virus (HIV) infection, hepatitis C infection 
(subjects with hepatitis C that achieve a sustained virologic response following 
antiviral therapy are allowed) 
217 
Ongoing graft-versus-host disease 
218 
Subjects with grade 3 or worse neuropathy within 14 days prior to enrollment. 
219 
Antitumor therapy (eg, chemotherapy, immunotherapy, antibody therapy) or 
investigational agent within 28 days before enrollment or not recovered from any 
acute toxicity 
220 
Subjects on immunosuppressive therapy for graft versus host disease, even if it 
has resolved 
221 
Glucocorticoid therapy within 14 days before first dose that exceeds a cumulative 
dose of 160 mg or dexamethasone or equivalent dose of other corticosteroids 
222 
Focal radiation therapy within 7 days before enrollment.  Radiation therapy to an 
extended field involving significant volume of bone marrow within 28 days prior to 
enrollment (ie, prior radiation must have been to less than 30% of the bone 
marrow) 
223 
Autologous stem cell transplant less than 100 days prior to enrollment 
224 
Prior treatment with Kyprolis (carfilzomib) 
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225 
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.  Other investigational procedures while participating in this study are 
excluded. 
226 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment, during any breaks (interruptions) in the treatment, 
and for an additional 30 days before the last dose of Kyprolis.  Females of 
childbearing potential should only be included in the study after a confirmed 
menstrual period and a negative highly sensitive urine or serum pregnancy test. 
227 
Female subjects of childbearing potential unwilling to use 1 highly effective 
method of contraception during treatment, during any breaks (interruptions) in the 
treatment, and for an additional 30 days after the last dose of Kyprolis.  Refer to 
Appendix 5 for additional contraceptive information. 
NOTE:  Female subjects of childbearing potential being treated with lenalidomide 
must agree to use 2 methods of contraception for at least 28 days before starting 
treatment, during treatment, during any breaks (interruptions) in the treatment, 
and for an additional 30 days after the last dose of treatment.  See Table 12-2 for 
lenalidomide-specific contraceptive guidance. 
228 
Male subjects with a female partner of childbearing potential who are unwilling to 
practice sexual abstinence (refrain from heterosexual intercourse) or use 
contraception during treatment and for an additional 90 days after the last dose 
of Kyprolis.  Refer to Appendix 5 for additional contraceptive information. 
NOTE:  Male subjects being treated with lenalidomide must agree to use a male 
condom with spermicide even if they have undergone a successful vasectomy.  
See Table 12-2 for lenalidomide-specific contraceptive guidance. 
229 
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 Kyprolis. 
230 
Male subjects unwilling to abstain from donating sperm during treatment and for 
an additional 90 days after the last dose of Kyprolis. 
231 
Subject likely to not be available to complete all protocol required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge. 
232 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 
6.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of written approval for study protocol issued by Health Authority and a 
copy of the site’s written institutional review board/independent ethics committee 
(IRB/IEC) approval of the protocol, informed consent form (ICF), and all other subject 
information and/or recruitment material, if applicable (see Appendix 3). 
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The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen-approved informed consent before commencement of 
study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment electronic case report form (eCRF). 
Each subject who enters into the screening period for the study (up to 28 days before 
enrollment) receives a unique subject identification number before any study-related 
activities/procedures are performed.  The subject identification number will be assigned 
by Interactive Voice/Web Response System (IxRS).  This number will be used to identify 
the subject throughout the clinical study and must be used on all study documentation 
related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
6.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened 1 time.  
7. 
Treatments 
Study treatment is defined as any investigational product(s) or non-investigational 
product(s) intended to be administered to a study subject according to the study 
protocol.  An individual subject will receive study treatment for a maximum of 18 months 
(if receiving the triplet combination [KRd], consistent with the approved use in this 
combination) or up to a maximum of 3 years if the subject has not yet experienced 
disease progression (if receiving the doublet combination [Kd]). 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of Kyprolis. 
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7.1 
Treatment Procedures 
7.1.1 
Investigational Products 
Subjects will receive Kyprolis according to the locally approved label either as triplet 
(KRd) or doublet (Kd) combination, assigned by the investigator based on clinical 
evaluation and before the decision to include the patient in this study. 
Kyprolis will be provided by Amgen. 
The IPIM, a document external to this protocol, contains detailed information regarding 
the storage, preparation, destruction, and administration of Kyprolis. 
Table 7-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational Product:a 
Kyprolis 
Dosage Formulation 
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 Kyprolis drug product with an 
elastomeric stopper and flip-off lid.  Upon reconstitution with 
preservative-free sterile water for injection (sWFI), the 
reconstituted solution contains 2 mg/mL Kyprolis, sulfobutylether 
beta-cyclodextrim sodium (SBECD), and citrate buffer. 
Kyprolis is supplied in labelled cartons containing 4 single use 
vials per carton. 
Unit Dose Strength(s)/ 
Dosage Level(s) and 
Dosage Frequency 
10 minute infusion:  20/27 mg/m2 
30 minute infusion:  20/56 mg/m2 
Route of Administration 
IV infusion 
Accountability 
The planned dose (mg/m2), actual dose (mg) administered, start 
date/time, stop date/time, reason for change in planned dose, 
reason for dose change/withheld, reason for dose delay, and 
package lot number of Kyprolis is to be recorded on each subject's 
eCRF(s). 
Dosing Instructions 
Triplet:  See Section 7.1.2.1 
Doublet:  See Section 7.1.2.2 
a Kyprolis will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug 
distribution procedures. 
7.1.2 
General Dosing Instructions 
Each subject’s first dose of Kyprolis will be calculated based upon baseline body surface 
area (BSA) per institutional standards.  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  20% change in body weight in which 
case the BSA and dose should be recalculated.  The recalculated BSA becomes the 
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new baseline.  The dose can also be modified in response to toxicity following the 
dose modification guideline table in local Kyprolis Prescribing Information. 
Lenalidomide and dexamethasone (if administered orally [PO]) may be self-administered 
at home by the subject and should be taken at approximately the same time each day.  
Missed doses of dexamethasone and lenalidomide will not be made up.  Subjects will 
maintain a diary of outpatient dexamethasone and lenalidomide administration. 
For triple combination therapy dosing instructions, see Section 7.1.2.1.  For doublet 
combination therapy dosing instructions, see Section 7.1.2.2. 
7.1.2.1 
Kyprolis in Combination With Lenalidomide and Dexamethasone 
(KRd) 
For the triplet combination with lenalidomide and dexamethasone, Kyprolis will be 
administered as an infusion over approximately 10 minutes on days 1, 2, 8, 9, 15, and 
16 of repeated 28-day treatment cycles.  The recommended starting dose of Kyprolis is 
20 mg/m2 on days 1 and 2 of cycle 1, and if tolerated, escalated to a target dose of 
27 mg/m2 starting on day 8 of cycle 1 and thereafter.  From cycle 13, the day 8 and day 
9 doses of Kyprolis will be omitted.  After cycle 18, Kyprolis will be discontinued 
(Table 7-2).  Lenalidomide 25 mg is taken orally on days 1 to 21 and dexamethasone 
40 mg by mouth or intravenously on days 1, 8, 15, and 22 of the 28-day cycles. 
For patients with mild or moderate hepatic impairment, reduce the dose of Kyprolis by 
25% (ie, 15 mg/m2 day 1 and 2 of cycle 1 and 20 mg/m2 day 8 cycle 1 and thereafter.  If 
hepatic function returns to normal, the dose may be re-escalated to the intended 
dose after the first cycle (ie, 27 mg/m2 in KRd). 
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Table 7-2.  Kyprolis (10-minute Infusion) Dosing in Combination With 
Lenalidomide and Dexamethasone (Triplet Combination) 
 
Cycle 1 
Week 
1 
2 
3 
4 
Day 
1 
2 
3-7 
8 
9 
10-14 
15 
16 
17-21 
22 23-28 
Kyprolis (mg/m2)a, b 
20 
20 
- 
27 
27 
- 
27 
27 
- 
- 
- 
Dexamethasone (mg)c 
40  
- 
- 
40 
- 
- 
40 
- 
- 
40 
- 
Lenalidomidec 
25 mg daily on days 1-21 
- 
- 
 
Cycles 2 to 12 
Week 
1 
2 
3 
4 
Day 
1 
2 
3-7 
8 
9 
10-14 
15 
16 
17-21 
22 23-28 
Kyprolis (mg/m2)a, b 
27 
27 
- 
27 
27 
- 
27 
27 
- 
- 
- 
Dexamethasone (mg)c 
40  
- 
- 
40 
- 
- 
40 
- 
- 
40 
- 
Lenalidomidec 
25 mg daily on days 1-21 
- 
- 
 
Cycles 13 and laterd 
Week 
1 
2 
3 
4 
Day 
1 
2 
3-7 
8 
9 
10-14 
15 
16 
17-21 
22 23-28 
Kyprolis (mg/m2)a, b 
27 
27 
- 
- 
- 
- 
27 
27 
- 
- 
- 
Dexamethasone (mg)c 
40  
- 
- 
40 
- 
- 
40 
- 
- 
40 
- 
Lenalidomidec 
25 mg daily on days 1-21 
- 
- 
a Refer to the local Kyprolis Prescribing Information for dose modifications.  For patients with mild or 
moderate hepatic impairment, reduce the dose of Kyprolis by 25% (ie, 15 mg/m2 day 1 and 2 of cycle 1 
and 20 mg/m2 day 8 cycle 1 and thereafter. 
b See Section 7.1.2.3 for information regarding IV prehydration before Kyprolis infusion. 
c Refer to the local lenalidomide and dexamethasone Prescribing Information for concomitant medications, 
such as the use of anticoagulant and antacid prophylaxis that may be required with those agents. 
d Kyprolis is administered through cycle 18; lenalidomide and dexamethasone may be continued outside of 
the study. 
7.1.2.2 
Kyprolis in Combination With Dexamethasone (Kd) 
For the doublet combination with dexamethasone, Kyprolis should be administered as a 
30-minute infusion on days 1, 2, 8, 9, 15, and 16 of repeated 28-day treatment cycles.  
The recommended starting dose of Kyprolis is 20 mg/m2 on days 1 and 2, and if 
tolerated, escalated to a target dose of 56 mg/m2 starting on day 8 of cycle 1 and 
thereafter (Table 7-3).  Dexamethasone 20 mg is taken by mouth or intravenously on 
days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. 
For patients with mild or moderate hepatic impairment, reduce the dose of Kyprolis by 
25% (ie, 15 mg/m2 day 1 and 2 of cycle 1 and 42 mg/m2 day 8 cycle 1 and thereafter.  If 
hepatic function returns to normal, the dose may be re-escalated to the intended 
dose after the first cycle (ie, 56 mg/m2 in Kd). 
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Table 7-3.  Kyprolis (30-minute Infusion) Dosing in Combination With 
Dexamethasone (Double Combination) 
 
Cycle 1 
Week 
1 
2 
3 
4 
Day 
1 
2 
3-7 
8 
9 
10-14 15 
16 17-21 22 
23 24-28 
Kyprolis (mg/m2)a, b 
20 
20 
- 
56 
56 
- 
56 
56 
- 
- 
- 
- 
Dexamethasone (mg)c 
20 
20 
- 
20 
20 
- 
20 
20 
- 
20 
20 
- 
 
Cycles 2 and laterd 
Week 
1 
2 
3 
4 
Day 
1 
2 
3-7 
8 
9 
10-14 15 
16 17-21 22 
23 24-28 
Kyprolis (mg/m2)a, b 
56 
56 
- 
56 
56 
- 
56 
56 
- 
- 
- 
- 
Dexamethasone (mg)c 
20 
20 
- 
20 
20 
- 
20 
20 
- 
20 
20 
- 
IV = intravenous 
a Refer to the local Kyprolis Prescribing Information for dose modifications.  For patients with mild or 
moderate hepatic impairment, reduce the dose of Kyprolis by 25% (ie, 15 mg/m2 day 1 and 2 of cycle 1 
and 42 mg/m2 day 8 cycle 1 and thereafter. 
b See Section 7.1.2.3 for information regarding IV prehydration before Kyprolis infusion. 
c Refer to dexamethasone Prescribing Information for other concomitant medications 
d Treatment may be continued until disease progression or unacceptable toxicity occurs (or for a maximum 
of 3 years). 
7.1.2.3 
Intravenous Prehydration 
Subjects may receive intravenous (IV) pre-hydration (normal saline or other 
appropriate IV fluid) prior to each carfilzomib infusion during cycle 1.  
Investigators must consider IV pre-hydration in subjects at high-risk for tumor 
lysis or renal toxicity.  All subjects must be monitored for fluid overload and 
hydration should be tailor to individual needs.  It is recommended to use no more 
than 750 mL IV fluids as a combination of pre- and post-hydration.  Thereafter, 
carfilzomib pre- and/or post-hydration may only be administered if the subject’s 
condition and/or risk factors require it.  The total volume of pre- and/or 
post-hydration and the indication will be recorded on the Concomitant 
Medications eCRF.  
7.1.3 
Non-investigational Products 
Dexamethasone and lenalidomide, both non-Amgen non-investigational products, will 
also be used in this study.  See Full Prescribing Information for dosage, reconstitution 
and preparation for administration.  Lenalidomide and dexamethasone will not be 
provided by Amgen. 
The planned dose (mg), actual dose (mg) administered, start date/time, stop date/time, 
reason for change in planned dose, reason for dose change/withheld, reason for dose 
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delay, and package lot number of lenalidomide and/or dexamethasone is to be recorded 
on each subject's eCRF(s). 
7.1.4 
Medical Devices 
There are no investigational medical devices being 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 provided or reimbursed by Amgen.  The investigator will 
be responsible for obtaining supplies of these devices. 
7.1.5 
Other Protocol-required Therapies 
All other protocol-required therapies listed below are commercially available and will not 
be provided by Amgen.  The investigator will be responsible for obtaining supplies of 
these protocol-required therapies. 
7.1.5.1 
Antiviral Prophylaxis 
An antiviral is required concomitant medication for the duration of treatment with 
Kyprolis.  Acyclovir (eg, 400 mg PO 3 times a day, or 800 mg PO 2 times a day or per 
institutional standards), famcyclovir (eg, 125 mg PO given 3 days, twice a day or per 
institutional standards), or valacyclovir (eg, 500 mg PO, twice 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 Kyprolis. 
7.1.5.2 
Proton-pump Inhibitor 
Proton-pump inhibitor (omeprazole or equivalent) is required while on dexamethasone. 
7.1.5.3 
Prophylaxis for Hepatitis B Virus 
Hepatitis B virus reactivation prophylaxis should be considered for patients at risk 
(ie, patients tested positive on serology or had a prior history of HBV infection), as 
per institutional guidelines. 
7.1.5.4 
Supportive Therapies 
Refer to the local Kyprolis Prescribing Information for Warnings and Precautions, as 
well as recommended supportive therapies and medications. 
7.1.6 
Other Treatment Procedures 
Not applicable. 
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7.1.7 
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 drug(s), device(s) or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) includes investigational product.   
 
Kyprolis 
Any product complaint(s) associated with an investigational product(s), 
non-investigational product(s), device(s), or combination product(s) supplied by Amgen 
are to be reported according to the instructions provided in the IPIM. 
7.1.8 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Concurrent therapy with a marketed or investigational anticancer therapeutic or radiation 
to large bone marrow reserves for either palliative or therapeutic intent is excluded. 
Corticosteroids given short-term (up to 2 weeks) for nonmalignant conditions (eg, 
asthma, inflammatory bowel disease) are permitted provided that the cumulative 
dose is less than 40 mg per week dexamethasone or equivalent dose (see 
Appendix 12 for corticosteroid dose equivalents).  Medical monitor should be 
contacted if short-term corticosteroid use is required  2 weeks or at cumulative 
dose of more than 40 mg dexamethasone equivalent or 20 mg for subjects 
 75 years of age.  Investigational agents are not to be used during the study. 
7.2 
Method of Treatment Assignment 
The assignment of subjects to protocol treatment will be decided by the investigator 
based on clinical evaluation before the decision to include the subject in this study.  
Subjects who meet eligibility criteria will be included in the study. 
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment eCRF. 
7.3 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
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7.4 
Dose Modification 
Kyprolis may be discontinued, temporarily delayed, or dosage reduced, in the event of a 
treatment-related toxicity that, in the opinion of the investigator, warrants the 
discontinuation, temporary delay or dose reduction, as indicated in the Kyprolis 
Prescribing Information (refer to Posology and method of administration and Special 
warnings and precautions for use sections).  See the lenalidomide and 
dexamethasone Prescribing Information respectively for dosing recommendations. 
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. 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.1.1 
Amgen Investigational Product:  Kyprolis 
The reason for dose change of Kyprolis is to be recorded on each subject’s eCRF(s).  A 
subject is considered to be on protocol treatment while receiving Kyprolis.  See Table 5 
of the Kyprolis Prescribing Information for guidance on dose modifications for toxicity 
during Kyprolis treatment. 
7.4.1.2 
Non-Amgen Non-investigational Product:  Lenalidomide and 
Dexamethasone 
The reason for dose change of lenalidomide and dexamethasone is to be recorded on 
each subject’s eCRF(s). 
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product are provided in the IPIM. 
7.6 
Treatment Compliance 
Administration of IV medicinal products will occur at the study site. 
Oral medication may be dispensed for self-administration at home.  Subjects are to 
document all administered doses and missed doses in a medication diary for all 
study-required medication taken at home.  Subjects are to be instructed to return the 
medication diary at each visit.  Non-compliance is to be documented in the medical file 
and will be reflected in the eCRF.  Non-compliant subjects are to be re-educated on the 
importance of adhering to the study drug administration schedule and reminded that 
repeated cycles of non-compliance could be a reason for discontinuation of study 
treatment. 
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7.7 
Treatment of Overdose 
Refer to the local Kyprolis label for signs and symptoms of overdose (Section 4.9). 
In the event of an overdose, the patient should be monitored, specifically for the side 
effects and/or adverse drug reactions in the product label. 
7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
Prior therapies that were being taken/used from 30 days prior to enrollment through 
signing the informed consent will be collected.  All prior medications that continue after 
the informed consent are to be recorded as concomitant medication. 
For prior therapies being taken for multiple myeloma (eg, chemotherapy), collect therapy 
name, dose, outcome, start date and stop date.  For all other prior therapies, collect 
therapy name, indication, dose, unit, frequency, route, start date and stop date and enter 
in the subject’s eCRF. 
Prior lines of multiple myeloma treatment are defined as a planned course of therapy.  
Therefore, during initial treatment, the induction ± autologous stem cell 
transplant ± consolidation and maintenance would be considered 1 line of therapy (see 
Appendix 9 for additional guidance on lines of therapy). 
7.8.2 
Concomitant Treatment 
A concomitant medication is defined as any prescription or over-the-counter preparation 
including vitamins and supplements.  Throughout the study, investigators may prescribe 
any concomitant medications or treatments deemed necessary to provide adequate 
supportive care except for those listed in Section 7.1.8. 
All administered concomitant medicines and therapies are to be collected from informed 
consent through 30 days following the last dose of Kyprolis. 
For concomitant therapies being taken, collect therapy name, indication, dose, unit, 
frequency, route, start date, stop date, and enter in the subject’s eCRF. 
Concomitant medications used prophylactically should be described as such in 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 
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and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 8.1, 8.2.1, and 8.2.2. 
8.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study.  If this occurs, the investigator is to discuss with the subject the 
appropriate processes for discontinuation from investigational product including 
completion of an end of study visit 30 days after the last dose of investigational product. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by a separate protocol or as provided for by the local country’s regulatory mechanism, 
based on parameters consistent with Appendix 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 
 
Pregnancy and lactation 
The primary reason for treatment discontinuation will be documented in the eCRF. 
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.  The investigator is to discuss with the 
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subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records. 
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Appendix 6 for further details).  Refer to the Schedule of Activities for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
8.2.1 
Reasons for Removal From Washout, Run-in or Invasive Procedures 
Not applicable. 
8.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Discontinuation of Kyprolis 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
8.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
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. 
9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1).  
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As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before starting any screening procedure.  After the 
subject has signed the ICF, 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. 
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, 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 
re-screening 1 time. 
Rescreen subjects must first be registered as screen failures in IxRS and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 28 day 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 30 days 
after the original signing of the ICF, all screening procedures, including informed 
consent, must be repeated. 
9.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 2-1).  On-study visits may be 
completed within 2 days.  The date of the first dose of investigational product is defined 
as cycle 1 day 1.  All subsequent doses and study visits will be scheduled based on the 
day 1 date.  Administration of protocol-required therapies is to be administered last 
during each visit that it is required. 
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9.1.3 
End of Study 
Upon permanent discontinuation from the study treatment for any reason, the end of 
study visit will be performed approximately 30 (+ 3) days after the last dose of 
investigational product. 
9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
9.2.1 
General Assessments  
9.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed.  Any procedures done as part of routine standard of care prior to signing the 
ICF may be used as long as they fall within the windows specified in the Schedule of 
Activities (Table 2-1). 
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 30 days prior to informed consent.  Medical history will include information 
on the subject’s concurrent medical conditions.  Record all findings on the medical 
history eCRF. 
In addition to the medical history above, multiple myeloma history must date back to the 
original diagnosis.  For subjects who are being referred to the research site, critical 
referral information will constitute multiple myeloma information from source notes. 
9.2.1.4 
Physical Examination 
Physical examination will be performed as per standard of care.  A complete physical 
examination is to include examination of cardiovascular and respiratory systems, 
abdominal examination, and general neurologic examination. 
Clinically significant abnormal physical examination findings identified prior to the signing 
of informed consent should be reported as part of medical history, not as adverse 
events.  Physical examination findings should be recorded on the appropriate eCRF (eg, 
medical history, event). 
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9.2.1.5 
Physical Measurements 
Weight (in kilograms) and height (in centimeters) will be measured (height will be 
measured only at the screening physical examination).  Body surface area will be 
determined per institutional guidelines/standards. 
9.2.1.6 
Performance Status 
The subject’s performance status will be assessed using the ECOG performance scale 
(see Appendix 10) at intervals identified in the Schedule of Assessments (Table 2-1).  
9.2.2 
Efficacy Assessments 
Disease status will be evaluated by the investigator using IMWG-URC (see 
Appendix 11) starting from screening until EOT and documented at intervals specified in 
the Schedule of Activities (Table 2-1).  Patients with confirmed sCR, CR, VGPR, or PR 
will be considered to have achieved an overall response. 
9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(Table 2-1). 
9.2.3.1 
Adverse Events 
9.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
9.2.3.1.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE and is 
described in Appendix 4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product(s) through the end of study visit are reported using the Event eCRF. 
9.2.3.1.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after the last dose of investigational product are reported using 
the Event eCRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours, as indicated in Appendix 4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 
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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 Appendix 4. 
9.2.3.1.1.4 
Reporting a Safety Endpoint as a Study Endpoint 
Not applicable. 
9.2.3.1.1.5 
Serious Adverse Events That Are Not to be Reported by the Sponsor 
to Regulatory Agencies in an Expedited Manner 
Not applicable. 
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 Appendix 4. 
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All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event eCRF. 
9.2.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
9.2.3.1.5 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and, if indicated, female 
partners of male subjects will be collected after the start of study treatment and until 
30 days following the last dose of investigational product. 
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 Appendix 5.  
Amgen Global Patient Safety will follow-up with the investigator regarding additional 
information that may be requested. 
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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 Appendix 5. 
9.2.3.2 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Vital sign measurements are performed prior to 
administration of study drug(s) in all cycles. 
Subjects must be in a rested and calm state for at least 5 minutes before blood pressure 
assessments are conducted.  The position selected for a subject should be the same 
that is used throughout the study and documented in the medical record and on the vital 
sign eCRF.  Take at least 2 blood pressure measurements spaced 1 to 2 minutes apart 
and additional measurements if the first 2 are quite different (Appendix 8).  Record the 
average blood pressure on the vital sign eCRF. 
The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the vital signs eCRF. 
9.2.3.3 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  The ECG must 
include the following measurements:  heart rate, QRS, QT, QTc, and PR intervals. 
The primary investigator will review all ECGs.  Once signed, the original ECG tracing will 
be retained with the subject’s source documents.  At the request of the sponsor, a copy 
of the original ECG will be made available to Amgen. 
Electrocardiograms will be required in all subjects at screening and may be repeated 
more often, if clinically indicated. 
9.2.3.4 
Other Safety 
9.2.3.4.1 
Echocardiogram 
All subjects will have a baseline transthoracic ECHO (TTE) or MUGA during 
screening, including assessments of systolic and diastolic left ventricular 
function and right ventricular function.  Echocardiograms are to be repeated every 
6 months ( 2 weeks), at the end of study, and/or if clinically indicated.  An ECHO 
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must be performed within 72 hours of the onset of a suspected cardiac failure 
event. 
9.2.3.4.2 
Hepatitis B 
All hepatitis testing will be performed locally.  All subjects will be tested at 
screening for HBsAg, anti-HBs, and anti-HBc, unless performed within 6 months 
of screening and there was no change in the subject’s risk factors within these 
6 months. 
Subjects with no history of HBV infection that are negative for hepatitis serologies 
at screening should be followed as clinically indicated. 
Subjects with positive testing or who have a prior history of HBV infection should 
have consultation with a specialist in HBV and have HBV DNA testing and 
monitoring of HBV DNA every 12 weeks  2 weeks through end of study visit.  
Subjects that have received hepatitis B vaccination with only anti-HBs positivity 
and no clinical signs of hepatitis do not require HBV DNA monitoring. 
Any subject who becomes HBV DNA positive or develops reactivation of HBV will 
have study treatment interrupted and received appropriate anti-viral treatment as 
per a specialist in hepatitis B.  Resumption of clinical study treatment may be 
considered in subjects whose HBV reactivation is controlled and where the 
benefits of clinical study treatment outweigh the risks.  After cessation of study 
treatment for any reason, any ongoing monitoring and anti-viral treatment should 
be under the guidance of a specialist in HBV. 
9.2.4 
Clinical Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event eCRF.  The 
investigator must determine whether an abnormal value in an individual study subject 
represents a clinically significant change from the subject’s baseline values.  In general, 
abnormal laboratory findings without clinical significance (based on the investigator's 
judgment) are not to be recorded as adverse events.  However, laboratory value 
changes that require treatment or adjustment in current therapy are considered adverse 
events.  Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event. 
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All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities. 
9.2.4.1 
Pregnancy Testing 
A high sensitive (urine or serum) pregnancy test should be completed at screening 
(within 10 to 14 days of initiation of investigational product) and a urine pregnancy test 
within 24 hours prior to initiation of investigational product for females of childbearing 
potential.   
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 Appendix 5 for contraceptive requirements and 
Table 12-2 for lenalidomide-specific contraception requirements.  
Additional pregnancy testing should be performed within 24 hours prior to day 1 of each 
subsequent cycle and 30 days after the last dose of protocol-required therapies. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
10. 
Statistical Considerations 
10.1 
Sample Size Determination 
Approximately 100 subjects with previously treated RRMM will be enrolled as directed by 
the Indian Regulatory Authority. 
A total of 100 subjects is large enough, with 95% confidence, to rule out an adverse 
event incidence rate greater than 3.6% if none is observed. 
10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
The primary analysis of safety and efficacy will be performed on the Safety Analysis Set.  
The Safety Analysis Set will include all subjects who received at least 1 dose of the 
investigational product. 
10.2.2 
Covariates 
The relationship of baseline covariates to endpoints will be explored if appropriate. 
10.2.3 
Subgroups 
The baseline covariates will be explored if appropriate to examine safety and efficacy in 
subgroups.  
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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 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).  No imputation will be done for the primary analysis of the primary and key 
secondary endpoints. 
Details of missing data analysis and imputation rules will be described in 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 
Primary Analysis 
The primary analysis will occur when the last subject enrolled has had the opportunity to 
receive the study treatment for at least 9 months. 
10.3.1.2 
Final Analysis 
The final analysis will occur when last subject completes the last assessment in the 
study (last subject last visit) or a study duration up to 3 years, whichever occurs earlier. 
10.3.2 
Methods of Analyses 
10.3.2.1 
General Considerations 
In general, summaries of all data will be presented mainly by overall safety analysis set 
and also by different regimens, including Kd and KRd. 
Summary statistics will be provided for selected endpoints.  For continuous variables, 
the number of subjects with non-missing data (n), mean, standard deviation, median, 
minimum, and maximum will be presented.  For categorical data, the frequency and 
percent distribution will be presented.  Time to event endpoints will be summarized with 
Kaplan-Meier (KM) curves, KM proportions at select time points, KM quartiles (when 
estimable), the number of subjects with events, the number of subjects censored, and 
the pattern of censoring.  Point estimates for efficacy endpoints will be accompanied by 
2-sided 95% confidence intervals including estimates of KM quartiles 
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(Klein and Moeschberger, 1997), KM proportions (Kalbfleisch and Prentice, 1980), and 
binomial proportions (Clopper and Pearson, 1934). 
10.3.2.2 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
Not Applicable 
Secondary 
Secondary efficacy endpoints include PFS, ORR, CBR, TTR, and DOR. 
PFS is defined as the time from first dose of the study treatment until the 
earliest date of disease progression or death due to any cause, whichever 
is the earliest.  Subjects alive who did not have progression will be 
censored at last date of tumor assessment.  If the last disease assessment 
date is after the date that triggers the analysis, the subject will be censored 
at the analysis trigger date.  PFS will be summarized descriptively using 
with the KM method.  
ORR is defined as the proportion of subjects with either best overall 
response of sCR, CR, VGPR, or PR.  CBR is defined as the proportion of 
subjects with either best overall response of sCR, CR, VGPR, PR, or MR.  
The point estimates of ORR and CBR will be summarized along with exact 
binomial 95% confidence intervals.  
TTR and DOR are calculated only for the responders.  TTR is defined as 
the time from first dose of study treatment to the earliest date a response 
of PR or better is first achieved and subsequently confirmed.  DOR is 
defined as the time from initial response (sCR, CR, VGPR, or PR) to the 
date of disease progression.  A subject who did not have progression of 
disease, or death will be censored at last tumor assessment date.  If the 
last disease assessment date is after the date that triggers the analysis, 
the subject will be censored at the analysis trigger date.  TTR will be 
summarized descriptively.  KM method will be used to analyze DOR. 
Exploratory 
Not applicable 
 
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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 
The subject incidence, severity, and outcome of treatment emergent adverse 
events using NCI CTCAE v. 4.03 including clinical significant laboratory 
parameter changes over time.  
Each reported adverse event term will be mapped to a Preferred Term and a 
System Organ Class (SOC) using the Medical Dictionary for Regulatory 
Activities (MedDRA).  Treatment-emergent adverse events are defined as 
adverse events that start on or after the first day of study treatment and within 
30 days of the last day of study treatment. 
Treatment-emergent adverse events will be summarized based on the 
number (%) of subjects experiencing events by MedDRA SOC and preferred 
term.  The denominator for the percentage will be based on the number of 
subjects in the Safety population.  
A subject reporting the same treatment-emergent adverse event more than 
once will be counted only once when calculating 1) within a given SOC, and 
2) within a given SOC and preferred term combination.  For such cases, the 
maximum NCI; US - CTCAE 4.03 toxicity grade and strongest causal 
relationship to study treatment for the event will be used in the incidence 
calculations.  Treatment-emergent adverse events will also be summarized by 
severity, seriousness, and by relationship to study treatment. 
 
10.3.2.3.2 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class, preferred term, and severity grade.  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 by 
treatment group.  Changes will be calculated relative to the baseline visit.  Shifts in 
grades of safety laboratory values between the baseline and the worst on-study value 
will be tabulated by treatment group. 
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10.3.2.3.4 
Vital Signs 
The analyses of vital signs will include summary statistics at selected time points by 
treatment group.  Changes will be calculated relative to the baseline visit.  Shifts in vital 
sign values between the baseline and the worst on-study value will be tabulated by 
treatment group. 
10.3.2.3.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics at scheduled 
time points by treatment group.  Changes will be calculated relative to the baseline visit. 
10.3.2.3.6 
Electrocardiogram 
The ECG measurements from this clinical study were performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.  Since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data; summaries and 
statistical analyses of ECG measurements are not planned, and these data would not be 
expected to be useful for meta-analysis with data from other trials. 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters. 
10.3.2.3.7 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to Kyprolis.  The number 
of cycles will be summarized with an additional breakdown of the number of cycles 
completed, discontinued, and re-started.  In addition, the duration of therapy, the 
cumulative dose, and the percent of intended dose will be summarized by cycle and 
overall.  The number and percent of subjects with dose modifications (eg, dose changes 
and dose interruptions) and reason for modification will be summarized. 
Descriptive statistics will be produced to describe the exposure to non-Amgen 
non-investigational products (dexamethasone and/or lenalidomide).  The cumulative 
dose, number of cycles, duration of usage, number and percentage of subjects with 
dose modifications, reasons for modification will be summarized using descriptive 
statistics. 
10.3.2.3.8 
Exposure to Other Protocol-required Therapy 
Descriptive statistics of average daily dose and duration of usage will be produced to 
describe the exposure to other protocol-required therapies by treatment group. 
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10.3.2.3.9 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving concomitant medications will be 
summarized by preferred term or category as coded by the World Health Organization 
Drug (WHODRUG) dictionary. 
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11. 
References 
Arastu-Kapur S, Shenk KD, Kirk CJ, et al.  Nonproteasomal targets of proteasome 
inhibitors bortezomib and carfilzomib [abstract].  Haematologica.  2009;94(s2).  14th 
Congress of the European Hematology Association.  Abstract 0939. 
Carfilzomib Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
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. 
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 uniform response criteria for 
multiple myeloma.  Leukemia.  2006;20(9):1467-1473. 
Ferlay J, Soerjomataram I, Dikshit R, et al.  Cancer incidence and mortality worldwide:  
sources, methods and major patterns in GLOBOCAN 2012.  Int J Cancer.  
2015;136(5):E359-E386. 
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/ 
International Committee of Medical Journal Editors (ICMJE), Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
Kalbfleisch JD, Prentice RL.  The Statistical Analysis of Failure Time Data, New York:  
John Wiley & Sons, 1980. 
Klein JP, Moeschbeger ML.  Survival Analysis:  Techniques for Censored and Truncated 
Data, New York:  Springer-Verlag, 1997. 
Kuhn DJ, Chen Q, Voorhees PM, et al.  Potent activity of carfilzomib, a novel, 
irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of 
multiple myeloma.  Blood.  2007;110(9):3281-3290. 
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, Therneau TM, Gertz MA, et al.  Clinical course of patients with relapsed 
multiple myeloma.  Mayo Clin Proc.  2004;79:867-874. 
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. 
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 PG, Sonneveld P, Schuster MW, et al.  Extended follow-up of a phase 3 trial 
in relapsed multiple myeloma:  final time-to-event results of the APEX trial.  Blood.  
2007;110(10):3557-3560. 
Suzuki E, Demo S, Deu E, et al.  Molecular mechanisms of bortezomib resistant 
adenocarcinoma cells.  PLos ONE.  2011;6(12):e27996. 
WHO Fact Sheet:  http://globocan.iarc.fr/Pages/fact_sheets_population.aspx 
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12. 
Appendices 
 
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Appendix 1.  List of Abbreviations and Definitions of Terms 
Abbreviation or Term 
Definition/Explanation 
ANC 
absolute neutrophil count 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BSA 
body surface area 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CR 
complete response 
CrCl 
creatinine clearance 
DOR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
eCRF 
electronic case report form 
ESC 
European Society of Cardiology 
ESH 
European Society of Hypertension 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Study (primary 
completion) 
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  
End of Study (end of trial) 
defined as the date when the last subject 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 
eSAE 
electronic serious adverse event 
FCBP 
females of childbearing potential 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
anti-HBc 
Hepatitis B core antibody 
anti-HBs 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
hepatitis B virus 
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Abbreviation or Term 
Definition/Explanation 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
HRT 
hormonal replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IMiD 
immunomodulatory agent 
IMWG-URC 
International Myeloma Working Group-Uniform Response 
Criteria 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
IV 
intravenous 
IxRS 
Interactive Voice/Web Response System   
Kd 
Kyprolis in combination with dexamethasone 
KM 
Kaplan-Meier 
KRd 
Kyprolis in combination with lenalidomide plus dexamethasone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
minimal response 
MUGA 
multigated acquisition scan 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PN 
peripheral neuropathy 
PO 
orally 
POEMS 
polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes 
POR 
proof of receipts 
PR 
partial response 
QTc 
corrected QT interval 
RBC 
red blood cell 
RRMM 
relapsed or refractory multiple myeloma 
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Abbreviation or Term 
Definition/Explanation 
SAg 
surface antigen 
SAP 
statistical analysis plan 
SBECD 
sulfobutylether beta-cyclodextrim sodium 
sCR 
stringent complete response 
SD 
stable disease 
SFLC 
serum free light chains 
SOC 
system organ class 
SPEP 
serum protein electrophoresis 
SPD 
maximal perpendicular diameter 
SUSAR 
suspected unexpected serious adverse reaction 
sWFI 
sterile water for injection 
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. 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TTE 
transthoracic echocardiogram 
TTR 
time to response 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
US FDA 
United States Food and Drug Administration’s 
VGPR 
very good partial response 
WHODRUG 
World Health Organization Drug 
 
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Appendix 2.  Clinical Laboratory Tests 
All laboratory tests detailed in Table 12-1 will be performed by the local laboratory.  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 6.1 to 6.2. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Evaluation of lab results for dose determination as required per Schedule of 
Assessments must be documented prior to dosing in each cycle.  Any local lab values 
that lead to dose modification decisions must be recorded in the electronic case report 
form (eCRF).  Any local lab results that fulfill  grade 3 values per CTCAE must be 
recorded in the eCRF.  For cycle 1 day 1, hematology and serum chemistry panel from 
screening may be used if within 14 days of day 1.  For subsequent visits in cycle 1, 
hematology and chemistry may be completed up to 72 hours prior to scheduled dose 
weekly for cycle 1.  Starting in cycle 2, only day 1 is required. 
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Table 12-1.  Analyte Listing 
Chemistry 
Coagulation 
Hematology 
Other Labs 
Amylase (screening only) 
Lipase (screening only) 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Calcium corrected (if 
albumin < 4) 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Creatinine clearance (CrCl) 
Uric acid 
Total bilirubin 
Direct bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
PT 
PTT/INR 
(aPTT or PTT) 
Circulating plasma 
cells (screening only) 
RBC count 
Hemoglobin 
Hematocrit 
Platelet count 
WBC count with 
differential: 
 
Neutrophils 
 
Eosinophils 
 
Basophils 
 
Lymphocytes 
 
Monocytes 
Serum or highly 
sensitive urine 
pregnancy  
NTproBNPa 
BNPa 
CK2b 
CPKMBb 
Troponin Ib 
Troponin Tb 
Hepatitis B 
serologies (HBsAg, 
anti-HBs, and 
anti-HBc)c 
HBV DNAd 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; BNP = b-type natriuretic peptide; BUN = blood urea nitrogen; 
CK2 = creatine kinase 2; CPKMB = creatine kinase-muscle/brain; anti-HBc = hepatitis B core 
antibody; anti-HBs = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; INR = international normalized ratio; LDH = lactate dehydrogenase; 
NTproBPN = N-terminal pro b-type natriuretic peptide; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; SGOT = serum glutamic-oxaloacetic transaminase; 
SGPT = serum glutamic-pyruvic transaminase; WBC = white blood cell count.  
a NTproBNP is only required at screening and BNP can be recorded if NTproBNP is not available. 
b As clinically indicated.  
c Testing is required for all subjects at screening unless obtained within 6 months of screening and 
there was no change in the subject’s risk factors within these 6 months. 
d If prior history of HBV infection obtain HBV DNA at screening and every 12 weeks through safety 
follow-up.   Subjects that have received hepatitis B vaccination with only anti-HBs positivity and no 
clinical signs of hepatitis do not require HBV DNA monitoring. 
Approved 
 
 


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Appendix 3.  Study Governance Considerations 
Data Monitoring Committee(s) 
Not applicable. 
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 (CIOMS) International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure, and other relevant documents (eg, subject recruitment advertisements) must 
be submitted to an Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
by the investigator and reviewed and approved by the IRB/IEC.  A copy of written 
approval for study protocol issued by Health Authority and a copy of the written approval 
of the protocol and ICF issued by the IRB/IEC must be received from the investigator, by 
Amgen before recruitment of subjects into the study and shipment of Amgen 
investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
Approved 
 
 


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 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the US Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Informed Consent Process 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the sample ICF are to be 
communicated formally in writing from the Amgen Trial Manager to the investigator.  The 
written ICF is to be prepared in the language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICF. 
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. 
Approved 
 
 


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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 ICF is to be signed and personally dated by the subject or a legally 
acceptable representative and by the person who conducted the informed consent 
discussion.  Subject withdrawal of consent or discontinuation from study treatment 
and/or procedures must also be documented in the subject’s medical records; refer to 
Section 8. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
The original signed ICF is to be retained in accordance with institutional policy, and a 
copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF 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 ICF if the rescreening occurs 
within 30 days from the previous ICF 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 electronic case report form (eCRF) demographics page, in addition to the unique 
subject identification number, include the age at time of enrollment. 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
Approved 
 
 


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In compliance with ICH GCP Guidelines, it is required that the investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the 
IRB/IEC direct access to review the subject’s original medical records for verification of 
study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of 
the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, the investigator will obtain input and 
assistance from Amgen staff as appropriate. 
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 (ICMJE 2013) Recommendations for 
the Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical 
Journals, which states: 
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above. 
Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship. 
All persons designated as authors must qualify for authorship, and all those who qualify 
are to be listed. 
Each author must have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content. 
Approved 
 
 


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All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An Investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or eCRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements per the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing eCRFs, are resolved. 
Approved 
 
 


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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, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, ICH 
GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
eCRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language.  Consult the country-specific 
language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
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 eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
eCRF 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 eCRF entries if the eCRF 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 entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained.  The 
Approved 
 
 


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CONFIDENTIAL   
 
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 ICFs, and subject identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the [IRB/IEC] 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts (POR), 
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.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
Approved 
 
 


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CONFIDENTIAL   
 
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, echocardiogram [ECG], radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered clinically 
significant in the medical and scientific judgment of the investigator (ie, not related to 
progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported regardless of 
sequelae. 
 
For situations when an adverse event or serious adverse event is due to multiple myeloma 
report all known signs and symptoms.  Death due to disease progression in the absence of 
signs and symptoms should be reported as the primary tumor type (eg, 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. 
Approved 
 
 


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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. 
Approved 
 
 


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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 electronic case report form (eCRF). 
 
Additionally, the investigator is required to report a fatal disease-related event on the 
Event eCRF. 
 
The investigator must assign the following adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
 
Dates of onset and resolution (if resolved); 
 
Severity (or toxicity defined below); 
 
Assessment of relatedness to investigational product, and 
 
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 eCRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to Amgen in lieu of completion of the Event eCRF 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 (CTCAE), version 4.03 which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Approved 
 
 


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Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational product, 
protocol-required therapies, and each occurrence of each adverse event/serious adverse 
event. 
 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product Information, 
for marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in the 
medical notes that he/she has reviewed the adverse event/serious adverse event and has 
provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up information 
and send a serious adverse event follow-up report with the updated causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Amgen to 
elucidate the nature and/or causality of the adverse event or serious adverse event as fully 
as possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up period, 
the investigator will provide Amgen with a copy of any post-mortem findings including 
histopathology. 
 
New or updated information will be recorded in the originally completed Event eCRF. 
 
The investigator will submit any updated serious adverse event data to Amgen within 
24 hours of receipt of the information. 
Approved 
 
 


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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 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 Event (eSAE) Contingency 
Report Form (see Figure 12-1) within 24 hours of the investigator’s knowledge of the event. 
 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or receives 
updated data on a previously reported serious adverse event after the EDC has been 
taken off-line, then the site can report this information on the eSAE Contingency Report 
Form (see Figure 12-1). 
Approved 
 
 


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


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Approved 
 
 


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Approved 
 
 


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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.  For subjects receiving Kyprolis in combination with 
lenalidomide plus dexamethasone (KRd) triplet therapy, see Table 12-2 for 
lenalidomide-specific contraceptive guidelines. 
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, during treatment interruptions, and for: 
 
female subjects:  30 days after the last dose of Kyprolis 
 
male subjects:  90 days after the last dose of Kyprolis 
Kyprolis could decrease the effectiveness of oral contraceptives.  The investigator 
should notify subjects of this risk when choosing the methods of birth control. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and for an increased length of time.  In addition, male subjects 
may also be required to use contraception.  The investigator must discuss these 
contraceptive changes with the subject.  For subjects receiving KRd triplet therapy, see 
Table 12-2 for lenalidomide-specific contraceptive guidelines. 
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. 
Approved 
 
 


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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 
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 (IUD) 
 
Intrauterine hormonal-releasing system (IUS) 
 
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, IUD, IUS, female barrier method (diaphragm, cap, 
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sponge [a female condom is not an option because there is a risk of tearing when both 
partners use a condom]). 
Note:  If the male’s sole female partner is of non-childbearing potential or has had a 
bilateral tubal ligation/occlusion, he is not required to use additional forms of 
contraception during the study. 
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 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 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. 
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 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Appendix 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 last dose of 
protocol-required therapies. 
 
Information will be recorded on the Lactation Notification Worksheet (Figure 12-2) 
and submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
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 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion (See Section 6.2). 
 
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 last dose of 
protocol-required therapies after discontinuing protocol-required therapies. 
Table 12-2.  Lenalidomide:  Contraceptive Guidelines and Collection of Pregnancy 
and Lactation Information 
Risks Associated with Pregnancy 
(For the region specific use of lenalidomide, please refer to the regional label) 
Lenalidomide is structurally related to thalidomide.  Thalidomide is a known human teratogenic 
active substance that causes severe life-threatening birth defects.  An embryo fetal 
development study in animals indicates that lenalidomide produced malformations in the 
offspring of female monkeys who received the drug during pregnancy.  The teratogenic effect 
of lenalidomide in humans cannot be ruled out.  Therefore, a risk minimization plan to prevent 
pregnancy must be observed. 
Criteria for Females of Childbearing Potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman who:  
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 
24 consecutive months). 
Counseling 
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following 
are met (ie, all females of childbearing potential must be counseled concerning the following 
risks and requirements prior to the start of lenalidomide study therapy): 
 
She understands the potential teratogenic risk to the unborn child  
 
She understands the need for effective contraception, without interruption, 4 weeks before 
starting study treatment, throughout the entire duration of study treatment, dose 
interruption, and 28 days after the end of study treatment 
 
She should be capable of complying with effective contraceptive measures  
 
She is informed and understands the potential consequences of pregnancy and the need 
to notify her study doctor immediately if there is a risk of pregnancy  
Page 1 of 4 
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Table 12-2.  Lenalidomide:  Contraceptive Guidelines and Collection of Pregnancy 
and Lactation Information 
Counseling (Continued) 
 
She understands the need to commence the study treatment as soon as study drug is 
dispensed following a negative pregnancy test  
 
She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol 
 
She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
The investigator must ensure that for females of childbearing potential: 
 
Complies with the conditions for pregnancy risk minimization, including confirmation that 
she has an adequate level of understanding  
 
Acknowledge the aforementioned requirements 
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the 
following are met (ie, all females NOT of childbearing potential must be counseled concerning 
the following risks and requirements prior to the start of lenalidomide study therapy): 
 
She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
 
Traces of lenalidomide have been found in semen.  Male subjects taking lenalidomide 
must meet the following conditions (ie, all males must be counseled concerning the 
following risks and requirements prior to the start of lenalidomide study therapy): 
 
Understand the potential teratogenic risk if engaged in sexual activity with a pregnant 
female or a female of childbearing potential  
 
Understand the need for the use of a condom even if he has had a vasectomy, if 
engaged in sexual activity with a pregnant female or a female of childbearing potential. 
Contraception 
FCBP enrolled in this protocol must agree to use 2 reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual contact during the 
following time periods related to this study:  1) for at least 28 days before starting study drug; 
2) while participating in the study; 3) dose interruptions; and 4) for at least 28 days after study 
treatment discontinuation.  
The 2 methods of reliable contraception must include 1 highly effective method and 
1 additional effective (barrier) method.  FCBP must be referred to a qualified provider of 
contraceptive methods if needed.  The following are examples of highly effective and additional 
effective methods of contraception: 
Highly effective methods: 
 
IUD 
 
Hormonal (birth control pills, injections, implants) 
 
Tubal ligation 
 
Partner’s vasectomy 
Page 2 of 4 
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Table 12-2.  Lenalidomide:  Contraceptive Guidelines and Collection of Pregnancy 
and Lactation Information 
Contraception (Continued) 
Additional effective methods: 
 
Male condom or female condom, with or without spermicide 
 
Diaphragm with spermicide 
 
Cervical Cap with spermicide 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased 
risk of infection at the time of insertion and irregular vaginal bleeding.  Prophylactic antibiotics 
should be considered particularly in subjects with neutropenia. 
Pregnancy Testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below. 
Before Starting Lenalidomide 
Female Subjects 
 
FCBP must have 2 negative pregnancy tests (combined sensitivity of at least 50 mIU/mL) 
prior to starting lenalidomide.  The first pregnancy test must be performed within 10 to 
14 days prior to the start of lenalidomide and the second pregnancy test must be 
performed within 24 hours prior to the start of lenalidomide.  The subject may not receive 
lenalidomide until the Investigator has verified that the results of these pregnancy tests are 
negative. 
 
Will be warned that sharing study drug is prohibited and will be counseled about pregnancy 
precautions and potential risks of fetal exposure. 
 
Must agree to abstain from donating blood during study participation and for at least 
28 days after discontinuation from the study. 
Male Subjects 
 
Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following discontinuation 
from the study even if he has undergone a successful vasectomy. 
 
Will be warned that sharing study drug is prohibited and will be counseled about pregnancy 
precautions and potential risks of fetal exposure. 
 
Must agree to abstain from donating blood, semen, or sperm during study participation and 
for at least 28 days after discontinuation from the study. 
Page 3 of 4 
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Table 12-2.  Lenalidomide:  Contraceptive Guidelines and Collection of Pregnancy 
and Lactation Information 
During Study Participation and for 28 Days Following Discontinuation From the Study 
Female Subjects 
 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, at study 
discontinuation, and at day 28 following discontinuation from the study.  If menstrual cycles 
are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 
14 days while on study, at study discontinuation, and at days 14 and 28 following 
discontinuation from the study. 
 
In addition to the required pregnancy testing, the Investigator must confirm with FCBP that 
she is continuing to use 2 reliable methods of birth control at each visit. 
 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days and at the time that lenalidomide treatment is 
discontinued.  During counseling, subjects must be reminded to not share study drug and 
to not donate blood. 
 
Pregnancy testing and counseling must be performed if a subject misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment must 
be discontinued during this evaluation. 
 
Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after discontinuation from the study. 
 
If pregnancy or a positive pregnancy test does occur in a study subject, study drug must be 
immediately discontinued. 
Male Subjects 
 
Counseling about the requirement for latex condom use during sexual contact with females 
of childbearing potential and the potential risks of fetal exposure must be conducted at a 
minimum of every 28 days and at the time that lenalidomide treatment is discontinued.  
During counseling, subjects must be reminded to not share study drug and to not donate 
blood, sperm, or semen. 
 
If pregnancy or a positive pregnancy test does occur in the partner of a male study subject 
during study participation, the investigator must be notified immediately. 
Additional Precautions 
 
Subjects should be instructed never to give this medicinal product to another person and to 
return any unused capsules to the study doctor at the end of treatment.  
 
Female subjects should not donate blood during therapy and for at least 28 days following 
discontinuation of study drug.  
 
Male subjects should not donate blood, semen or sperm during therapy or for at least 
90 days following discontinuation of study drug.  
 
Only enough study drug for 1 cycle of therapy may be dispensed with each cycle of 
therapy. 
Page 4 of 4 
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Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 
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Appendix 6.  Sample Storage and Destruction 
Not applicable. 
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Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and Follow-up 
Assessments 
Please refer to Sections 7.1.2.1, 7.1.2.2, and 7.4.1.1 for details regarding dose 
modification and toxicity. 
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Appendix 8.  2013 ESH/ESC Office Blood Pressure Measurement 
 
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Appendix 9.  Guidelines for Documenting Prior Treatment 
Subjects must have documented relapse after at least 1, but no more than 3 prior 
treatment regimens or lines of therapy for multiple myeloma.  When documenting prior 
treatments for multiple myeloma, the following guidelines should be used: 
 
A new line of therapy is considered to start when a planned course of therapy is 
modified to include other treatment agents (alone or in combination) as a result of 
lack of adequate response, progressive disease (PD) (even if the level of 
progression has not yet met International Myeloma Working Group-Uniform 
Response Criteria [IMWG-URC] for PD), relapse, or toxicity. 
 
An increase in dose of therapy, with the intention of recapturing response in a 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 
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Appendix 10.  ECOG Performance Scale 
Grade 
Description 
0 
Normal activity, fully active, able to carry on all predisease performance 
without restriction. 
1 
Symptoms, but fully ambulatory, restricted in physically strenuous but 
ambulatory and able to carry out work of a light or sedentary nature 
(eg, light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead 
ECOG = Eastern Cooperative Oncology Group. 
Source:  Oken et al, 1982. 
Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair 
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Appendix 11.  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 by 
immunohistochemistry or 2- to 4-color FC  
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 
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 
 
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 
Stable Disease 
 
Not meeting criteria for CR, VGPR, PR, or PD 
Page 1 of 2 
Footnotes defined on the next page of the table. 
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Summary of International Myeloma Working Group-Uniform Response Criteria 
(IMWG-URC) 
Response 
Subcategory 
Multiple Myeloma Response Criteria 
PD 
 
Increase of 25% from lowest response value in one or more of the 
following: 
 
Serum M-component (absolute increase must be ≥ 0.5 g/dL) 
and/or 
 
Urine M-component (absolute increase must be ≥ 200 mg per 
24 hours) and/or 
 
Only in patients without measurable serum and urine 
M protein levels:  the difference between involved and 
uninvolved FLC levels (absolute increase must be 
> 10 mg/dL) 
 
Only in patients without measurable serum and urine 
M-protein levels and without measurable disease by FLC 
levels, bone marrow plasma cell 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  
 
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; FC = flow cytometry; FLC = free light chain; IMWG-URC = International Myeloma 
Working Group-Uniform Response Criteria MR = minimal response; PD = progressive disease; PR = partial 
response; sCR = stringent complete response; SFLC = serum free light chain; SPD = maximal perpendicular 
diameter; 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 initiation of any new therapy, as well as no 
known evidence of progressive or new bone lesions if radiographic studies were 
performed.  Radiographic studies are not required to satisfy these response 
requirements.  Bone marrow, plasmacytoma, and skeletal survey assessments are not 
required to be confirmed by repeat testing.   
For sCR:  presence/absence of clonal cells is based upon the kappa lambda.  
“Measurable” disease is defined by at least 1 of serum protein electrophoresis 
(SPEP) ≥ 0.5 g/dL, urine protein electrophoresis (UPEP) ≥ 200 mg per 24 hours, or in 
subjects without detectable serum or urine M-protein, serum free light chain 
(SFLC) > 100 mg/L (involved light chain) and an abnormal kappa lambda ratio. 
Determination of progressive disease (PD) requires 2 consecutive assessments made at 
any time before classification of PD and/or the institution of new therapy.  Serum 
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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. 
Sources:  Kumar et al, 2016; Rajkumar et al, 2011; Durie et al, 2006. 
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Appendix 12.  Corticosteroid Dose Equivalents 
Equivalent Dose (mg) 
Steroid 
1.5 
dexamethasone (long-acting) 
8 
methylprednisolone (intermediate-acting) 
10 
prednisone (intermediate-acting) 
10 
prednisolone (intermediate-acting) 
40 
hydrocortisone (short-acting) 
 
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CONFIDENTIAL 
 
 
Superseding Amendment 1 
Protocol Title:  Post-marketing Phase 4 Study to Evaluate Safety, Tolerability, and 
Efficacy of Kyprolis® (Carfilzomib) in Indian Patients With Relapsed or Refractory 
Multiple Myeloma:  A Prospective, Open-label, Non-comparative, Multicenter 
Study 
 
Amgen Protocol Number (carfilzomib) 20160372 
 
Amendment Date: 
08 October 2019 
Superseding Amendment Date: 
29 October 2019 
 
Superseding Amendment 1 Rationale:  Superseding amendment 1 has been issued 
to correct a shift in eligibility criteria numbering introduced in Amendment 1.  The 
correction is required to avoid extensive reprogramming in IVRS and RAVE systems.  
Exclusion criterion 216, per protocol amendment 1, has been corrected to exclusion 
criterion 233 and all other exclusion criteria have reverted back to the original criteria 
numbers as was presented in the original protocol.  
Amendment 1 Rationale: 
The protocol is amended to: 
 
Hepatitis B testing (hepatitis B surface antigen, hepatitis B surface antibody, and 
hepatitis B core antibody) has been expanded to include all subjects that do not 
already have a prior medical history of hepatitis B or who have not had testing within 
the previous 12 weeks. Guidance has been provided regarding HBV DNA testing 
and monitoring for subjects with positive hepatitis B serology or a prior history of 
HBV.  In addition, guidance has been provided on the prophylaxis of HBV 
reactivation in patients at risk.  
 
Implement ECHO assessments every 6 months, EOS, and/or if clinically indicated. 
An ECHO must be performed within 72 hours of the onset of a suspected cardiac 
failure. 
 
Removed Self-Evident Corrections as they are no longer completed by DM per 
change in Amgen processes. 
 
Removed Adjusted calcium from lab analyte chart (redundant with Calcium corrected 
[if albumin < 4]). Added NTproBNP, BNP, CK2, CKMB, Troponin I, and Troponin T to 
lab analyte chart 
 
Added clarification around dose adjustments required for change of body weight 
> 20%. 
 
Added clarification around concomitant short- and long-term corticosteroid use. 
 
Added clarification around Intravenous Pre-hydration use. 
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CONFIDENTIAL 
 
 
Description of Changes: 
Section:  Global 
Change:  Minor corrections (eg, correcting typographical and formatting errors) have 
been introduced throughout the protocol. 
Section:  Global 
Change:  Version date has been updated from 09 June 2017 to 29 October 2019 
Section:  Title Page 
Add:  Amendment 1 08 October 2019 
Add:  Superseding Amendment 1 29 October 2019 
Section:  Synopsis, Procedures  
Replace:  Informed consent must be obtained before starting any screening procedure.  
The following procedures will occur per the Schedule of Assessments:  demographics, 
medical/surgical history, physical measurements, vital signs, ECG, ECOG performance 
status, ECHO/multigated acquisition (MUGA) scan, review of adverse event/serious 
adverse event, concomitant medications, and review of disease status.  Laboratory 
assessments will include pregnancy testing, coagulation tests, and hematology and 
chemistry tests. 
With:  Informed consent must be obtained before starting any screening procedure.  The 
following procedures will occur per the Schedule of Assessments:  demographics, 
medical/surgical history, physical measurements, vital signs, ECG, ECOG performance 
status, ECHO/multigated acquisition (MUGA) scan, review of adverse event/serious 
adverse event, concomitant medications, and review of disease status.  Laboratory 
assessments will include pregnancy testing, coagulation tests, hematology, chemistry 
tests, and other analytes specified in Table 12-1. 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 3 of 24 
CONFIDENTIAL 
 
 
Section:  2.2 Schedule of Activities, Table 2-1.  Schedule of Activities 
Replace: 
Procedure 
SCRa 
Treatment Period Days (All Cycles) 
End of 
Study 
Visitb 
Notes 
1 
2 
8 
9 
15 
16 
22 
General and Safety Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
Including multiple myeloma history 
Physical measurements:  height 
X 
 
 
 
 
 
 
 
 
 
Physical measurements:  
weight, BSA 
X 
X 
 
 
 
 
 
 
 
BSA should be calculated per institutional standard and 
utilized to calculate required study drug doses.  BSA 
should be recalculated if there is 20% change in body 
weight. 
Physical examination 
X 
X 
 
 
 
 
 
 
X 
C1D1:  Screening exam may be used if within 7 days prior 
to C1D1. 
ECG 
X 
 
 
 
 
 
 
 
X 
 
Vital signs:  Kd arm (all cycles) 
and KRd arm (cycles 1-12) 
X 
X 
X 
X 
X 
X 
X 
 
X 
Checked prior to administration of study drug in all cycles. 
Vital signs:  KRd arm (cycle 13+) 
 
X 
X 
 
 
X 
X 
 
X 
Checked prior to administration of study drug in all cycles. 
ECOG performance status 
X 
 
 
 
 
 
 
 
X 
 
ECHO/MUGA scan 
X 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes and abbreviation definitions are after last page of table. 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 4 of 24 
CONFIDENTIAL 
 
 
Procedure 
SCRa 
Treatment Period Days (All Cycles) 
End of 
Study 
Visitb 
Notes 
1 
2 
8 
9 
15 
16 
22 
Review of AE/SAE 
Continually 
 
Concomitant medications 
Continually 
Will be collected from 30 days prior to signing of informed 
consent to 30 days after last dose of study treatment. 
Review of disease status 
Performed per local standards 
Disease status will be evaluated by the investigator using 
IMWG-URC starting from screening until EOT. 
Laboratory Assessments 
Serum or urine pregnancy test 
(FCBP)c 
X 
X 
 
 
 
 
 
 
X 
Must be confirmed negative at screening, on day 1 of 
each cycle prior to dosing, and at end of study visit. 
Additional serum or urine 
pregnancy test (KRd-treated 
FCBP only)d:  Cycle 1 
 
Xe 
 
X 
 
X 
 
X 
 
Weekly pregnancy tests required during cycle 1. 
See Table 12-2 for additional information on 
lenalidomide-specific pregnancy testing requirements. 
Coagulation tests 
X 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
(X) 
 
(X) 
 
 
 
C1D1:  Results from screening may be used if taken 
within 14 days prior to C1D1. 
(X):  Day 8 and 15 samples only collected during cycle 1. 
Chemistry 
X 
X 
 
(X) 
 
(X) 
 
 
 
Page 2 of 2 
AE = adverse events; BSA = body surface area; CXDX = cycle X day X; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology 
Group; FCBP = female of child bearing potential; IMWG-URC = International Myeloma Working Group-Uniform Response Criteria; MUGA = multigated acquisition 
scan; SAE = serious adverse event; SCR = screening. 
a Screening:  up to 28 days before enrollment 
b End of study visit is 30 days (+ 3) after last dose of Kyprolis 
c 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. 
d The subject may not receive lenalidomide until the investigator has verified that the results of these pregnancy tests are negative. 
e KRd-treated FCBP must have 2 negative pregnancy tests (combined sensitivity of at least 50 mIU/mL) prior to starting lenalidomide.  The first pregnancy test must be 
performed within 10 to 14 days prior to the start of lenalidomide and the second pregnancy test must be performed within 24 hours prior to the start of lenalidomide.  
If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study discontinuation, and at 
days 14 and 28 following discontinuation from the study. 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 5 of 24 
CONFIDENTIAL 
 
 
With: 
Procedure 
SCRa 
Treatment Period Days (All Cycles) 
End of 
Study 
Visitb 
Notes 
1 
2 
8 
9 
15 
16 
22 
General and Safety Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
Including multiple myeloma history 
Physical measurements:  height 
X 
 
 
 
 
 
 
 
 
 
Physical measurements:  
weight, BSA 
X 
X 
 
 
 
 
 
 
 
BSA should be calculated per institutional standard and 
utilized to calculate required study drug doses.  BSA 
should be recalculated if there is  20% change in body 
weight. 
Physical examination 
X 
X 
 
 
 
 
 
 
X 
C1D1:  Screening exam may be used if within 7 days prior 
to C1D1. 
ECG 
X 
 
 
 
 
 
 
 
X 
 
Vital signs:  Kd arm (all cycles) 
and KRd arm (cycles 1-12) 
X 
X 
X 
X 
X 
X 
X 
 
X 
Checked prior to administration of study drug in all cycles. 
Vital signs:  KRd arm (cycle 13+) 
 
X 
X 
 
 
X 
X 
 
X 
Checked prior to administration of study drug in all cycles. 
ECOG performance status 
X 
 
 
 
 
 
 
 
X 
 
Page 1 of 3 
Footnotes and abbreviation definitions are after last page of table. 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 6 of 24 
CONFIDENTIAL 
 
 
Procedure 
SCRa 
Treatment Period Days (All Cycles) 
End of 
Study 
Visitb 
Notes 
1 
2 
8 
9 
15 
16 
22 
ECHO/MUGA scan 
X 
 
 
 
 
 
 
 
X 
Repeated ECHO every 6 months ( 2 weeks) from 
C1D1 until end of study visit, or if clinically indicated.  
An ECHO must be performed within 72 hours of the 
onset of a suspected cardiac failure event. 
Review of AE/SAE 
Continually 
 
Concomitant medications 
Continually 
Will be collected from 30 days prior to signing of informed 
consent to 30 days after last dose of study treatment. 
Review of disease status 
Performed per local standards 
Disease status will be evaluated by the investigator using 
IMWG-URC starting from screening until EOT. 
Laboratory Assessments 
Serum or urine pregnancy test 
(FCBP)c 
X 
X 
 
 
 
 
 
 
X 
Must be confirmed negative at screening, on day 1 of 
each cycle prior to dosing, and at end of study visit. 
Additional serum or urine 
pregnancy test (KRd-treated 
FCBP only)d:  Cycle 1 
 
Xe 
 
X 
 
X 
 
X 
 
Weekly pregnancy tests required during cycle 1. 
See Table 12-2 for additional information on 
lenalidomide-specific pregnancy testing requirements. 
Coagulation tests 
X 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
(X) 
 
(X) 
 
 
 
C1D1:  Results from screening may be used if taken 
within 14 days prior to C1D1. 
(X):  Day 8 and 15 samples only collected during cycle 1. 
Chemistry 
X 
X 
 
(X) 
 
(X) 
 
 
 
NTproBNP 
X 
 
 
 
 
 
 
 
 
 
Page 2 of 3 
Footnotes and abbreviation definitions are after last page of table. 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 7 of 24 
CONFIDENTIAL 
 
 
Procedure 
SCRa 
Treatment Period Days (All Cycles) 
End of 
Study 
Visitb 
Notes 
1 
2 
8 
9 
15 
16 
22 
Hepatitis B Virus (HBV) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local serology testing for HBsAg, anti-HBs, and anti-HBc.  
Testing is required: 
 
For subjects with a prior history of HBV infection at 
screening and HBV DNA testing every 12 weeks 
 2 weeks through end of study visit. 
 
For all other subjects at screening unless obtained 
within 6 months of screening and there was no 
change in the subject’s risk factors within these 
6 months.  
 
For subjects positive at screening, who become 
positive for serology during treatment, or who are 
at risk of becoming positive, HBV DNA testing will 
be performed every 12 weeks  2 weeks (and as 
clinically indicated) through end of study visit.   
A specialist should be consulted for all subjects who test 
positive for HBV serology. Subjects who have received 
Hepatitis B vaccination with only anti-HBs positivity and no 
clinical signs of hepatitis do not require HBV DNA 
monitoring. 
 
Page 3 of 3 
AE = adverse events; BNP = b-type natriuretic peptide; BSA = body surface area; CXDX = cycle X day X; ECG = electrocardiogram; ECHO = echocardiogram; 
ECOG = Eastern Cooperative Oncology Group; FCBP = female of child bearing potential; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface 
antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; IMWG-URC = International Myeloma Working Group-Uniform Response Criteria; 
MUGA = multigated acquisition scan; NTproBNP = N-terminal pro b-type natriuretic peptide; SAE = serious adverse event; SCR = screening. 
a Screening:  up to 28 days before enrollment 
b End of study visit is 30 days (+ 3) after last dose of Kyprolis 
c 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. 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 8 of 24 
CONFIDENTIAL 
 
 
d The subject may not receive lenalidomide until the investigator has verified that the results of these pregnancy tests are negative. 
e KRd-treated FCBP must have 2 negative pregnancy tests (combined sensitivity of at least 50 mIU/mL) prior to starting lenalidomide.  The first pregnancy test must be 
performed within 10 to 14 days prior to the start of lenalidomide and the second pregnancy test must be performed within 24 hours prior to the start of lenalidomide.  
If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study discontinuation, and at 
days 14 and 28 following discontinuation from the study. 
 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 9 of 24 
CONFIDENTIAL 
 
 
Section:  6.2 Exclusion Criteria 
Add: 
233 
Active hepatitis B virus (HBV) infection.  Subjects with positive hepatitis B 
surface antigen (HBsAg) or core antibody (anti-HBc) that achieve sustained 
virologic response with antiviral therapy directed at hepatitis B are allowed.  
Subjects with known history or resolved infection (negative for HBsAg but 
positive for antibodies to surface antigen, and/or core antigen) must be 
screened with HBV DNA levels.  EXCEPTION:  Subjects with serologic findings 
suggestive of HBV vaccination (hepatitis B surface antibody 
[anti-HBs] positivity as the only serologic marker) AND a known history of 
prior HBV vaccination, do not need to be tested for HBV DNA. 
Section:  6.2 Exclusion Criteria 
Delete: 
216 
Known human immunodeficiency virus (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 [SAg] or core antibody that achieve sustained virologic response with 
antiviral therapy directed at hepatitis B are allowed) 
Section:  7.1.1 Investigational Products, Table 7-1.  Study Treatments 
Replace: 
Study Treatment Name 
Amgen Investigational Product:a 
Kyprolis 
Dosage Formulation 
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 Kyprolis drug product with an 
elastomeric stopper and flip-off lid.  Upon reconstitution with 
preservative-free sterile water for injection (sWFI), the 
reconstituted solution contains 2 mg/mL Kyprolis, sulfobutylether 
beta-cyclodextrim sodium (SBECD), and citrate buffer. 
Kyprolis is supplied in labelled cartons containing 4 single use 
vials per carton. 
Unit Dose Strength(s)/ 
Dosage Level(s) and 
Dosage Frequency 
10 minute infusion:  20/27 mg/m2 
30 minute infusion:  20/56 mg/m2 
Route of Administration 
IV infusion 
Accountability 
The planned dose (mg/m2), dose (mg), start date/time, stop 
date/time, reason for change in planned dose, reason for dose 
change/withheld, reason for dose delay, and package lot number 
of Kyprolis is to be recorded on each subject's eCRF(s). 
Dosing Instructions 
Triplet:  See Section 7.1.2.1 
Doublet:  See Section 7.1.2.2 
a Kyprolis will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug 
distribution procedures. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 10 of 24 
CONFIDENTIAL 
 
 
With: 
Study Treatment Name 
Amgen Investigational Product:a 
Kyprolis 
Dosage Formulation 
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 Kyprolis drug product with an 
elastomeric stopper and flip-off lid.  Upon reconstitution with 
preservative-free sterile water for injection (sWFI), the 
reconstituted solution contains 2 mg/mL Kyprolis, sulfobutylether 
beta-cyclodextrim sodium (SBECD), and citrate buffer. 
Kyprolis is supplied in labelled cartons containing 4 single use 
vials per carton. 
Unit Dose Strength(s)/ 
Dosage Level(s) and 
Dosage Frequency 
10 minute infusion:  20/27 mg/m2 
30 minute infusion:  20/56 mg/m2 
Route of Administration 
IV infusion 
Accountability 
The planned dose (mg/m2), actual dose (mg) administered, start 
date/time, stop date/time, reason for change in planned dose, 
reason for dose change/withheld, reason for dose delay, and 
package lot number of Kyprolis is to be recorded on each subject's 
eCRF(s). 
Dosing Instructions 
Triplet:  See Section 7.1.2.1 
Doublet:  See Section 7.1.2.2 
a Kyprolis will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug 
distribution procedures. 
Section:  7.1.2  
General Dosing Instructions 
Replace:  Each subject’s first dose of Kyprolis will be calculated based upon baseline 
body surface area (BSA) per institutional standards.  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  20% change in body 
weight in which case the BSA and dose should be recalculated.  The recalculated BSA 
becomes the new baseline.  The dose can also be modified in response to toxicity 
following the dose modification guideline table in local Kyprolis Prescribing Information. 
With:  Each subject’s first dose of Kyprolis will be calculated based upon baseline body 
surface area (BSA) per institutional standards.  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  20% change in body 
weight in which case the BSA and dose should be recalculated.  The recalculated BSA 
becomes the new baseline.  The dose can also be modified in response to toxicity 
following the dose modification guideline table in local Kyprolis Prescribing 
Information. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 11 of 24 
CONFIDENTIAL 
 
 
Section:  7.1.2.1 
Kyprolis in Combination With Lenalidomide and Dexamethasone 
(KRd)  
Replace:  For the triplet combination with lenalidomide and dexamethasone, Kyprolis will 
be administered as an infusion over approximately 10 minutes on days 1, 2, 8, 9, 15, 
and 16 of repeated 28-day treatment cycles.  The recommended starting dose of 
Kyprolis is 20 mg/m2 on days 1 and 2, and if tolerated, escalated to a target dose of 
27 mg/m2 starting on day 8 of cycle 1 and thereafter.  From cycle 13, the day 8 and day 
9 doses of Kyprolis will be omitted.  After cycle 18, Kyprolis will be discontinued 
(Table 7-2).  Lenalidomide 25 mg is taken orally on days 1 to 21 and dexamethasone 
40 mg by mouth or intravenously on days 1, 8, 15, and 22 of the 28-day cycles. 
For patients with mild or moderate hepatic impairment, reduce the dose of Kyprolis by 
25% (ie, 15 mg/m2 day 1 and 2 of cycle 1 and 20 mg/m2 day 8 cycle 1 and thereafter. 
With:  For the triplet combination with lenalidomide and dexamethasone, Kyprolis will be 
administered as an infusion over approximately 10 minutes on days 1, 2, 8, 9, 15, and 
16 of repeated 28-day treatment cycles.  The recommended starting dose of Kyprolis is 
20 mg/m2 on days 1 and 2 of cycle 1, and if tolerated, escalated to a target dose of 
27 mg/m2 starting on day 8 of cycle 1 and thereafter.  From cycle 13, the day 8 and day 
9 doses of Kyprolis will be omitted.  After cycle 18, Kyprolis will be discontinued 
(Table 7-2).  Lenalidomide 25 mg is taken orally on days 1 to 21 and dexamethasone 
40 mg by mouth or intravenously on days 1, 8, 15, and 22 of the 28-day cycles. 
For patients with mild or moderate hepatic impairment, reduce the dose of Kyprolis by 
25% (ie, 15 mg/m2 day 1 and 2 of cycle 1 and 20 mg/m2 day 8 cycle 1 and thereafter.  If 
hepatic function returns to normal, the dose may be re-escalated to the intended 
dose after the first cycle (ie, 27 mg/m2 in KRd). 
Section 7.1.2.1 
Kyprolis in Combination With Lenalidomide and Dexamethasone 
(KRd) (Paragraph 2) 
Replace:  For patients with mild or moderate hepatic impairment, reduce the dose of 
Kyprolis by 25% (ie, 15 mg/m2 day 1 and 2 of cycle 1 and 20 mg/m2 day 8 cycle 1 and 
thereafter. 
With:  For patients with mild or moderate hepatic impairment, reduce the dose of 
Kyprolis by 25% (ie, 15 mg/m2 day 1 and 2 of cycle 1 and 20 mg/m2 day 8 cycle 1 and 
thereafter.  If hepatic function returns to normal, the dose may be re-escalated to 
the intended dose after the first cycle (ie, 56 mg/m2 in Kd). 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 12 of 24 
CONFIDENTIAL 
 
 
Section 7.1.2.3 
Intravenous Prehydration 
Replace:  Adequate hydration is required prior to each Kyprolis infusion in cycle 1, 
especially in subjects at high risk of tumor lysis syndrome or renal toxicity.  Prehydration 
will consist of 250 to 500 mL normal saline or other appropriate intravenous (IV) fluid.  
Thereafter, Kyprolis prehydration should continue only if the subject’s condition and/or 
risk factors require it.  The total volume and the reason for prehydration after cycle 1 will 
be recorded.  Monitor subjects for evidence of volume overload and adjust hydration to 
individual subject needs, especially in subjects with or at risk for cardiac failure. 
With: Subjects may receive intravenous (IV) pre-hydration (normal saline or other 
appropriate IV fluid) prior to each carfilzomib infusion during cycle 1.  
Investigators must consider IV pre-hydration in subjects at high-risk for tumor 
lysis or renal toxicity.  All subjects must be monitored for fluid overload and 
hydration should be tailor to individual needs.  It is recommended to use no more 
than 750 mL IV fluids as a combination of pre- and post-hydration.  Thereafter, 
carfilzomib pre- and/or post-hydration may only be administered if the subject’s 
condition and/or risk factors require it.  The total volume of pre- and/or 
post-hydration and the indication will be recorded on the Concomitant 
Medications eCRF. 
Section:  7.1.3  
Non-investigational Products (Paragraph 2) 
Replace: The planned dose (mg/m2), dose (mg), start date/time, stop date/time, reason 
for change in planned dose, reason for dose change/withheld, reason for dose delay, 
and package lot number of lenalidomide and/or dexamethasone is to be recorded on 
each subject's eCRF(s). 
With: The planned dose (mg), actual dose (mg) administered, start date/time, stop 
date/time, reason for change in planned dose, reason for dose change/withheld, reason 
for dose delay, and package lot number of lenalidomide and/or dexamethasone is to be 
recorded on each subject's eCRF(s). 
Section:  7.1.5.3 
Prophylaxis for Hepatitis B Virus 
Add:  7.1.5.3 Prophylaxis for Hepatitis B Virus 
Hepatitis B virus reactivation prophylaxis should be considered for patients at risk 
(ie, patients tested positive on serology or had a prior history of HBV infection), as 
per institutional guidelines. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 13 of 24 
CONFIDENTIAL 
 
 
Section:  7.1.5.4 
Supportive Therapies 
Replace:  Refer to the local Kyprolis label for Warnings and Precautions, as well as 
recommended supportive therapies and medications. 
With:  Refer to the local Kyprolis Prescribing Information for Warnings and 
Precautions, as well as recommended supportive therapies and medications. 
Section:  7.1.8  
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Replace:  Concurrent therapy with a marketed or investigational anticancer therapeutic 
or radiation to large bone marrow reserves for either 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 > 2 mg/day are not permitted.  Higher steroid doses given for short term 
exacerbations of nonmalignant conditions (eg, asthma flare) are permitted with the 
approval of the study medical monitor.  Investigational agents are not to be used during 
the study. 
With:  Concurrent therapy with a marketed or investigational anticancer therapeutic or 
radiation to large bone marrow reserves for either palliative or therapeutic intent is 
excluded. 
Corticosteroids given short-term (up to 2 weeks) for nonmalignant conditions (eg, 
asthma, inflammatory bowel disease) are permitted provided that the cumulative 
dose is less than 40 mg per week dexamethasone or equivalent dose (see 
Appendix 12 for corticosteroid dose equivalents).  Medical monitor should be 
contacted if short-term corticosteroid use is required  2 weeks or at cumulative 
dose of more than 40 mg dexamethasone equivalent or 20 mg for subjects 
 75 years of age.  Investigational agents are not to be used during the study. 
Section:  7.4 Dose Modification 
Replace: Kyprolis may be discontinued, temporarily delayed, or dosage reduced, in the 
event of a treatment-related toxicity that, in the opinion of the investigator, warrants the 
discontinuation, temporary delay or dose reduction, as indicated in the Kyprolis 
Prescribing Information (refer to Warnings and Precautions section).  See the 
lenalidomide and dexamethasone Prescribing Information respectively for dosing 
recommendations. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 14 of 24 
CONFIDENTIAL 
 
 
With:  Kyprolis may be discontinued, temporarily delayed, or dosage reduced, in the 
event of a treatment-related toxicity that, in the opinion of the investigator, warrants the 
discontinuation, temporary delay or dose reduction, as indicated in the Kyprolis 
Prescribing Information (refer to Posology and method of administration and Special 
warnings and precautions for use sections).  See the lenalidomide and 
dexamethasone Prescribing Information respectively for dosing recommendations. 
Section:  9.2.3.4.1  
Echocardiogram 
Replace:  9.2.3.4 
Other Safety 
All subjects will have a baseline transthoracic ECHO (TTE) or MUGA during screening, 
including assessments of systolic and diastolic left ventricular function and right 
ventricular function.  Echocardiograms are to be repeated if clinically indicated.  
With: 9.2.3.4 Other Safety 
9.2.3.4.1  
Echocardiogram 
All subjects will have a baseline transthoracic ECHO (TTE) or MUGA during screening, 
including assessments of systolic and diastolic left ventricular function and right 
ventricular function.  Echocardiograms are to be repeated every 6 months ( 2 weeks), 
at the end of study, and/or if clinically indicated.  An ECHO must be performed 
within 72 hours of the onset of a suspected cardiac failure event. 
Section 9.2.3.4.2 
Hepatitis B 
Add:  9.2.3.4.2 
Hepatitis B 
All hepatitis testing will be performed locally.  All subjects will be tested at 
screening for HBsAg, anti-HBs, and anti-HBc, unless performed within 6 months 
of screening and there was no change in the subject’s risk factors within these 
6 months. 
Subjects with no history of HBV infection that are negative for hepatitis serologies 
at screening should be followed as clinically indicated. 
Subjects with positive testing or who have a prior history of HBV infection should 
have consultation with a specialist in HBV and have HBV DNA testing and 
monitoring of HBV DNA every 12 weeks  2 weeks through end of study visit.  
Subjects that have received hepatitis B vaccination with only anti-HBs positivity 
and no clinical signs of hepatitis do not require HBV DNA monitoring. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 15 of 24 
CONFIDENTIAL 
 
 
Any subject who becomes HBV DNA positive or develops reactivation of HBV will 
have study treatment interrupted and received appropriate anti-viral treatment as 
per a specialist in hepatitis B.  Resumption of clinical study treatment may be 
considered in subjects whose HBV reactivation is controlled and where the 
benefits of clinical study treatment outweigh the risks.  After cessation of study 
treatment for any reason, any ongoing monitoring and anti-viral treatment should 
be under the guidance of a specialist in HBV. 
Section:  Appendix 2 Clinical Laboratory Tests, Table 12-1.  Analyte Listing 
Replace: 
Chemistry 
Coagulation 
Hematology 
Other Labs 
Amylase (screening only) 
Lipase (screening only) 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Calcium corrected (if 
albumin < 4) 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Creatinine clearance (CrCl) 
Uric acid 
Total bilirubin 
Direct bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
PT 
PTT/INR 
(aPTT or PTT) 
Circulating plasma 
cells (screening only) 
RBC count 
Hemoglobin 
Hematocrit 
Platelet count 
WBC count with 
differential: 
 
Neutrophils 
 
Eosinophils 
 
Basophils 
 
Lymphocytes 
 
Monocytes 
Serum or highly 
sensitive urine 
pregnancy  
ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; BUN = blood urea nitrogen; INR = international normalized ratio; 
LDH = lactate dehydrogenase; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood 
cell; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; 
WBC = white blood cell count. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 16 of 24 
CONFIDENTIAL 
 
 
With:  
Chemistry 
Coagulation 
Hematology 
Other Labs 
Amylase (screening only) 
Lipase (screening only) 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Calcium corrected (if 
albumin < 4) 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Creatinine clearance (CrCl) 
Uric acid 
Total bilirubin 
Direct bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
PT 
PTT/INR 
(aPTT or PTT) 
Circulating plasma 
cells (screening only) 
RBC count 
Hemoglobin 
Hematocrit 
Platelet count 
WBC count with 
differential: 
 
Neutrophils 
 
Eosinophils 
 
Basophils 
 
Lymphocytes 
 
Monocytes 
Serum or highly 
sensitive urine 
pregnancy  
NTproBNPa 
BNPa 
CK2b 
CPKMBb 
Troponin Ib 
Troponin Tb 
Hepatitis B 
serologies (HBsAg, 
anti-HBs, and 
anti-HBc)c 
HBV DNAd 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; BNP = b-type natriuretic peptide; BUN = blood urea nitrogen; 
CK2 = creatine kinase 2; CPKMB = creatine kinase-muscle/brain; anti-HBc = hepatitis B core 
antibody; anti-HBs = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; INR = international normalized ratio; LDH = lactate dehydrogenase; 
NTproBPN = N-terminal pro b-type natriuretic peptide; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; SGOT = serum glutamic-oxaloacetic transaminase; 
SGPT = serum glutamic-pyruvic transaminase; WBC = white blood cell count.  
a NTproBNP is only required at screening and BNP can be recorded if NTproBNP is not available. 
b As clinically indicated.  
c Testing is required for all subjects at screening unless obtained within 6 months of screening and 
there was no change in the subject’s risk factors within these 6 months. 
d If prior history of HBV infection obtain HBV DNA at screening and every 12 weeks through safety 
follow-up.   Subjects that have received hepatitis B vaccination with only anti-HBs positivity and no 
clinical signs of hepatitis do not require HBV DNA monitoring. 
Section:  Appendix 3 Study Governance Considerationos, Data Quality Assurance 
(Paragraph 10) 
Delete:  Amgen (or designee) will perform Self-Evident Corrections (SECs) to obvious 
data errors in the clinical trial database.  SECs will be documented in the eCRF 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 17 of 24 
CONFIDENTIAL 
 
 
Standard Instructions and the eCRF 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, [eg, C1D9 and 
C1D15]) and updating a specific response if the confirming datum is provided in the 
“other, specify” field (eg, for race, reason for ending study). 
Section:  Appendix 5 Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information, Table 12-2.  Lenalidomide:  Contraceptive Guidelines and 
Collection of Pregnancy and Lactation Information 
Replace: 
Risks Associated with Pregnancy 
(For the region specific use of lenalidomide, please refer to the regional label) 
Lenalidomide is structurally related to thalidomide.  Thalidomide is a known human teratogenic 
active substance that causes severe life-threatening birth defects.  An embryo fetal 
development study in animals indicates that lenalidomide produced malformations in the 
offspring of female monkeys who received the drug during pregnancy.  The teratogenic effect 
of lenalidomide in humans cannot be ruled out.  Therefore, a risk minimization plan to prevent 
pregnancy must be observed. 
Criteria for Females of Childbearing Potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman who:  
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 
24 consecutive months). 
Counseling 
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following 
are met (ie, all females of childbearing potential must be counseled concerning the following 
risks and requirements prior to the start of lenalidomide study therapy): 
 
She understands the potential teratogenic risk to the unborn child  
 
She understands the need for effective contraception, without interruption, 4 weeks before 
starting study treatment, throughout the entire duration of study treatment, dose 
interruption, and 28 days after the end of study treatment 
 
She should be capable of complying with effective contraceptive measures  
 
She is informed and understands the potential consequences of pregnancy and the need 
to notify her study doctor immediately if there is a risk of pregnancy  
 
She understands the need to commence the study treatment as soon as study drug is 
dispensed following a negative pregnancy test  
 
She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol 
 
She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 18 of 24 
CONFIDENTIAL 
 
 
The investigator must ensure that for females of childbearing potential: 
 
Complies with the conditions for pregnancy risk minimization, including confirmation that 
she has an adequate level of understanding  
 
Acknowledge the aforementioned requirements 
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the 
following are met (ie, all females NOT of childbearing potential must be counseled concerning 
the following risks and requirements prior to the start of lenalidomide study therapy): 
 
She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
 
Traces of lenalidomide have been found in semen.  Male subjects taking lenalidomide 
must meet the following conditions (ie, all males must be counseled concerning the 
following risks and requirements prior to the start of lenalidomide study therapy): 
 
Understand the potential teratogenic risk if engaged in sexual activity with a pregnant 
female or a female of childbearing potential  
 
Understand the need for the use of a condom even if he has had a vasectomy, if 
engaged in sexual activity with a pregnant female or a female of childbearing potential. 
Contraception 
FCBP enrolled in this protocol must agree to use 2 reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual contact during the 
following time periods related to this study:  1) for at least 28 days before starting study drug; 
2) while participating in the study; 3) dose interruptions; and 4) for at least 28 days after study 
treatment discontinuation.  
The 2 methods of reliable contraception must include 1 highly effective method and 
1 additional effective (barrier) method.  FCBP must be referred to a qualified provider of 
contraceptive methods if needed.  The following are examples of highly effective and additional 
effective methods of contraception: 
Highly effective methods: 
 
IUD 
 
Hormonal (birth control pills, injections, implants) 
 
Tubal ligation 
 
Partner’s vasectomy 
Additional effective methods: 
 
Male condom 
 
Diaphragm 
 
Cervical Cap 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased 
risk of infection at the time of insertion and irregular vaginal bleeding.  Prophylactic antibiotics 
should be considered particularly in subjects with neutropenia. 
Pregnancy Testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 19 of 24 
CONFIDENTIAL 
 
 
Before Starting Lenalidomide 
Female Subjects 
 
FCBP must have 2 negative pregnancy tests (combined sensitivity of at least 50 mIU/mL) 
prior to starting lenalidomide.  The first pregnancy test must be performed within 10 to 
14 days prior to the start of lenalidomide and the second pregnancy test must be 
performed within 24 hours prior to the start of lenalidomide.  The subject may not receive 
lenalidomide until the Investigator has verified that the results of these pregnancy tests are 
negative. 
 
Will be warned that sharing study drug is prohibited and will be counseled about pregnancy 
precautions and potential risks of fetal exposure. 
 
Must agree to abstain from donating blood during study participation and for at least 
28 days after discontinuation from the study. 
Male Subjects 
 
Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following discontinuation 
from the study even if he has undergone a successful vasectomy. 
 
Will be warned that sharing study drug is prohibited and will be counseled about pregnancy 
precautions and potential risks of fetal exposure. 
 
Must agree to abstain from donating blood, semen, or sperm during study participation and 
for at least 28 days after discontinuation from the study. 
During Study Participation and for 28 Days Following Discontinuation From the Study 
Female Subjects 
 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, at study 
discontinuation, and at day 28 following discontinuation from the study.  If menstrual cycles 
are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 
14 days while on study, at study discontinuation, and at days 14 and 28 following 
discontinuation from the study. 
 
In addition to the required pregnancy testing, the Investigator must confirm with FCBP that 
she is continuing to use 2 reliable methods of birth control at each visit. 
 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days and at the time that lenalidomide treatment is 
discontinued.  During counseling, subjects must be reminded to not share study drug and 
to not donate blood. 
 
Pregnancy testing and counseling must be performed if a subject misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment must 
be discontinued during this evaluation. 
 
Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after discontinuation from the study. 
 
If pregnancy or a positive pregnancy test does occur in a study subject, study drug must be 
immediately discontinued. 
Male Subjects 
 
Counseling about the requirement for latex condom use during sexual contact with females 
of childbearing potential and the potential risks of fetal exposure must be conducted at a 
minimum of every 28 days and at the time that lenalidomide treatment is discontinued.  
During counseling, subjects must be reminded to not share study drug and to not donate 
blood, sperm, or semen. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 20 of 24 
CONFIDENTIAL 
 
 
 
If pregnancy or a positive pregnancy test does occur in the partner of a male study subject 
during study participation, the investigator must be notified immediately. 
Additional Precautions 
 
Subjects should be instructed never to give this medicinal product to another person and to 
return any unused capsules to the study doctor at the end of treatment.  
 
Female subjects should not donate blood during therapy and for at least 28 days following 
discontinuation of study drug.  
 
Male subjects should not donate blood, semen or sperm during therapy or for at least 
90 days following discontinuation of study drug.  
 
Only enough study drug for 1 cycle of therapy may be dispensed with each cycle of 
therapy. 
With: 
Risks Associated with Pregnancy 
(For the region specific use of lenalidomide, please refer to the regional label) 
Lenalidomide is structurally related to thalidomide.  Thalidomide is a known human teratogenic 
active substance that causes severe life-threatening birth defects.  An embryo fetal 
development study in animals indicates that lenalidomide produced malformations in the 
offspring of female monkeys who received the drug during pregnancy.  The teratogenic effect 
of lenalidomide in humans cannot be ruled out.  Therefore, a risk minimization plan to prevent 
pregnancy must be observed. 
Criteria for Females of Childbearing Potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman who:  
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 
24 consecutive months). 
Counseling 
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following 
are met (ie, all females of childbearing potential must be counseled concerning the following 
risks and requirements prior to the start of lenalidomide study therapy): 
 
She understands the potential teratogenic risk to the unborn child  
 
She understands the need for effective contraception, without interruption, 4 weeks before 
starting study treatment, throughout the entire duration of study treatment, dose 
interruption, and 28 days after the end of study treatment 
 
She should be capable of complying with effective contraceptive measures  
 
She is informed and understands the potential consequences of pregnancy and the need 
to notify her study doctor immediately if there is a risk of pregnancy  
Page 1 of 4 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 21 of 24 
CONFIDENTIAL 
 
 
Counseling (Continued) 
 
She understands the need to commence the study treatment as soon as study drug is 
dispensed following a negative pregnancy test  
 
She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol 
 
She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
The investigator must ensure that for females of childbearing potential: 
 
Complies with the conditions for pregnancy risk minimization, including confirmation that 
she has an adequate level of understanding  
 
Acknowledge the aforementioned requirements 
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the 
following are met (ie, all females NOT of childbearing potential must be counseled concerning 
the following risks and requirements prior to the start of lenalidomide study therapy): 
 
She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
 
Traces of lenalidomide have been found in semen.  Male subjects taking lenalidomide 
must meet the following conditions (ie, all males must be counseled concerning the 
following risks and requirements prior to the start of lenalidomide study therapy): 
 
Understand the potential teratogenic risk if engaged in sexual activity with a pregnant 
female or a female of childbearing potential  
 
Understand the need for the use of a condom even if he has had a vasectomy, if 
engaged in sexual activity with a pregnant female or a female of childbearing potential. 
Contraception 
FCBP enrolled in this protocol must agree to use 2 reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual contact during the 
following time periods related to this study:  1) for at least 28 days before starting study drug; 
2) while participating in the study; 3) dose interruptions; and 4) for at least 28 days after study 
treatment discontinuation.  
The 2 methods of reliable contraception must include 1 highly effective method and 
1 additional effective (barrier) method.  FCBP must be referred to a qualified provider of 
contraceptive methods if needed.  The following are examples of highly effective and additional 
effective methods of contraception: 
Highly effective methods: 
 
IUD 
 
Hormonal (birth control pills, injections, implants) 
 
Tubal ligation 
 
Partner’s vasectomy 
Page 2 of 4 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 22 of 24 
CONFIDENTIAL 
 
 
Contraception (Continued) 
Additional effective methods: 
 
Male condom or female condom, with or without spermicide 
 
Diaphragm with spermicide 
 
Cervical Cap with spermicide 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased 
risk of infection at the time of insertion and irregular vaginal bleeding.  Prophylactic antibiotics 
should be considered particularly in subjects with neutropenia. 
Pregnancy Testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below. 
Before Starting Lenalidomide 
Female Subjects 
 
FCBP must have 2 negative pregnancy tests (combined sensitivity of at least 50 mIU/mL) 
prior to starting lenalidomide.  The first pregnancy test must be performed within 10 to 
14 days prior to the start of lenalidomide and the second pregnancy test must be 
performed within 24 hours prior to the start of lenalidomide.  The subject may not receive 
lenalidomide until the Investigator has verified that the results of these pregnancy tests are 
negative. 
 
Will be warned that sharing study drug is prohibited and will be counseled about pregnancy 
precautions and potential risks of fetal exposure. 
 
Must agree to abstain from donating blood during study participation and for at least 
28 days after discontinuation from the study. 
Male Subjects 
 
Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following discontinuation 
from the study even if he has undergone a successful vasectomy. 
 
Will be warned that sharing study drug is prohibited and will be counseled about pregnancy 
precautions and potential risks of fetal exposure. 
 
Must agree to abstain from donating blood, semen, or sperm during study participation and 
for at least 28 days after discontinuation from the study. 
Page 3 of 4 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 23 of 24 
CONFIDENTIAL 
 
 
During Study Participation and for 28 Days Following Discontinuation From the Study 
Female Subjects 
 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, at study 
discontinuation, and at day 28 following discontinuation from the study.  If menstrual cycles 
are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 
14 days while on study, at study discontinuation, and at days 14 and 28 following 
discontinuation from the study. 
 
In addition to the required pregnancy testing, the Investigator must confirm with FCBP that 
she is continuing to use 2 reliable methods of birth control at each visit. 
 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days and at the time that lenalidomide treatment is 
discontinued.  During counseling, subjects must be reminded to not share study drug and 
to not donate blood. 
 
Pregnancy testing and counseling must be performed if a subject misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment must 
be discontinued during this evaluation. 
 
Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after discontinuation from the study. 
 
If pregnancy or a positive pregnancy test does occur in a study subject, study drug must be 
immediately discontinued. 
Male Subjects 
 
Counseling about the requirement for latex condom use during sexual contact with females 
of childbearing potential and the potential risks of fetal exposure must be conducted at a 
minimum of every 28 days and at the time that lenalidomide treatment is discontinued.  
During counseling, subjects must be reminded to not share study drug and to not donate 
blood, sperm, or semen. 
 
If pregnancy or a positive pregnancy test does occur in the partner of a male study subject 
during study participation, the investigator must be notified immediately. 
Additional Precautions 
 
Subjects should be instructed never to give this medicinal product to another person and to 
return any unused capsules to the study doctor at the end of treatment.  
 
Female subjects should not donate blood during therapy and for at least 28 days following 
discontinuation of study drug.  
 
Male subjects should not donate blood, semen or sperm during therapy or for at least 
90 days following discontinuation of study drug.  
 
Only enough study drug for 1 cycle of therapy may be dispensed with each cycle of 
therapy. 
Page 4 of 4 
Section:  Appendix 7:  Hepatotoxicity Stopping Rules:  Suggested Actions and Follow-up 
Assessments 
Replace:  Please refer to Section 7.4.1.1 for details regarding dose modification and 
toxicity. 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  29 October 2019 
Page 24 of 24 
CONFIDENTIAL 
 
 
With:  Please refer to Sections 7.1.2.1, 7.1.2.2, and 7.4.1.1 for details regarding dose 
modification and toxicity. 
Section:  Appendix 12.  Corticosteroid Dose Equivalents 
Add: Appendix 12.  Corticosteroid Dose Equivalents 
Equivalent Dose (mg) 
Steroid 
1.5 
dexamethasone (long-acting) 
8 
methylprednisolone (intermediate-acting) 
10 
prednisone (intermediate-acting) 
10 
prednisolone (intermediate-acting) 
40 
hydrocortisone (short-acting) 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160372 
Date:  08 October 2019 
Page 1 of 24 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  Post-marketing Phase 4 Study to Evaluate Safety, Tolerability, and 
Efficacy of Kyprolis® (Carfilzomib) in Indian Patients With Relapsed or Refractory 
Multiple Myeloma:  A Prospective, Open-label, Non-comparative, Multicenter 
Study 
 
Amgen Protocol Number (carfilzomib) 20160372 
 
Amendment Date: 
08 October 2019 
 
Rationale: 
The protocol is amended to: 
 
Hepatitis B testing (hepatitis B surface antigen, hepatitis B surface antibody, and 
hepatitis B core antibody) has been expanded to include all subjects that do not 
already have a prior medical history of hepatitis B or who have not had testing within 
the previous 12 weeks. Guidance has been provided regarding HBV DNA testing 
and monitoring for subjects with positive hepatitis B serology or a prior history of 
HBV.  In addition, guidance has been provided on the prophylaxis of HBV 
reactivation in patients at risk.  
 
Implement ECHO assessments every 6 months, EOS, and/or if clinically indicated. 
An ECHO must be performed within 72 hours of the onset of a suspected cardiac 
failure. 
 
Removed Self-Evident Corrections as they are no longer completed by DM per 
change in Amgen processes. 
 
Removed Adjusted calcium from lab analyte chart (redundant with Calcium corrected 
[if albumin < 4]). Added NTproBNP, BNP, CK2, CKMB, Troponin I, and Troponin T to 
lab analyte chart 
 
Added clarification around dose adjustments required for change of body weight 
> 20%. 
 
Added clarification around concomitant short- and long-term corticosteroid use. 
 
Added clarification around Intravenous Pre-hydration use. 
 

SAP_001.pdf: 
Product:  Carfilzomib  
Protocol Number:  20160372 
Date:  18 February 2023 
Page 1 of 36 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
Protocol Title: 
Post-marketing Phase 4 Study to Evaluate Safety, 
Tolerability, and Efficacy of Kyprolis®  
(Carfilzomib) in Indian Patients With Relapsed or 
Refractory Multiple Myeloma:  A Prospective, Open 
label, Non-comparative, Multicenter Study 
Short Protocol Title: 
Phase 4 Study to Evaluate Safety, Tolerability and 
Efficacy of Kyprolis (Carfilzomib) in Relapsed or 
Refractory Multiple Myeloma 
Protocol Number: 
20160372 
NCT Number: 
03934684 
Authors: 
, 
Biostatistician, PAREXEL International 
, 
Biostatistician, PAREXEL International 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
Amendment 1 (v2.0) 
Amendment 2 (v3.0) 
Amendment 3 (v4.0) 
22 November 2017 
3 January 2020 
22 June 2021 
18 February 2023 
 


Product:  Carfilzomib  
Protocol Number:  20160372 
Date:  18 February 2023 
Page 2 of 36 
CONFIDENTIAL  
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
22 November 2017 
 
Amendment 1 (v2.0) 
3 January 2020 
Section 7.1: added section interim 
analysis. 
 
Section 9.6.2: removed ‘All AEs, 
including TEATs, will be included in 
individual subject listings.’ 
 
Section 9.6.2: added ‘treatment related 
TEAEs,… will be tabulated’. 
 
Section 9.6.3: removed ‘the minimums, 
maximums, last observed values’, 
which is irrelevant or duplicate with lab 
summaries. 
 
Section 9.6.4: removed ‘ECOG status 
scores will also be summarized for 
each treatment group at baseline and 
end of study visit.’ to be consistent with 
protocol specification. 
 
Section 9.6.7: added ‘re-started’, 
replaced ‘median, and average does 
per administration’ with ‘percent of 
intended dose’ to be consistent with 
protocol language. 
 
Section 9.6.9: replaced ‘therapies of 
interest’ with ‘concomitant medications’ 
to be consistent with protocol 
language. 
 
Section 9.7.1: added section 
echocardiogram per protocol 
amendment. 
 
Section 10: added section change from 
protocol-specified analyses per India 
agency request. 
Amendment 2 (v3.0) 
22 June 2021 
 
List of Abbreviations: Add NE, RDI and 
ISS 
 
Section 2.1: revised the description of 
the secondary endpoints. 
 


Product:  Carfilzomib  
Protocol Number:  20160372 
Date:  18 February 2023 
Page 3 of 36 
CONFIDENTIAL  
 
 
Section 3.2: revised the description of 
the sample size. 
 
Section 5: revised the definition of 
Baseline  
 
Section 5: added the definition of Cycle 
1 Day 1 (C1D1)  
 
Section 5: revised the definition of 
secondary endpoints including Best 
overall response, Clinical Benefit Rate 
(CBR), Duration of response (DOR), 
Overall Response Rate (ORR), 
Progression-free survival (PFS), and 
Time to response (TTR) 
 
Section 5: added the definition of 
Duration of investigational product 
treatment (/non-investigational product 
treatment) 
 
Section 5: deleted the definition of 
Enrollment Date 
 
Section 5: deleted the definition of First 
Dose Date 
 
Section 5: added the definition of 
Investigational product and Non-
investigational product 
 
Section 5: added the definition of Last 
Subject Last Visit 
 
Section 5: added the definition of 
Relative Dose Intensity (RDI)  
 
Section 5: added the definition of Study 
treatment  
 
Section 5: replaced “First Dose Date” 
with “the first dose date of any study 
treatment” in the definition of Time 
(months) since initial diagnosis 
 


Product:  Carfilzomib  
Protocol Number:  20160372 
Date:  18 February 2023 
Page 4 of 36 
CONFIDENTIAL  
 
 
Section 5: revised the definition of 
Treatment emergent adverse events  
 
Section 6.1: added Full Analysis Set 
 
Section 6.2: re-organized section 
numbering 
 
Section 8.3: removed “then there is a 
data error and” from the Imputation 
rules for partial or missing stop dates 
 
Section 8.3: typo corrected in the 
Imputation for date of initial diagnosis  
 
Section 9.1: revised the general 
considerations  
 
Section 9.2: added “completed 
investigational product and non-
investigational products” and “The 
number and percent of subject enrolled 
will be tabulated by study site” in 
Subject Accountability 
 
Section 9.2: replaced “study treatment” 
with “investigational product, non-
investigational products” 
 
Section 9.4: added “If multiple races 
have been reported for a subject, the 
subject will be categorized as other.” 
 
Section 9.4: replaced “Bortezomib” 
with “Bortezomib (Yes, No)” and 
replaced “Revlimid” with “Revlimid 
(Yes, No)” 
 
Section 9.4: replaced  “ISS stage at 
diagnosis” with “ISS stage at diagnosis 
(stage I, stage II, stage III, unknown)”  
 
Section 9.4:  added "As continuous 
variable" and "As categorical 
variable..." for Number of prior lines 
 


Product:  Carfilzomib  
Protocol Number:  20160372 
Date:  18 February 2023 
Page 5 of 36 
CONFIDENTIAL  
 
 
Section 9.4: added “derived in RAVE 
according to” and added additional 
criteria if albumin is 4 g/dL or greater 
for Corrected calcium 
 
Section 9.4: added “derived in RAVE” 
for Creatinine clearance 
  
Section 9.5: added Table 9-1.  Efficacy 
Endpoint Summary Table 
 
Section 9.5.1 & 9.5.2: re-organized 
section numbering 
 
Section 9.6.1: transcribed content to 
Table 9-4. Safety Endpoint Summary 
Table 
 
Section 9.6.2: updated MedDRA to 
version 22.0 
 
Section 9.6.2: replaced “withdrawal” 
with “discontinuation” 
 
Section 9.6.2: added “in alphabetical 
order” in “Subject incidence of all 
treatment-emergent adverse events 
(TEAEs)… by system organ class and 
preferred term in alphabetical order” 
 
Section 9.6.2: removed 'and serious' in 
'Summaries of treatment-emergent and 
serious adverse events...and worst 
grade.' 
 
Section 9.6.3: removed Monocytes and 
Calcium from the selected laboratory 
endpoints of interest 
 
Section 9.6.4: added “Shifts in vital 
sign value between the baseline and 
the worst on-study value will be 
tabulated by treatment group.” 
 
Section 9.6.7: replaced 'The number of 
cycles will be summarized ... intended 
dose will be summarized by cycle and 


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overall.' with 'The number of cycles 
subjects that received Carfilzomib ... 
and relative dose intensity will be 
summarized' 
 
Section 9.6.7 & 9.6.8: re-organized 
section numbering 
 
Section 9.7.1: replaced 
“Echocardiogram” with 
“Echocardiograms” and deleted the list 
of ECHO parameters of interest 
 
Section 9.7.2: added analyses for 
COVID-19 impact 
 
Section 10: updated the changes from 
protocol-specified analyses  
Amendment 3 (v4.0) 
18 February 2023 
Section 8.3: move imputation rules 
for incomplete and partial dates for 
adverse events and concomitant 
medications, incomplete/missing 
death dates, the initial diagnosis 
date to appendix A1-A3 
 
Section 9.4: add definition of 
categorical variable for hemoglobin, 
platelet count, absolute neutrophil 
count, albumin, corrected calcium; 
replace the unit (mm3) of absolute 
neutrophil count with 109/L 
 
Section 9.5.2: remove "and will be 
summarized using descriptive 
statistics” 
 
Section 9.6.2: add summary of 
“adverse events leading to 
discontinuation of lenalidomide” by 
system organ class/preferred term 
and preferred term 
 
Section 9.6.2: add summary of 
“adverse events leading to 
discontinuation of any study drug” 
by system organ class/preferred 
term and preferred term  


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Section 9.6.2: add "in alphabetical 
order” to illustrate the order when 
reporting adverse events by events 
of interest or system organ class 
 
Section 9.6.2: add summary of 
"Exposure-adjusted incidence rate 
… by preferred term." and "All 
TEAEs will be included in individual 
subject listings." 
 
Section 9.6.3: add “The summary of 
post-baseline grade 3 or 4 
laboratory toxicities will be 
included.” and “Incidence of 
potential Hy's Law cases and listing 
of subjects with ALT/AST  3x ULN 
or Total Bilirubin  2x ULN will be 
provided.” 
 
Section 9.6.4: remove “Shifts in vital 
sign ... by treatment group” 
and add “For the summary of 
changes from baseline by visit, 
subjects without a baseline and/or 
post baseline value will be 
excluded; values from unscheduled 
assessments will be excluded.” 
 
Section 9.6.5: add “For the summary 
of changes from baseline by visit, 
subjects without a baseline and/or 
post baseline value will be 
excluded; values from unscheduled 
assessments will be excluded.” 
 
Section 9.6.6: add “For the summary 
of changes from baseline by visit, 
subjects without a baseline and/or 
post baseline value will be 
excluded; values from unscheduled 
assessments will be excluded.” 
 
Section 9.6.9: remove “Descriptive 
statistics of average daily dose and 
duration of usage….to other 
protocol-required therapies by 
treatment group.” and add “The 
number and proportion of subjects 


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receiving therapies … by preferred 
term or category...” 
 
Section 9.7.1: add “For the summary 
of changes from baseline by visit, 
subjects without a baseline and/or 
post baseline value will be 
excluded; values from unscheduled 
assessments will be excluded.” 
 
Section 9.7.2.2: add Section 9.7.2.2 
to describe the impact of COVID-19 
on Adverse Event 
 
Section 10: updated the changes 
from Protocol-specified Analyses   
 
Appendix A: replace "2" with "n/a" 
in the case where partial stop date 
( 1st dose yyyymm) while partial 
start date(1st dose date yyyymm) 
 
Appendix A: add imputation rules 
for other protocol-required therapy 
in appendix A1; imputation rules for 
new antimyeloma therapy start date 
in appendix A4; imputation rules for 
prior multiple myeloma therapy and 
relapse/progression to prior 
multiple myeloma therapy date in 
appendix A5  
 


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Table of Contents 
List of Abbreviations ...................................................................................................... 11 
1. 
Introduction ........................................................................................................... 13 
2. 
Objectives, Endpoints and Hypotheses ................................................................. 13 
2.1 
Objectives and Endpoints/Estimands ........................................................ 13 
2.2 
Hypotheses and/or Estimations ................................................................. 15 
3. 
Study Overview .................................................................................................... 15 
3.1 
Study Design ............................................................................................. 15 
3.2 
Sample Size .............................................................................................. 15 
3.3 
Adaptive Design ........................................................................................ 15 
4. 
Covariates and Subgroups ................................................................................... 15 
4.1 
Planned Covariates ................................................................................... 15 
4.2 
Subgroups ................................................................................................. 15 
5. 
Definitions ............................................................................................................. 16 
6. 
Analysis Sets ........................................................................................................ 21 
6.1 
Full Analysis Set........................................................................................ 21 
6.2 
Safety Analysis Set ................................................................................... 21 
7. 
Planned Analyses ................................................................................................. 21 
7.1 
Interim Analysis ......................................................................................... 21 
7.2 
Primary Analysis ....................................................................................... 22 
7.3 
Final Analysis ............................................................................................ 22 
8. 
Data Screening and Acceptance ........................................................................... 22 
8.1 
General Principles ..................................................................................... 22 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 22 
8.3 
Handling of Missing and Incomplete Data ................................................. 22 
8.4 
Detection of Bias ....................................................................................... 22 
8.5 
Outliers ..................................................................................................... 22 
8.6 
Distributional Characteristics ..................................................................... 22 
8.7 
Validation of Statistical Analyses ............................................................... 22 
9. 
Statistical Methods of Analysis.............................................................................. 23 
9.1 
General Considerations ............................................................................. 23 
9.2 
Subject Accountability ............................................................................... 23 
9.3 
Important Protocol Deviations ................................................................... 23 
9.4 
Demographic and Baseline Characteristics ............................................... 24 
9.5 
Efficacy Analyses ...................................................................................... 25 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) .............. 25 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 26 
9.6 
Safety Analyses ........................................................................................ 26 


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9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 26 
9.6.2 
Adverse Events ......................................................................... 27 
9.6.3 
Laboratory Test Results ............................................................ 28 
9.6.4 
Vital Signs ................................................................................. 29 
9.6.5 
Physical Measurements ............................................................ 29 
9.6.6 
Electrocardiogram ..................................................................... 29 
9.6.7 
Exposure to Investigational Product .......................................... 30 
9.6.8 
Exposure to Non-investigational Product ................................... 30 
9.6.9 
Exposure to Other Protocol-required Therapy ........................... 30 
9.6.10 
Exposure to Concomitant Medication ........................................ 30 
9.7 
Other Analyses ......................................................................................... 30 
9.7.1 
Echocardiogram ........................................................................ 30 
9.7.2 
Analyses for COVID-19 Impact .................................................. 31 
9.7.2.1 
Impact of COVID-19 on Trial Conduct ..................... 31 
9.7.2.2 
Impact of COVID-19 on Adverse Event ................... 31 
10. 
Changes From Protocol-specified Analyses.......................................................... 31 
11. 
Literature Citations / References ........................................................................... 33 
12. 
Appendices ........................................................................................................... 34 
Appendix A.  Handling of Dates, Incomplete Dates and Missing Dates  ................ 34 
 
List of Table 
Table 5-1.  Conventions for Censoring for PD dates ...................................................... 16 
Table 5-2.  Planned number of treatment weeks calculation .......................................... 18 
Table 5-3.  Planned Carfilzomib Dose per Week ........................................................... 18 
Table 8-1.  Imputation Rules for Partial or Missing Start Dates ...................................... 21 
Table 9-1.  Efficacy Endpoint Summary Table ............................................................... 24 
Table 9-4.  Safety Endpoint Summary Table ................................................................. 26 
 
 


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List of Abbreviations 
 
Abbreviation 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BSA 
body surface area 
CBR 
clinical benefit rate 
CR 
complete response 
DOR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
eCRF 
electronic case report form 
IMWG-URC 
International Myeloma Working Group-Uniform Response 
Criteria 
ISS 
International Staging System 
Kd 
Kyprolis in combination with dexamethasone 
KM 
Kaplan-Meier 
KRd 
Kyprolis in combination with lenalidomide plus dexamethasone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
minimal response 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NE 
Not Evaluable 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PR 
partial response 
QTc 
corrected QT interval 
RDI 
Relative Dose Intensity 
RRMM 
relapsed or refractory multiple myeloma 
SAP 
statistical analysis plan 
sCR 
stringent complete response 
SD 
stable disease 
SOC 
system organ class 


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TTR 
time to response 
US FDA 
United States Food and Drug Administration 
VGPR 
very good partial response 
WHODRUG 
World Health Organization Drug 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol superseding amendment 1 for study 
20160372, Carfilzomib (Kyprolis) dated 29 October 2019.  The scope of this plan 
includes the interim analysis, primary analysis and final analysis that are planned and 
will be executed by the Amgen Global Biostatistical Science department unless 
otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To characterize safety associated 
with the use of Kyprolis under the 
locally approved label 
 
The subject incidence, severity, and 
outcome of treatment-emergent adverse 
events using National Cancer Institute 
Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v.4.03 
including clinically significant laboratory 
parameter changes over time 
Secondary 
 
To characterize efficacy of 
Kyprolis when administered under 
the locally approved label 
Progression free survival (PFS), overall 
response rate (ORR), clinical benefit rate 
(CBR), time to response (TTR), and duration 
of response (DOR) will be evaluated by the 
investigator as per local standard procedure 
using International Myeloma Working Group-
Uniform Response Criteria (IMWG-URC). 
 
PFS is defined as the time from the first 
dose of any study treatment until the first 
documentation of disease progression or 
death due to any cause, whichever 
occurs first in the absence of subsequent 
anticancer therapy and if not > 120 days 
from the last non-NE, post-baseline 
disease assessment. 
 
ORR is defined as the proportion of 
subjects with a best overall response of 
either stringent complete response (sCR), 
complete response (CR), very good 
partial response (VGPR), or partial 
response (PR) 
 
CBR is defined as the proportion of 
subjects with a best overall response of 


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either sCR, CR, VGPR, PR, and minimal 
response (MR) 
 
TTR is calculated only for subjects who 
achieve a best overall response of PR or 
better and is defined as the time from first 
dose of study treatment to the earliest 
date a response of PR or better is first 
achieved and subsequently confirmed 
 
DOR is defined as the time from first 
evidence of PR or better per IMWG-URC 
to the earliest of disease progression or 
death due to any cause for subjects with 
a best response of PR or better. DOR will 
be censored as per the primary PFS 
endpoint. 
 


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2.2 
Hypotheses and/or Estimations 
This phase 4 study is descriptive in nature. There is no hypothesis to be tested. The 
study will provide descriptive data on the safety profile associated with the use of 
Kyprolis under the locally approved label as well as its efficacy in terms of PFS, ORR, 
CBR, TTR, and DOR. 
3. 
Study Overview 
3.1 
Study Design 
This open-label, multicenter, non-comparative phase 4 study of Kyprolis is part of 
Amgen’s post-marketing requirement to the Indian Regulatory Authority. The study 
population consists of approximately 100 subjects with RRMM and for whom Kyprolis is 
indicated in accordance with the approved prescribing information in India. 
The assignment of subjects to protocol treatment will be decided by the investigator 
based on clinical evaluation and before the decision to include the subject in this study. 
A subject will be considered on study treatment while receiving Kyprolis. If Kyprolis is 
discontinued, lenalidomide and/or dexamethasone may be continued outside of the 
study.  No crossover between the treatments will be allowed. 
Safety assessments include the collection of adverse events and serious adverse events 
until the last follow-up visit. All subjects will be evaluated by the investigator for multiple 
myeloma disease response based on local standard procedures. Following disease 
progression or discontinuation of study treatment, all subjects will have one final 
assessment that occurs 30 days (+3 days) after the last dose of Kyprolis. 
3.2 
Sample Size 
Approximately 100 subjects with previously treated RRMM will be enrolled as directed by 
the India Regulatory Authority. A total of 100 subjects is considered to be large enough 
to rule out an adverse event incidence rate greater than 3.6% if none is observed, with 
95% confidence. 
3.3 
Adaptive Design 
Not applicable. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Not applicable. 
4.2 
Subgroups 
Not applicable. 


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5. 
Definitions 
Baseline 
Unless otherwise specified, the baseline value is defined as the last assessment 
prior to the administration of the first dose of any study treatment. If a subject doesn't 
receive any study treatment, the latest value prior to or on enrollment date will be used. 
Best overall response 
Best overall response will be assessed by investigator according to International 
Myeloma Working Group Uniform Response Criteria (IMWG-URC). Best overall 
response for a subject is the best observed post baseline confirmed disease response 
prior to subsequent anticancer therapy. 
Clinical Benefit Rate (CBR) 
CBR is defined as the proportion of subjects with a best overall response of either 
sCR, CR, VGPR, PR, and MR. 
Cycle 1 Day 1 (C1D1) 
The date of the first dose of investigational product is defined as cycle 1 day 1. 
Duration of investigational product treatment (non-investigational product treatment) 
Duration of investigational product treatment (non-investigational product treatment) 
is calculated as the time from the first dose date of investigational product (non-
investigational product treatment) to the last dose date of investigational product (non-
investigational product treatment). 
Duration (weeks) = (last dose date of the drug – first dose date of the drug + 1) / 7 
Duration of response (DOR) 
DOR is defined as the time from first evidence of PR or better per IMWG-URC to the 
earliest of disease progression or death due to any cause for subjects with a best response 
of PR or better. DOR will be censored as per the primary PFS endpoint.  The determination 
of progression disease and censoring date will also follow conventions as in Table 5-1.  
DOR (months) = (PD / death – response start date + 1) / 30.4 
Investigational product 
Investigational product for this study refers to Kyprolis® (carfilzomib). 
Last Subject Last Visit 


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The date when the last subject is assessed or receives an intervention for evaluation 
in the study. 
Non-investigational product 
Non-investigational products for this study refer to dexamethasone and 
lenalidomide. 
Overall Response Rate (ORR) 
ORR is defined as the proportion of subjects with a best overall response of either 
stringent complete response (sCR), complete response (CR), very good partial response 
(VGPR), or partial response (PR). 
Progression-free survival (PFS) 
PFS is defined as the time from the first dose of any study treatment until the first 
documentation of disease progression or death due to any cause, whichever occurs first 
in the absence of subsequent anticancer therapy and if not > 120 days from the last non-
NE, post-baseline disease assessment. PFS will be censored at the last non-NE, post-
baseline disease assessment or the earlier of the following, where applicable: (a) the last 
non-NE, post-baseline disease assessment prior to subsequent anticancer therapy, or 
(b) the last non-NE, post-baseline assessment followed > 120 days later by disease 
progression or death; otherwise, at first dose date. Disease progression is defined by the 
IMWG-URC [2016] as assessed by investigator assessment. 
PFS time in months: (date of disease progression, death or censoring - first dose 
date of any study treatment +1)/30.4 
The censoring rules for the primary analysis of PFS are described in Table 5-1. 
 
 
Table 5-1.  Conventions for Censoring for PD dates 
Situation 
Date of Progression or Censoring 
Outcome 
No PD or death, no new 
anticancer treatment 
Last visit; otherwise, the first dose 
date of any study treatment 
Censored 


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No PD or death, new 
anticancer treatment 
Last visit prior to new treatment; 
otherwise, the first dose date of any 
study treatment 
Censored 
PD or death > 120 days 
after last visit 
Last visit prior to PD or death; 
otherwise, the first dose date of any 
study treatmenta 
Censored 
PD or death, no prior new 
anticancer therapy 
Earlier of PD or deathb 
Event 
No PD, new anticancer 
treatment, death 
Last visit prior to new treatment; 
otherwise, the first dose date of any 
study treatmentb 
Censored 
“Visit” refers to a post-baseline non-NE, disease assessment.  
aIf new anticancer therapy starts prior to PD or death, PFS will be censored at the earliest of the 
following: (a) the last non-NE, post-baseline disease assessment prior to subsequent anticancer 
therapy, or (b) the last non-NE, post-baseline assessment followed > 120 days later by disease 
progression or death; otherwise, first dose date. 
bPFS will be censored if PD or death > 120 days after last non-NE, disease assessment. 
Relative Dose Intensity (RDI) 
RDI reflects whether the dose intensity of a therapy was implemented as planned. It 
will be calculated as the ratio of actual dose intensity relative to planned dose intensity. 
Relative Dose Intensity (%) = 100× Actual Dose Intensity
Planned Dose Intensity
 
Carfilzomib: Actual dose intensity is defined as the actual amount of drug in mg/m2 
delivered to a subject per week of treatment. 
Actual Dose Intensity (mg/m2/week) = Cumulative Dose of Carfilzomib (mg/m2)
Number of Weeks of Actual Treatment
 
Cumulative dose of Carfilzomib in mg/m2 will be calculated as the summation of 
dose received (mg) divided by BSA (m2). The baseline BSA will be used in the 
calculation unless the subject experiences a > 20% change in body weight per dosing 
instruction specified in protocol. When BSA is recalculated, the new BSA will be used in 


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the calculation thereafter. Number of weeks of actual treatment will be calculated as (last 
dose date of Carfilzomib – first dose date of Carfilzomib + i)/7, where i is specified as 
follows: 
Arm 
Cycle of last carfilzomib infusion (c) 
Last infusion day 
i 
KRd 
Cycle 1-12 
Day 1, 8 
7 
Day 2, 9 
6 
Day 15 
14 
Day 16 
13 
Cycle 13-18 
Day 1, 15 
14 
Day 2, 16 
13 
Kd 
All cycles 
Day 1, 8 
7 
Day 2, 9 
6 
Day 15 
14 
Day 16 
13 
 
Planned dose intensity is defined as the planned amount of carfilzomib in mg/m2 
delivered to a subject per week of treatment. It will be calculated as the planned 
cumulative dose of carfilzomib in mg/m2 divided by the planned number of weeks for the 
treatment per protocol based on the corresponding cycle and day of the last carfilzomib 
infusion. Per protocol, one cycle is 28 days (4 weeks); so, the planned number of 
treatment weeks will be calculated as 4 x (c-1) + j, where c is the cycle in which the last 
carfilzomib infusion is given and j is specified in Table 5-2. The planned cumulative dose 
of carfilzomib is the summation of planned carfilzomib dose per week as specified in 
Table 5-3. 
Table 5-2.  Planned number of treatment weeks calculation 
Arm 
Cycle of last carfilzomib infusion (c) 
Last infusion day 
j 
KRd 
1 to 12 
Day 1, 2 
1 


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Day 8, 9 
2 
Day 15, 16 
4 
13 to 18 
Day 1, 2 
2 
Day 15, 16 
4 
Kd 
All cycles 
Day 1, 2 
1 
Day 8, 9 
2 
Day 15, 16 
4 
 
Table 5-3.  Planned Carfilzomib Dose per Week 
Arm 
Cycle 
Week 
Protocol Specified Dose for 
Treatment Week  (mg/m2 ) 
KRd 
1 
1st   
20+20 
2 or later 
1st   
27+27 
1 to 12 
2nd   
27+27 
13 to 18 
2nd   
0 
All cycles 
3rd  
27+27 
All cycles 
4th  
0 
Kd 
1 
1st  
20+20 
2 or later 
1st  
56+56 
All cycles 
2nd, 3rd  
56+56 
All cycles 
4th  
0 


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Study treatment 
Study treatment is defined as any investigational product(s) or non-investigational 
product(s) intended to be administered to a study subject according to the study 
protocol. 
Time (months) since initial diagnosis 
Time since initial diagnosis is defined as the time (months) from first diagnosis of 
multiple myeloma to the first dose date of any study treatment or to enrollment date for 
subjects who did not receive Kyprolis. 
Time to response (TTR) 
TTR is calculated only for subjects who achieve a best overall response of PR or 
better and is defined as the time from first dose of study treatment to the earliest date a 
response of PR or better is first achieved and subsequently confirmed. 
TTR (months) = (Response start date - first dose date of study treatment + 1) / 30.4 
Treatment emergent adverse events 
Treatment emergent adverse events (TEAEs) are defined as Adverse Events that 
start on or after first dose of any study treatment and up to the End of Study date.  
6. 
Analysis Sets 
6.1 
Full Analysis Set 
The Full Analysis Set will include all enrolled subjects. All subjects will be analyzed 
according to the treatment arm to which they are enrolled. Full Analysis Set will be used 
for the medical history, demographic and baseline characteristics analyses.  
6.2 
Safety Analysis Set 
This analysis set includes all enrolled subjects who have received at least one dose of 
the investigational product. This analysis set will be used for both safety and efficacy 
endpoints. 
7. 
Planned Analyses 
7.1 
Interim Analysis 
The interim analysis will be performed to support interim report submitted to India 
agency. The data cutoff date will be determined to submit this report within two years 
since approval from Central Drugs Standard Control Organization.  


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All subjects enrolled before data cutoff date will be included. All data by data cutoff date 
will be used. The analysis scope is specified in section 10. 
7.2 
Primary Analysis 
The primary analysis will occur when the last subject enrolled has had the opportunity 
to receive the study treatment for at least 9 months. 
7.3 
Final Analysis 
The final analysis will occur when last subject completes the last assessment in the 
study (last subject last visit) or a study duration up to 3 years, whichever occurs earlier. 
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 
Rules for handing missing data related to endpoints are described in the endpoint 
definitions (Section 5) or the description of analyses (Section 9).  
The handing of incomplete and partial dates for adverse events and concomitant 
medications are described in Appendix A. 
8.4 
Detection of Bias 
If applicable, the methods to detect bias are described in the analyses of particular 
endpoints. 
8.5 
Outliers 
Not Applicable 
8.6 
Distributional Characteristics 
If applicable, the distributional characteristics will be explored for particular endpoints 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   


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Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
In general, the summaries of medical history, demographic and baseline characteristics 
will be based on the Full Analysis Set. The summaries of safety and efficacy data will be 
based on the Safety Analysis Set. All data will be analyzed by treatment groups, 
including Kyprolis in combination with dexamethasone (Kd) and Kyprolis in combination 
with lenalidomide and dexamethasone (KRd). 
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, received study 
treatment, completed investigational product, and completed non-investigational 
products will be summarized by treatment group. The number and percent of subjects 
who discontinued investigational product, non-investigational products and study will 
also be tabulated by treatment group, along with the reason for discontinuation. Key 
study dates for the first subject enrolled, last subject enrolled, and data cut-off date for 
analysis will be presented. The number and percent of subjects enrolled will be tabulated 
by study site. 
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 


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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 
by treatment group. If multiple races have been reported for a subject, the subject will be 
categorized as other. 
Baseline demographics and characteristics includes following variables: 
 
Age  
 
As continuous variable 
 
As categorical variable: <75, ≥ 75 years and <65, ≥ 65 years 
 
Sex (Male, Female) 
 
Race (Asian, Other) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)  
 
Weight (kg) 
 
Body surface area (m2) 
 
Body mass index 
 
ECOG performance scale (0, 1, 2) 
 
Number of prior lines 
 
As continuous variable 
 
As categorical variable: 1, 2, 3, > 3 
 
Prior Bortezomib (Yes, No) 
 
Prior Revlimid (Yes, No) 
Baseline organ function and comorbid conditions: 
 
Time since initial diagnosis (months) 
 
ISS stage at diagnosis (stage I, stage II, stage III, unknown) 
 
Left ventricular ejection fraction (%) 
 
Hepatic function (ALT, AST, Total and direct bilirubin) 
 
Hemoglobin (g/L) (as continuous variable; as categorical variable: <105, 
>=105 (g/L)) 
 
Absolute Neutrophil Count (109/L) (as continuous variable; as categorical 
variable: <1.5, >=1.5 (109/L)) 
 
Platelet count (109/L) (as continuous variable as categorical variable: 
<150, >=150 (109/L)) 


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 
Albumin (g/dL) (as continuous variable; as categorical variable: <3.5, 
>=3.5 (g/dL)) 
 
Corrected calcium (mg/dL; as categorical variable: <=11.5, >11.5 mg/dL):  
as derived in RAVE according to  
[serum calcium (mg/dL) + 0.8×(4 - serum albumin (g/dL))] when albumin is 
less than 4 g/dL. If albumin is 4 g/dL or greater, corrected calcium is equal to 
calcium. 
 
Creatinine clearance (CrCl, mL/min; as categorical variable:15 - < 30, 30-<50, 
50-<80, >=80 mL/min):  as derived in RAVE according to the Cockcroft-Gault 
formula: 
CrCl ( mL min
⁄
) = (140-Age)×Weight(kg)
72×SCr(mg dL
⁄
)
×(0.85female) 
 
9.5 
Efficacy Analyses 
The analysis of efficacy endpoints will be based on Safety Analysis Set and will be 
analyzed by treatment groups. 
Table 9-1.  Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method  
Sensitivity Analysis 
Progression-Free 
Survival 
 
Will be summarized by Kaplan-
Meier method to estimate median 
and quartiles and associated 95 
confidence intervals 
 
Not applicable. 
Overall Response 
Rate 
Clinical Benefit Rate 
 
Point estimate of ORR/CBR and 
95 confidence interval (Clopper-
Person method) will be summarized 
 
Not applicable. 
Time to Response 
 
Descriptive summary statistics will 
be provided 
 
Not applicable. 
Duration of Response 
 
Will be summarized by Kaplan-
Meier method to estimate median 
and quartiles and associated 95 
confidence intervals 
 
Not applicable. 
 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
Not applicable. 


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9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
Safety Analysis set will be used to perform efficacy analyses, which will include following 
endpoints: PFS, ORR, CBR, TTR, and DOR. All response subcategories used in 
aforementioned endpoints are determined by investigator according to International 
Myeloma Working Group Uniform Response Criteria (IMWG-URC) per standard 
procedure.  
PFS will be summarized descriptively using the KM method. Kaplan-Meier curves will be 
used to estimate the distribution of PFS and the median and other quartiles in addition to 
the corresponding two-sided 95% confidence intervals. 
Duration of follow-up for PFS will be summarized according to the Kaplan-Meier 
estimate of potential follow-up also termed “reverse Kaplan-Meier” (Schemper 1996).  
The point estimates of ORR and CBR will be summarized along with exact binomial 95% 
confidence intervals (Clopper-Person method).  
TTR and DOR will also be calculated only for the subjects with confirmed responses. 
Time to response will be summarized by the non-missing sample size (n), mean, 
standard deviation, median, minimum, and maximum for responders by treatment group. 
Kaplan-Meier curves will be used to estimate the distribution of DOR and median and 
other quartiles in addition to the corresponding two-sided 95% confidence intervals. 
 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
The analysis of safety endpoint will be based on Safety Analysis Set and will be 
analyzed by treatment groups. 
Table 9-4.  Safety Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method (Safety 
Analysis Set is used) 
Sensitivity Analysis 
Adverse Event 
The subject incidence, severity, and outcome of 
treatment emergent adverse events will be 
summarized using NCI CTCAE v. 4.03 including 
clinical significant laboratory parameter changes over 
time. 
Not applicable.  


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Each reported adverse event term will be mapped to a 
Preferred Term and a System Organ Class (SOC) 
using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Treatment-emergent adverse events will be 
summarized based on the number (%) of subjects 
experiencing events by MedDRA SOC and preferred 
term. The denominator for the percentage will be 
based on the number of subjects in the Safety 
population. 
A subject reporting the same treatment-emergent 
adverse event more than once will be counted only 
once when calculating 1) within a given SOC, and 2) 
within a given SOC and preferred term combination.  
For such cases, the maximum NCI; US - CTCAE 
4.03 toxicity grade and strongest causal relationship to 
study treatment for the event will be used in the 
incidence calculations. Treatment-emergent adverse 
events will also be summarized by severity, and 
seriousness, and by relationship to study treatment. 
 
 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 22.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, grade 3 or higher TEAE, serious adverse events, adverse events 
leading to discontinuation of investigational product, and fatal adverse events, and 
adverse events of interest (EOI). In the event that a subject experiences repeated 
episodes of the same AE, the subject will be counted once within each system organ 
class and similarly counted once within each preferred term and the event with the 
highest severity grade and/or strongest causal relationship to each treatment will be 
used for purposes of incidence tabulations. 


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Subject incidence of all treatment-emergent adverse events (TEAEs), treatment related 
TEAEs, grade 3 or higher TEAEs, serious TEAEs, adverse events leading to 
discontinuation of investigational product, adverse events leading to discontinuation 
of lenalidomide, adverse events leading to discontinuation of any study drug, and 
fatal adverse events will be tabulated by system organ class in alphabetical order and 
preferred term in descending order of frequency. 
In addition, summaries of treatment-emergent AEs, grade 3 or higher TEAEs, serious 
adverse events, adverse events leading to discontinuation of investigational product, 
adverse events leading to discontinuation of lenalidomide, adverse events leading 
to discontinuation of any study drug, and fatal adverse events by preferred term in 
any treatment arm will be provided in descending order of frequency.   
Subject incidence of events of interest (standardized MedDRA queries and/or Amgen 
customized queries) will also be summarized according to their categories in 
alphabetical order and preferred term in descending order of frequency. 
Summaries of treatment-emergent adverse events will be tabulated by system organ 
class, preferred term, and worst grade. 
Exposure-adjusted incidence rate will be summarized for all treatment-emergent 
adverse events, grade 3 or higher TEAEs, serious TEAEs, fatal TEAEs by system 
organ class and preferred term. Exposure-adjusted incidence rate will also be 
summarized for adverse events of interest and grade 3 or higher adverse events 
of interest by preferred term. 
All TEAEs will be included in individual subject listings. 
All on study deaths will be listed. 
9.6.3 
Laboratory Test Results 
For hematology, chemistry, and other laboratory values, the baseline values and 
changes from baseline by visit will be summarized descriptively by treatment group.   
For the summary of changes from baseline by visit, subjects without a baseline and/or 
post baseline value will be excluded; values from unscheduled assessments will be 
excluded.  Subjects with missing data for a scheduled assessment time point will be 
excluded from the summary for that time point.  Laboratory results from samples taken 
> 30 days after the last administration of protocol therapy will be excluded from the 
laboratory summaries.   


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Laboratory test results will be graded using the NCI CTCAE (Version 4.03).  Shifts in 
laboratory toxicity grades to outside the normal range will be evaluated for selected 
laboratory parameters below by assessing the maximum increase and/or decrease 
observed during the course of study treatment relative to the baseline toxicity grade. The 
summary of post-baseline grade 3 or 4 laboratory toxicities will be included. 
Incidence of potential Hy's Law cases and listing of subjects with ALT/AST > 3x 
ULN or Total Bilirubin > 2x ULN will be provided. The selected laboratory endpoints 
of interest are: 
Hematology 
Serum Chemistry 
 
Hemoglobin 
Albumin 
Glucose 
Platelet count 
ALP 
Magnesium 
WBC count with differential: 
ALT (SGPT) 
Phosphorus 
        Lymphocytes 
AST (SGOT) 
Potassium 
       Neutrophils  
Corrected Calcium 
Total bilirubin 
 
Creatinine 
Uric acid 
 
9.6.4 
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 by treatment group. . For the summary 
of changes from baseline by visit, subjects without a baseline and/or post 
baseline value will be excluded; values from unscheduled assessments will be 
excluded. 
9.6.5 
Physical Measurements 
The analyses of physical measurements (height (cm), weight (kg), BSA (m2)) will 
include summary statistics at scheduled time points by treatment group. Changes will be 
calculated relative to the baseline visit. For the summary of changes from baseline by 
visit, subjects without a baseline and/or post baseline value will be excluded; 
values from unscheduled assessments will be excluded.  
9.6.6 
Electrocardiogram 
The electrocardiogram (ECG) measurements from this clinical study were performed as 
per standard of care for routine safety monitoring, rather than for purposes of 
assessment of potential QT interval corrected (QTc) effect.  Summaries over time and/or 


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changes from baseline over time will be provided for all ECG parameters. For the 
summary of changes from baseline by visit, subjects without a baseline and/or 
post baseline value will be excluded; values from unscheduled assessments will 
be excluded. 
9.6.7 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to Kyprolis. The number 
of cycles that subjects received Carfilzomib and number of subjects who received 
Carfilzomib in each cycle will be summarized. In addition, the duration of therapy, the 
cumulative dose, the number of Carfilzomib administrations, the average dose per 
administration, and relative dose intensity will be summarized. The number and percent 
of subjects with dose modifications (e.g., dose changes and dose interruptions) and 
reason for modification will be summarized.  
9.6.8 
Exposure to Non-investigational Product  
Descriptive statistics will be produced to describe the exposure to non-Amgen non 
investigational products (dexamethasone and/or lenalidomide). The cumulative dose, 
number of cycles, duration of usage, number and percentage of subjects with dose 
modifications, reasons for modification will be summarized using descriptive statistics. 
9.6.9 
Exposure to Other Protocol-required Therapy 
The number and proportion of subjects receiving therapies of interest will be 
summarized by preferred term or category as coded by the World Health 
Organization Drug (WHO DRUG) dictionary by treatment group. 
9.6.10 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications will be 
summarized by preferred term or category as coded by the World Health Organization 
Drug (WHO DRUG) dictionary by treatment group. 
9.7 
Other Analyses 
9.7.1 
Echocardiogram 
Echocardiograms (ECHO) are to be repeated every 6 months (± 2 weeks) from cycle 1 
day 1, until end of study, or if clinically indicated. Results of LVEF% will be summarized 
at each scheduled visit using descriptive statistics and by treatment group. For the 
summary of changes from baseline by visit, subjects without a baseline and/or 
post baseline value will be excluded; values from unscheduled assessments will 
be excluded. 


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9.7.2 
Analyses for COVID-19 Impact 
9.7.2.1 
Impact of COVID-19 on Trial Conduct 
Additional summary of disposition impacted by COVID-19 will be summarized. Listing of 
protocol deviations related to COVID-19 control measures will be provided. Subject 
incidence of protocol deviation related to COVID-19 will be summarized. Missed 
investigational product due to COVID-19 will also be summarized. 
9.7.2.2 
Impact of COVID-19 on Adverse Event 
Treatment-emergent serious adverse events occurring on or after the COVID-19 
infection will be summarized. Summaries of treatment-emergent AEs, grade 3 or 
higher TEAEs, serious adverse events, and fatal adverse events identified by 
COVID-19 standard MedDRA query (SMQ) narrow scope will be provided. 
10. 
 Changes From Protocol-specified Analyses 
Per India regulatory authority request, an interim report of the study should be submitted 
within two years of approval from Central Drugs Standard Control Organization. The 
analysis scope of this report includes subject accountability (section 9.2), Important 
Protocol Deviations (section 9.3), demographic (section 9.4), adverse events (section 
9.6.2), lab test results (section 9.6.3), electrocardiogram (section 9.6.6), exposure to 
investigational product (section 9.6.7), and echocardiogram results (section 9.7.1).  
The snapshot for this analysis will be “as-is”. 
Per superseding protocol amendment 1 (section 4.1), PFS is defined as the time from 
first dose of study treatment until the earliest date of disease progression or death due to 
any cause. DOR is defined as the time from initial response (sCR, CR, VGPR, or PR) to 
date of disease progression.  
The definition of PFS and DOR in section 2.1 is modified. PFS is defined as the time 
from the first dose of study treatment until the first documentation of disease progression 
or death due to any cause, whichever occurs first in the absence of subsequent 
anticancer therapy and if not > 120 days from the last non-NE, post-baseline disease 
assessment. DOR is defined as the time from first evidence of PR or better per IMWG-
URC to the earliest of disease progression or death due to any cause for subjects with a 
best response of PR or better. DOR will be censored as per the primary PFS endpoint. 
The Full Analysis Set is added in section 6.1 and this analysis set will be used for the 
medical history, demographic and baseline characteristics analyses. 


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Per superseding protocol amendment 1 (section 10.3.2.3.7), the number of cycles will be 
summarized with an additional breakdown of the number of cycles completed, 
discontinued, and re-started. In addition, the duration of therapy, the cumulative dose, 
and the percent of intended dose will be summarized by cycle and overall. 
Instead of summarizing the number of cycles completed, discontinued, and re-started, 
summary of number of cycles that subjects received Carfilzomib as well as number of 
subjects who received Carfilzomib in each cycle will be tabulated. In addition, the 
percent of intended dose will not be summarized by cycle and overall. Alternatively, 
relative dose intensity will be summarized (section 9.6.7). 
Per superseding protocol amendment 1 (section 10.3.2.3.1), treatment-emergent 
adverse events are defined as adverse events that start on or after the first day of study 
treatment and within 30 days of the last day of study treatment. 
The definition of treatment-emergent adverse events is modified as adverse events that 
start on or after first dose of any study treatment and up to the End of Study date. 
Impact analyses of COVID-19 on the overall trail conduct and COVID-19 on adverse 
event are added in the statistical analysis plan (section 9.7.2).  
Per the superseding protocol amendment 1 (section 10.3.2.3.4), shifts in vital sign 
value between the baseline and the worst on-study value will be tabulated by 
treatment group. 
Since the worst on-study value for vital sign is not applicable to this study, shifts 
in vital sign value between the baseline and the worst on-study value will not be 
summarized. 
Per the superseding protocol amendment 1 (section 10.3.2.3.8), descriptive 
statistics of average daily dose and duration of usage will be produced to 
describe the exposure to other protocol-required therapies by treatment group. 
Instead of summarizing average daily dose and duration of usage, summary of  
exposure of other protocol-required therapy by the number and proportion of 
subjects receiving therapies of interest will be provided. 
These changes will also be documented in the Clinical Study Report. 
 


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11. 
Literature Citations / References 
Klein JP, Moeschbeger ML.  Survival Analysis:  Techniques for Censored and Truncated 
Data, New York:  Springer-Verlag, 1997. 
Kalbfleisch JD, Prentice RL.  The Statistical Analysis of Failure Time Data, New York: 
John Wiley & Sons, 1980. 
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. 
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 
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. 
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.  
Kaplan, E. L.; Meier, P. (1958). Nonparametric Estimation from Incomplete 
Observations. J. Amer. Statist. Assn. 53 (282): 457–481. JSTOR 2281868 
Schemper M; Smith T.L. (1996). A Note on Quantifying Follow-up in Studies of Failure 
Time . Controlled Clinical Trials 17:343-346 
 
 
 


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12. 
 Appendices 
Appendix A.  Handling of Dates, Incomplete Dates and Missing 
Dates  
A1. Incomplete and partial dates for adverse events, concomitant medications, 
other protocol-required therapy will be imputed by following algorithm:  
Imputation Rules for Partial or Missing Start Dates: 
 Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial:  
yyyymm 
Partial:  
yyyy 
missing 
 1st 
dose 
 1st 
dose 
 1st 
dose 
yyyymm 
 1st 
dose 
yyyymm 
 1st 
dose 
yyyy 
 1st 
dose 
yyyy 
Partial: 
yyyymm 
 1st dose 
yyyymm 
2 
1 
n/a 
1 
n/a 
1 
1 
 1st dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
 1st dose 
yyyy 
3 
1 
3 
1 
n/a 
1 
1 
 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1  Impute the date of first dose 
2  Impute the first day of the month 
3  Impute January 1 of the year 
4  Impute January 1 of the stop year 
Note: If the start date imputation leads to a start date that is after the stop date, 
then do not impute the start date. 
Imputation Rules for Partial or Missing Stop Dates: 
 
For partial stop date mmyyyy, impute the last day of the month. 
 
For partial stop date yyyy, impute December 31 of the year. 
 
For completely missing stop date, do not impute. 


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 
If the stop date imputation leads to a stop date that is after the death date, 
then impute the stop date as the death date. 
 
If the stop date imputation leads to a stop date that is before the start date, 
do not impute the stop date. (i.e., set the stop date as missing). 
 
A2. Incomplete/missing death dates will be imputed by following algorithm: 
1. 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. 
2. If both month and day are missing for death date or a death date is 
totally missing, do not impute. 
 
A3. The initial diagnosis date will be imputed by following algorithm:  
 
If the day is missing and month and year  month and year of enrollment 
then impute 15 for the day 
 
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. 
 
A4. The anti-cancer therapy date will be imputed by following algorithm: 


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If the start day of new anti-cancer therapy is missing and month and year are not 
the same as last dosing date of study treatment, it will be assumed to be the first 
day of the month. If the start day of new anti-cancer therapy is missing and month 
and year are same as last dosing date of study treatment, the start date will be 
assumed as last dosing date of study treatment. In other situations, do not 
impute. 
 
A5. The prior multiple myeloma therapy and relapse/progression to prior multiple 
myeloma therapy date will be imputed by following algorithm: 
If the day of prior multiple myeloma therapy or relapse/progression to prior 
multiple myeloma therapy is missing but month and year are available, then 
impute the date to 15th of the month. If month or year is missing or the date is 
completely missing, do not impute.