Conditions: Multiple Myeloma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 478
Healthy volunteers: no

Brief summary:
The purpose of the study is to compare the progression-free survival (PFS) of once-weekly carfilzomib dosing in combination with dexamethasone to twice-weekly carfilzomib dosing in combination with dexamethasone in adults with relapsed and refractory multiple myeloma, previously treated with bortezomib and an immunomodulatory agent (IMiD).

Detailed description:

Arms:
arm 1: Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter).

Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. arm 2: Participants received carfilzomib administered by IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter).

Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.

Interventions: intervention 1: Carfilzomib intervention 2: Dexamethasone
Intervention descriptions: intervention 1: Carfilzomib was administered as an IV infusion intervention 2: Commercially available dexamethasone was obtained by the investigational site.

Protocol document:
Prot_000.pdf: 
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Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 2 of 165 
Compliance Statement: 
This study will be conducted in accordance with 
Protocol 20140355, the International Conference on Harmonisation 
(ICH), Guideline for Good Clinical Practice (GCP), and the 
applicable country and regional (local) regulatory requirements. 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 3 of 165 
PROTOCOL ACCEPTANCE PAGE 
 
Issue/Date: 20140355 (Superseding Protocol Amendment 4.0)/07 March 2017 
 
I have read this protocol for Study 20140355 entitled: A Randomized, Open-label, 
Phase 3 Study in Subjects with Relapsed and Refractory Multiple Myeloma Receiving 
Carfilzomib in Combination with Dexamethasone, Comparing Once-weekly versus 
Twice-weekly Carfilzomib Dosing  
 
 
As investigator, I understand and agree to conduct this study as outlined herein. 
 
 
 
Investigator Name (print) 
 
 
Investigator Signature 
 
Date 
Signature on this page assures the sponsor that, to the best of the investigator’s knowledge, the affiliated 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) operates in accordance with the 
governing regulations, and that the investigator understands, and agrees to abide by, all governing 
regulatory obligations and the International Conference on Harmonisation (ICH) Guideline for Good 
Clinical Practice (GCP) and country and regional (local) requirements while conducting this clinical 
investigation.  Once signed, the original of this form should be detached from the protocol and returned to 
Onyx or its designee (please retain a copy for your files). 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 4 of 165 
SYNOPSIS 
Name of 
sponsor/company
: 
Onyx Therapeutics, Inc. 
Name of product: 
Carfilzomib for Injection 
Title of study and 
protocol number 
and phase: 
A Randomized, Open-label, Phase 3 Study in Subjects with Relapsed and 
Refractory Multiple Myeloma Receiving Carfilzomib in Combination with 
Dexamethasone, Comparing Once-weekly versus Twice-weekly Carfilzomib 
Dosing / 20140355 
Study 
objective(s): 
Primary Objective  
To compare the progression-free survival (PFS) of once-weekly carfilzomib 
dosing in combination with dexamethasone to the PFS of twice-weekly 
carfilzomib dosing in combination with dexamethasone in subjects with relapsed 
and refractory multiple myeloma who have received prior treatment with a 
proteasome inhibitor and an IMiD (immunomodulatory agent).   
Secondary Objectives 
To compare the following between treatment groups: 
• 
Overall response rate (ORR) 
• 
Overall survival (OS) 
• 
Safety and tolerability 
• 
Pharmacokinetics (PK) of carfilzomib using sparse sampling  
Exploratory Objectives 
• 
Intensive pharmacokinetics (PK) and pharmacodynamics (PDn) of 
carfilzomib in a subset of subjects (substudy) 
• 
All subscales of the European Organisation for Research and Treatment of 
Cancer (EORTC) Quality of Life Core Module (QLQ-C30), and the EORTC 
Quality of Life Multiple Myeloma Module 20 (QLQ-MY20) 
• 
European Quality of Life-5 Dimensions (EQ-5D-5L); a standardized 
measure of health status developed by the European Quality of Life 
(EuroQol) Group 
• 
Patient reported convenience and satisfaction with the carfilzomib schedule 
• 
Healthcare resource utilization 
Study design: 
This is an open-label, multicenter, randomized Phase 3 study comparing 
carfilzomib dosing in combination with dexamethasone administered once-weekly 
to twice-weekly carfilzomib dosing in subjects with relapsed and refractory 
multiple myeloma, previously treated with a proteasome inhibitor and an IMiD.  
The primary endpoint is PFS.  The study design is illustrated in the schema below.  
Eligible subjects will be randomized in a 1:1 ratio to receive a regimen consisting 
of either once-weekly or twice-weekly carfilzomib in combination with 
dexamethasone.   
The randomization will be stratified by: 
• 
The International Staging System (ISS) at study entry (Stage 1 versus 
Stage 2 or 3) per International Myeloma Working Group (Greipp 2005).  
See Appendix H 
• 
Refractory to bortezomib treatment (Yes versus No) 
• 
Age (< 65 versus ≥ 65 years)    
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 5 of 165 
Study design 
(cont’d): 
Study treatment will be administered in 28-day cycles.  Subjects will receive study 
treatment determined by randomization until disease progression, unacceptable 
toxicity, withdrawal of consent, or death (whichever occurs first).  No crossover 
between the 2 treatment groups will be allowed. 
Following termination of study treatment all subjects will be followed for disease 
status (if progressive disease [PD] has not been reached), subsequent antimyeloma 
treatment, and survival.  All subjects will be followed for safety at least 30 
additional days after the last study treatment administration.  All treatment-related 
adverse events (AEs) and serious adverse events (SAEs) will be followed until 
resolution or stabilization.   
Study 20140355 Schema  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG = Eastern Cooperative Oncology Group; IMiD = immunomodulatory agents; 
IV = intravenous(ly); ORR = overall response rate; OS = overall survival; 
PD = progressive disease; PFS = progression-free survival; PI = proteasome inhibitor; 
PO = orally. 
Subjects will be assessed for response using central laboratory results every 
28 days (± 4 days).  Subjects are followed for disease status until confirmed PD.  
Long-term follow-up (LTFU) for disease status (only in cases where subjects 
discontinued treatment prior to PD) and for survival (after reaching PD) will 
continue after treatment discontinuation or until the subject has withdrawn consent 
for further participation, is lost to follow-up, has died, or the sponsor makes a 
decision to close the study.  For subjects who discontinued treatment before 
disease progression occurred (such as for an adverse event, noncompliance, etc.), 
disease response assessments will be performed using central laboratory results 
every 28 days until disease progression.  Follow-up for survival will continue 
approximately every 12 weeks ± 28 days, or as needed, for all surviving subjects 
until study closure.  For any subject who is lost to follow-up, the study site will 
attempt to ascertain survival information via public database search.   
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


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Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 7 of 165 
Inclusion criteria: 
101. Age ≥ 18 years 
102. Able to provide written informed consent in accordance with federal, local, 
and institutional guidelines 
103. Relapsed multiple myeloma 
104. Refractory multiple myeloma, defined as meeting 1 or more of the 
following: 
a. 
Nonresponsive to most recent therapy (stable disease or PD while on 
treatment), or 
b. 
Disease progression within 60 days of discontinuation from most 
recent therapy 
105. At least 2 but no more than 3 prior lines of therapies for multiple myeloma  
106. Prior exposure to an immunomodulatory agent (IMiD) 
107. Prior exposure to a proteasome inhibitor (PI) 
108. Documented response of at least partial response (PR) to at least 1 prior line 
of therapy  
109. Measurable disease with at least 1 of the following assessed at a central 
laboratory within the 21 days prior to randomization: 
a. 
Serum M-protein ≥ 0.5 g/dL 
b. 
Urine M-protein ≥ 200 mg/24 hours  
c. 
In subjects without measurable serum or urine M-protein, serum free 
light chain (SFLC) ≥ 100 mg/L (involved light chain) and an 
abnormal serum kappa lambda ratio 
110. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 
or 1 
111. Left ventricular ejection fraction (LVEF) ≥ 40% within the 21 days prior to 
randomization  
112. Adequate organ and bone marrow function performed at a central laboratory 
within the 21 days prior to randomization, defined by: 
a. 
Bilirubin < 1.5 times the upper limit of normal (ULN) 
b. Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) < 3 times the ULN 
c. 
Absolute neutrophil count (ANC) ≥ 1 x 109/L (screening ANC must 
be independent of growth factor support for ≥ 7 days) 
d. Hemoglobin ≥ 8 g/dL (Use of erythropoietic stimulating factors and 
red blood cell [RBC] transfusions per institutional guidelines are 
allowed, however the most recent RBC transfusion may not have 
been done within 7 days prior to obtaining the screening hemoglobin) 
e. 
Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement 
in the bone marrow is > 50%.  Subjects must not have received 
platelet transfusions for at least 7 days prior to obtaining the 
screening platelet count) 
f. 
Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min.  
Calculation must be based on the Cockcroft and Gault formula:   
[(140 – Age) × Mass (kg) / (72 × Creatinine mg/dL)]; multiply result 
by 0.85 if female 
113. Females of childbearing potential (FCBP) must have a confirmed negative 
serum pregnancy test performed at a central laboratory within the 21 days 
prior to randomization and must not be breastfeeding  
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 8 of 165 
Inclusion criteria 
(cont’d): 
114. Females of childbearing potential must agree to use highly effective 
method(s) of contraception during the study and for 30 days following the 
last study drug administration.  (Refer to Appendix K for specific 
contraception requirements) 
115. Male subjects who are sexually active with an FCBP must agree to use 
condoms (unless they have had a vasectomy with medical confirmation of 
surgical success), during treatment and for an additional 90 days following 
the last study drug administration 
116. Male subjects must agree to not donate sperm, during treatment and for an 
additional 90 days following the last study drug administration 
Exclusion 
criteria: 
201. Waldenström macroglobulinemia 
202. Multiple myeloma of Immunoglobulin M (IgM) subtype 
203. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, 
monoclonal protein, and skin changes) 
204. Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard 
differential) 
205. Myelodysplastic syndrome 
206. Second malignancy within the past 5 years except: 
a. Adequately treated basal cell or squamous cell skin cancer 
b. 
Carcinoma in situ of the cervix 
c. Prostate cancer < Gleason score 6 with stable prostate-specific antigen 
(PSA) over 12 months 
d. 
Ductal breast carcinoma in situ with full surgical resection 
(i.e., negative margins) 
e. Treated medullary or papillary thyroid cancer 
f. Similar condition with an expectation of > 95% five-year disease-free 
survival 
207. History of or current amyloidosis 
208. Cytotoxic chemotherapy or other antineoplastic therapy, aside from 
immunotherapy or proteasome inhibitors, within the 28 days prior to 
randomization  
209. Immunotherapy, such as an IMiD or a proteasome inhibitor within the 
21 days prior to randomization  
210. Glucocorticoid therapy exceeding a cumulative dose of 160 mg of 
dexamethasone or equivalent within 14 days prior to randomization 
211. Radiation therapy: 
a. Focal therapy within the 7 days prior to randomization  
b. 
Extended field therapy within the 21 days prior to randomization  
212. Prior treatment with either carfilzomib or oprozomib 
213. Known history of allergy to Captisol (a cyclodextrin derivative used to 
solubilize carfilzomib) 
214. Contraindication to dexamethasone or any of the required concomitant 
medications or supportive treatments 
215. Active congestive heart failure (New York Heart Association [NYHA] Class 
III or IV, refer to Appendix F), symptomatic ischemia, conduction 
abnormalities uncontrolled by conventional intervention, acute diffuse 
infiltrative pulmonary disease, pericardial disease, or myocardial infarction 
within 6 months prior to randomization 
216. Active infection requiring systemic treatment within the 14 days prior to 
randomization 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 9 of 165 
Exclusion criteria 
(cont’d): 
217. Pleural effusions requiring thoracentesis within the 14 days prior to 
randomization  
218. Ascites requiring paracentesis within the 14 days prior to randomization  
219. Ongoing graft-versus-host disease 
220. Uncontrolled hypertension or diabetes mellitus 
221. Significant neuropathy (≥ Grade 3) within the 14 days prior to 
randomization  
222. Known cirrhosis 
223. Known human immunodeficiency virus (HIV) seropositivity, hepatitis C 
infection, or hepatitis B infection.  Subjects with past hepatitis B virus (HBV) 
infection, defined as having a negative HBsAg test and a positive antibody to 
hepatitis B core antigen (anti HBc) antibody test, are eligible.  Subjects 
positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA. 
224. Participation in another interventional study within the 28 days prior to 
randomization  
225. Major surgery (except kyphoplasty) within the 28 days prior to 
randomization  
226. Any other clinically significant medical disease or social condition that, in 
the investigator’s opinion, may interfere with protocol adherence or a 
subject’s ability to give informed consent, be compliant with study 
procedures, or provide accurate information 
Efficacy 
variables:  
The primary endpoint is PFS.   
Secondary endpoints are: ORR, overall survival (OS), safety and tolerability, and 
pharmacokinetics (sparse sampling) (PK).   
Disease assessments according to the International Myeloma Working 
Group-Uniform Response Criteria (IMWG-URC) will be conducted at baseline 
and then every 28 days (± 4 days) thereafter until progression. 
PK (sparse 
sampling) 
For both arms, blood samples will be collected from subjects who consent to the 
additional testing except for those participating in the intensive PK/PDn substudy 
for determination of plasma concentrations of carfilzomib on C2D1.   
Intensive PK and 
PDn Substudy 
Intensive pharmacokinetic (PK) and pharmacodynamic (PDn) samples will be 
obtained as a substudy (approximately n = 15 evaluable subjects in each arm) 
from subjects who consent to the additional testing at selected sites.  
Pharmacokinetic samples will be collected on Day 15 of Cycle 1 and PDn samples 
will be collected on Days 1, 15, 16, 17, and 22 of Cycle 1.   
Health related 
Quality of Life 
(HRQL): 
The following patient reported outcomes (PRO) will be collected in the study:  
• 
The EORTC 30-item QLQ-C30 questionnaire 
• 
The EORTC 20-item QLQ-MY20 module specifically designed to address 
the quality of life for those with multiple myeloma 
• 
The EQ-5D-5L and patient reported convenience and satisfaction 
questionnaire 
QLQ-C30, QLQ-MY20, and EQ-5D-5L questionnaires should be administered 
prior to study treatment on Day 1 of Cycle 1, then every second cycle (Cycle 1, 3, 
5, etc) during treatment and every 12 weeks (every 84 days ± 4 days) until 
progression, or withdrawal of consent during LTFU.  Patient convenience and 
satisfaction questionnaire will be collected at Day 1 Cycle 2 and end of treatment 
(EOT) only.  Healthcare resource utilization will be collected for all subjects 
during the study.  Details on hospitalizations (not related to adverse events) will 
also be collected. 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 10 of 165 
Safety variables:  
Safety and tolerability will be assessed by incidence and severity of adverse 
events and changes from baseline of all relevant parameters, including laboratory 
values, physical examination, vital signs, and electrocardiogram (ECG).  Severity 
of adverse events will be assessed according to the National Cancer 
Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
Version 4.03.  All subjects will be monitored for adverse events for at least 
30 days after the last administration of study treatment.   
Statistical 
methods and 
analyses: 
Efficacy analyses will be based on the ITT (Intent-To-Treat) Population, which 
includes all randomized subjects.   
The primary endpoint, PFS, will be calculated from the time of randomization 
until PD or death due to any cause, whichever occurs first.  If a subject is 
alive or lost to follow-up without experiencing documented disease 
progression by the data cutoff date, the PFS data for the subject will be 
censored at the date of last valid disease and response assessment.  The 
distribution of PFS will be estimated using the Kaplan-Meier method.  The 
inferential comparison between treatment groups will be made using the 
log-rank test stratified by the randomization stratification factors.  The HR 
and its 95% CI will be estimated using a Cox proportional hazards model 
stratified by the same randomization stratification factors.   
The following randomization stratification factors will be included in the model: 
• 
The ISS Stage at study entry (Stage 1 versus Stage 2 or 3)  
• 
Refractory to bortezomib treatment (Yes versus No) 
• 
Age (< 65 versus ≥ 65 years) 
Response and disease progression will be determined using a validated 
computer algorithm (Onyx Response Computational Assessment [ORCA]), 
as well as by local investigators and by an Independent Review Committee 
(IRC).  The primary analysis of PFS will be based on ORCA-assessed 
outcomes.  The PFS outcomes assessed by the investigator will serve as a 
supportive analysis of PFS, as will IRC-assessed outcomes.   
The secondary endpoint ORR is defined as the proportion of subjects 
achieving a best overall response of PR, very good partial response (VGPR), 
complete response (CR), or stringent complete response (sCR), based on the 
IMWG-URC.  The ORR will be calculated by treatment group, and the 
associated 95% confidence interval [CI] will be estimated using the 
Clopper-Pearson method.  The odds ratio (and its 95% CI) will be estimated using 
the logistic regression model.   
The duration of response (DOR), defined as time in months from the start date of 
the response to the earlier date of documented PD or death, will be calculated for 
subjects who achieve PR, VGPR, CR or sCR.  The DOR will be censored at date 
of the last valid assessment for responders who have not experienced PD or death.  
The distribution of the DOR, including the median will be estimated using the 
Kaplan-Meier method based on the subjects who achieve overall response.   
The secondary endpoint of OS will be analyzed using the log-rank test stratified 
by the randomization stratification factors.  The corresponding HRs will be 
estimated using a stratified Cox proportional hazards model.  The distribution of 
OS including medians will be summarized using the Kaplan-Meier method.   
 
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Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 12 of 165 
TABLE OF CONTENTS 
Page 
CLINICAL STUDY PROTOCOL ...................................................................................1 
PROTOCOL ACCEPTANCE PAGE ..............................................................................3 
SYNOPSIS ..........................................................................................................................4 
TABLE OF CONTENTS ................................................................................................12 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................19 
2 
BACKGROUND INFORMATION ...................................................................23 
2.1 
Introduction ................................................................................................23 
2.2 
Multiple Myeloma .....................................................................................23 
2.3 
Proteasome Background ............................................................................24 
2.3.1 
Carfilzomib Background (Nonclinical) ......................................24 
2.3.2 
Carfilzomib Background (Clinical) ............................................25 
2.4 
Study Rationale ..........................................................................................27 
2.5 
Dose Rationale ...........................................................................................28 
2.5.1 
Rationale for Once-weekly Dosing .............................................29 
2.5.2 
Pharmacokinetics and Pharmacodynamics Data for 
Once-weekly Dosing ...................................................................32 
3 
STUDY OBJECTIVES ........................................................................................35 
3.1 
Primary Objective ......................................................................................35 
3.2 
Secondary Objectives.................................................................................35 
3.3 
Exploratory Objectives ..............................................................................35 
4 
EXPERIMENTAL PLAN ...................................................................................35 
4.1 
Study Design ..............................................................................................35 
4.2 
Number of Centers .....................................................................................37 
4.3 
Number of Subjects....................................................................................37 
4.4 
Estimated Study Duration and Closure ......................................................37 
4.4.1 
End of Study ...............................................................................37 
5 
SUBJECT ELIGIBILITY ...................................................................................38 
5.1 
Inclusion Criteria .......................................................................................38 
5.2 
Exclusion Criteria ......................................................................................40 
6 
SUBJECT SCREENING .....................................................................................41 
7 
SUBJECT RANDOMIZATION .........................................................................42 
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Carfilzomib 
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8 
STUDY DRUGS ...................................................................................................43 
8.1 
Carfilzomib ................................................................................................43 
8.1.1 
Packaging and Labeling ..............................................................43 
8.1.2 
Storage ........................................................................................43 
8.2 
Dexamethasone ..........................................................................................43 
8.3 
Study Drug Accountability ........................................................................43 
8.4 
PRODUCT COMPLAINTS ......................................................................43 
9 
DOSAGE AND TREATMENT ADMINISTRATION .....................................44 
9.1 
Treatment Regimen ....................................................................................44 
9.2 
Intravenous preHydration ..........................................................................45 
9.2.1 
Study Treatment Administration.................................................45 
9.2.1.1 
Carfilzomib ...............................................................47 
9.2.1.2 
Dexamethasone .........................................................47 
9.3 
Dose Modification RULES ........................................................................47 
9.3.1 
Carfilzomib: RULES for Dose Modification ..............................48 
9.3.1.1 
Hematologic Toxicity ...............................................48 
9.3.1.2 
Nonhematologic Toxicity .........................................49 
9.3.2 
Dexamethasone: Guidelines for Toxicities and Dose 
Modification ................................................................................52 
9.3.3 
Conditions not Requiring Dose Reduction .................................54 
9.4 
Concomitant Medications and Therapies...................................................54 
9.4.1 
Required Concomitant Medications ...........................................54 
9.4.1.1 
Gastrointestinal Prophylaxis .....................................54 
9.4.1.2 
Pregnancy and Contraception ...................................55 
9.4.2 
Recommended Concomitant Medications ..................................55 
9.4.2.1 
Antiviral Prophylaxis ................................................55 
9.4.2.2 
Uric Acid-lowering Agents .......................................55 
9.4.2.3 
Mycostatin or Oral Fluconazole................................55 
9.4.2.4 
Antiemetics and Antidiarrheal Agents ......................55 
9.4.2.5 
Thrombophrophylaxis ...............................................55 
Venous thromboembolism has been observed in patients 
receiving carfilzomib.  Thromboprophylaxis 
may be considered on the basis of a benefit-risk 
assessment. ................................................................55 
9.4.3 
Excluded Concomitant Medications and Therapies ...................56 
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Carfilzomib 
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9.4.3.1 
Anticancer Agents .....................................................56 
9.4.3.2 
Radiation Therapy .....................................................56 
9.4.3.3 
Myeloid Growth Factors ...........................................56 
9.4.3.4 
Corticosteroids ..........................................................56 
9.4.3.5 
Plasmapheresis ..........................................................56 
9.4.3.6 
Novel Agents for Non-neoplastic Conditions ...........57 
10 
STUDY ASSESSMENTS AND PROCEDURES ..............................................57 
10.1 
Study Specific Procedures .........................................................................57 
10.1.1 
Multiple Myeloma History and Prior Lines of Therapy 
Assessment ..................................................................................57 
10.1.2 
Vital Signs ...................................................................................58 
10.1.3 
Complete Physical Examination .................................................58 
10.1.4 
Eastern Cooperative Oncology Group Performance Status ........59 
10.1.5 
International Staging System Stage Determination ....................59 
10.2 
Multiple Myeloma Disease Assessments ...................................................59 
10.3 
Multiple Myeloma Response Assessments ................................................61 
10.3.1 
Disease Response and Progression Assessments ........................61 
10.3.2 
Tumor Response Assessment .....................................................61 
10.3.3 
Disease Progression ....................................................................61 
10.4 
Laboratory Tests ........................................................................................62 
10.4.1 
Hematology .................................................................................63 
10.4.2 
Serum Chemistry ........................................................................63 
10.4.3 
Coagulation .................................................................................64 
10.4.4 
Pregnancy Testing .......................................................................64 
10.5 
Electrocardiogram ......................................................................................64 
10.6 
Echocardiogram .........................................................................................65 
10.7 
Patient Reported Outcomes........................................................................65 
10.8 
Healthcare Resource Utilization ................................................................67 
10.9 
Correlative Studies .....................................................................................67 
10.9.1 
Intensive Pharmacokinetics/Pharmacodynamics Substudy ........67 
10.9.2 
Sparse Pharmacokinetic Sampling ..............................................68 
10.10 Long-term Follow-up .................................................................................68 
10.10.1 Long-term Follow-up Before Disease Progression .....................69 
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Carfilzomib 
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10.10.2 Long-term Follow-up After Disease Progression 
(For Survival) ..............................................................................69 
11 
STUDY DISCONTINUATION ..........................................................................69 
11.1 
Withdrawal of Subjects from Study Treatment .........................................69 
11.2 
Withdrawal of Subjects from Study ...........................................................70 
11.3 
Study Termination .....................................................................................71 
12 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..........................71 
12.1 
Adverse Event Reporting ...........................................................................71 
12.1.1 
Adverse Event Terminology .......................................................71 
12.1.2 
Severity .......................................................................................72 
12.1.3 
Duration ......................................................................................73 
12.1.4 
Causality .....................................................................................73 
12.2 
Adverse Events Reporting Procedures .......................................................74 
12.2.1 
General ........................................................................................74 
12.3 
Serious Adverse Event Definition .............................................................75 
12.4 
Serious Adverse Event Reporting and Documentation Requirements ......75 
12.5 
Pregnancy and Lactation Exposure Reporting ...........................................76 
12.6 
Death Reporting .........................................................................................77 
13 
STATISTICAL CONSIDERATIONS ...............................................................77 
13.1 
Study Endpoints .........................................................................................78 
13.1.1 
Primary Endpoints ......................................................................78 
13.1.2 
Secondary Endpoints ..................................................................78 
13.2 
Study Populations ......................................................................................78 
13.2.1 
Intent-to-Treat Population ...........................................................78 
13.2.2 
Safety Analysis Population .........................................................78 
13.3 
Statistical Methods .....................................................................................78 
13.3.1 
Analysis of the Conduct of the Study .........................................78 
13.3.2 
Efficacy Analyses .......................................................................79 
13.3.2.1 
Primary Efficacy Endpoint .......................................79 
13.3.2.2 
Secondary Efficacy Endpoints ..................................80 
13.3.2.3 
Control of Family-wise Type I Error Rate ................81 
13.3.3 
Safety Analysis ...........................................................................81 
13.3.3.1 
Adverse Events .........................................................81 
13.3.3.2 
Safety Laboratory Values .........................................82 
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13.3.3.3 
Vital Signs .................................................................83 
13.3.4 
Sparse Pharmacokinetic Analyses ..............................................83 
13.3.5 
Exploratory Analyses ..................................................................84 
13.4 
Handling of Data ........................................................................................85 
13.4.1 
Handling Missing Data in Descriptive Analyses ........................85 
13.4.2 
Handling Missing or Partially Missing Dates .............................85 
13.4.3 
Missing Grade or Relationship of Adverse Event to Study 
Treatments...................................................................................86 
13.4.4 
Unscheduled Visits .....................................................................86 
13.5 
Determination of Sample Size ...................................................................86 
13.6 
Independent Review Committee ................................................................86 
13.7 
Data Monitoring Committee ......................................................................87 
13.8 
Interim Analysis .........................................................................................87 
14 
REGULATORY OBLIGATIONS .....................................................................88 
14.1 
Informed Consent.......................................................................................88 
14.2 
Compliance with Laws and Regulations....................................................89 
14.3 
Subject Confidentiality ..............................................................................90 
15 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .....................................90 
15.1 
Protocol Amendments ................................................................................90 
15.2 
Study Termination .....................................................................................91 
15.3 
Study Documentation and Archives ..........................................................91 
15.3.1 
Source Documents ......................................................................91 
15.3.2 
Archival of Records ....................................................................91 
15.4 
Data Collection and Study Monitoring ......................................................91 
15.4.1 
Electronic Case Report Forms ....................................................91 
15.4.2 
Study Monitoring ........................................................................92 
15.4.3 
Data Quality Assurance ..............................................................92 
15.5 
Publication Policy ......................................................................................93 
16 
REFERENCES .....................................................................................................94 
APPENDIX A 
SCHEDULE OF ASSESSMENTS ..........................................97 
APPENDIX B 
SCHEDULE OF DISEASE ASSESSMENTS ........................99 
APPENDIX C 
SCHEDULE OF STUDY TREATMENT 
ADMINISTRATION .........................................................................................100 
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Carfilzomib 
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APPENDIX D 
SCHEDULE OF STUDY ASSESSMENTS FOR THE 
PHARMACOKINETIC SPARSE SAMPLING AND INTENSIVE 
PHARMACOKINETIC & PHARMACODYNAMIC SUB-STUDY ...........101 
APPENDIX E 
ECOG PERFORMANCE STATUS ......................................103 
APPENDIX F 
NEW YORK HEART ASSOCIATION (NYHA) 
CLASSIFICATION ...........................................................................................104 
APPENDIX G 
SUMMARY OF INTERNATIONAL MYELOMA 
WORKING GROUP UNIFORM RESPONSE 
CRITERIA (IMWG-URC) ...............................................................................105 
APPENDIX H 
INTERNATIONAL STAGING SYSTEM ...........................107 
APPENDIX I 
NATIONAL CANCER INSTITUTE 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(NCI-CTCAE) GRADING SCALE..................................................................108 
PATIENT REPORTED OUTCOMES .................................109 
APPENDIX J 
APPENDIX K 
COUNTRY SPECIFIC PREGNANCY AND 
CONTRACEPTIVE SUPPLEMENT ..............................................................110 
APPENDIX L 
SAMPLE SERIOUS ADVERSE EVENT 
REPORT FORM ................................................................................................113 
APPENDIX M 
PREGANCY NOTIFICATION FORM ...............................118 
APPENDIX N 
LACTATION NOTIFICATION FORM ..............................119 
APPENDIX O 
SUMMARY OF CHANGES FOR PROTOCOL 
AMENDMENT 4 AND FOR SUPERSEDING PROTOCOL 
AMENDMENT 4 ...............................................................................................120 
LIST OF TABLES 
Table 1 
Summary of Pharmacokinetic Parameters from CHAMPION 1 .....................32 
Table 2 
Pharmacokinetic Parameters Comparison of CHAMPION 1 and 
PX-171-003 – Part 2 (A1) ................................................................................33 
Table 3 
Carfilzomib Dose Decrements .........................................................................48 
Table 4 
Carfilzomib Dose Modification Rules for Treatment-emergent 
Hematologic Toxicity ......................................................................................49 
Table 5 
Carfilzomib Dose Modifications for Nonhematologic Toxicity ......................50 
Table 6 
Dose Decrements for Dexamethasone .............................................................52 
Table 7 
Treatment Rules for Dexamethasone-related Toxicities ..................................53 
Table 8 
Laboratory Tests:  Hematology .......................................................................63 
Table 9 
Laboratory Tests:  Chemistry Panel .................................................................64 
Table 10 Study 20140355 Pharmacodynamics Sampling Timepoints ...........................67 
Table 11 Grading for Adverse Events not Covered in the NCI-CTCAE ........................72 
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Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 18 of 165 
Table 12 Stopping Boundaries for Progression-free Survival ........................................88 
LIST OF FIGURES 
Figure 1 
Proteasome Percent Activity in Peripheral Blood Mononuclear Cells ............34 
Figure 2 
Study 20140355 Schema..................................................................................36 
Figure 3 
Arm A and Arm B Carfilzomib with Dexamethasone Regimens ....................46 
 
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Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 19 of 165 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
ASCT 
autologous stem cell transplantation 
AST 
aspartate aminotransferase  
AUC 
area under the curve  
AUC0-last 
area under the curve from time 0 to last time measurable concentration 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBR 
clinical benefit rate  
CFZ 
carfilzomib 
CI 
confidence interval 
Cmax 
maximum plasma concentration  
C1D1 
Cycle 1 Day 1 
C2D1 
Cycle 2 Day 1 
CR 
complete response 
CrCl 
creatinine clearance 
CT 
computed tomography  
CT-L 
chymotrypsin-like 
D5W 
5% Dextrose Injection 
Dex 
dexamethasone 
DLT(s) 
dose-limiting toxicity(ies) 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
ECG 
electrocardiogram  
ECHO 
echocardiogram  
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EORTC 
European Organization for Research and Treatment of Cancer 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EOT 
End of Treatment 
EQ VAS 
EQ Visual Analogue scale 
EuroQOL  
European Quality of Life 
EQ-5D-5L 
European Quality of Life-5 Dimensions  
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Abbreviation 
Definition 
FDA 
Food and Drug Administration 
FCBP 
females of childbearing potential 
FISH 
Fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
H2 
histamine 2 
HIV 
human immunodeficiency virus 
HR(s) 
hazard ratio(s) 
HRQL 
health-related quality of life 
HUS 
hemolytic uremic syndrome 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IMiD(s) 
immunomodulatory agent(s) 
IMWG-URC 
International Myeloma Working Group-Uniform Response Criteria 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IP(s) 
investigational product(s) 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ISRG 
Independent Statistical Reporting Group 
IST(s) 
investigator-sponsored trial(s) 
ISS 
International Staging System 
ITT 
Intent-to-Treat 
IUD 
intrauterine device 
IV 
intravenous(ly) 
IVR/IWR 
Interactive Voice (IVR) and Web Response (IWR) 
LDH 
lactate dehydrogenase 
LFT(s) 
liver function test(s) 
LMP2 
latent membrane protein 2 
LMP7 
latent membrane protein 7 
LTFU 
Long-term follow-up 
LVEF 
left ventricular ejection fraction  
MECL-1 
multicatalytic endopeptidase complex-like 1 
MedDRA 
Medical Dictionary for Regulatory Activities  
MR 
minimal response 
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Carfilzomib 
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Abbreviation 
Definition 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose  
MUGA 
multigated acquisition  
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
ORCA 
Onyx Response Computational Assessment  
ORR 
overall response rate  
OS 
overall survival 
PBMC(s) 
peripheral blood mononuclear cell(s) 
PD 
progressive disease 
PDn 
pharmacodynamics 
PET 
positron emission tomography 
PK 
pharmacokinetic 
PFS 
progression-free survival 
PI 
proteasome inhibitor 
PN 
peripheral neuropathy 
prn 
as needed 
PO 
orally  
POEMS 
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin 
changes 
PR 
partial response 
PRO(s) 
patient reported outcome(s) (psychosocial measures) 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QLQ-C30 
Quality of Life Core Module 
QLQ-MY20 
Quality of Life Multiple Myeloma Module 20 
QOL 
Quality of Life 
QTc 
corrected QT-interval 
RBC(s) 
red blood cell(s) 
SAE(s) 
serious adverse event(s) 
SAg 
surface antigen 
SAP 
Statistical Analysis Plan 
SBE-CD 
sulfobutylether-beta-cyclodextrin (Captisol) 
SOC 
system organ class 
SWI 
Sterile Water for Injection 
sCR 
stringent complete response 
SFLC 
serum free light chain 
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Abbreviation 
Definition 
SOPs 
Standard Operating Procedures 
SPEP 
serum protein electrophoresis 
t1/2 
terminal half-life  
TEAE(s) 
treatment-emergent adverse event(s) 
TLS 
tumor lysis syndrome 
tmax 
time to maximum plasma concentration  
TTP 
thrombocytopenic thrombotic purpura 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
US 
United States 
USP 
United States Pharmacopeia 
VGPR 
very good partial response 
WBC(s) 
white blood cell(s) 
WOCBP 
woman of childbearing potential 
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Carfilzomib 
Page 23 of 165 
2 
BACKGROUND INFORMATION 
2.1 
INTRODUCTION 
Carfilzomib for Injection received accelerated approval from the United States Food and 
Drug Administration (US FDA) in July 2012 for the treatment of patients with multiple 
myeloma who have received at least 2 prior therapies, including bortezomib and an 
immunomodulatory agent (IMiD) and have demonstrated disease progression on or 
within 60 days of completion of the last therapy.  The approval was based on the results 
of the Study PX-171-003 – Part 2 (A1) in 266 subjects with relapsed and refractory 
multiple myeloma.   
Per the 2012 approved label, carfilzomib is administered intravenously (IV) over 
10 minutes, on 2 consecutive days each week for 3 weeks (Days 1, 2, 8, 9, 15, and 16 of a 
28-day cycle).  The recommended Cycle 1 dose is 20 mg/m2/day with an increase to 
27 mg/m2 on Cycle 2 Day 1 onwards.   
This study will assess the superiority of a higher dose level of carfilzomib (70 mg/m2) 
given once-weekly (Days 1, 8, and 15) over 30 minutes in combination with 
dexamethasone compared to the twice-weekly regimen at 20/27 mg/m2 in combination 
with dexamethasone.  Subjects will receive the study treatment determined by 
randomization until disease progression, unacceptable toxicity, withdrawal of consent, or 
mortality (whichever occurs first).  Subjects will be evaluated in long-term follow-up 
(LTFU) for health status and survival.   
2.2 
MULTIPLE MYELOMA 
Multiple myeloma, a clonal neoplastic proliferation of plasma cells, is the second most 
common hematologic malignancy and accounts for approximately 72,000 annual deaths 
worldwide (Ferlay 2010).  There are an estimated 11,000 deaths per year in the US and 
more than 19,000 deaths per year in Europe (American Cancer Society 2014; 
Boyle 2005).  Multiple myeloma is characterized by anemia, bone destruction, 
monoclonal gammopathy, renal failure, hypercalcemia, and increased susceptibility to 
infections.  The disease is systemic and chemotherapy is indicated for management of 
symptomatic myeloma.   
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Historically, multiple myeloma was treated with chemotherapy with the introduction of 
melphalan in the 1960s.  Subsequent treatment paradigms for the next three decades 
relied largely on combination of chemotherapy regimens with corticosteroids, with 
minimal to no incremental improvements in survival.  In the 1990s, the introduction of 
autologous stem cell transplantation (ASCT) after a conditioning regimen that 
incorporates high doses of melphalan resulted in improvements in survival.  Additional 
improvements in survival followed the advent of the IMiDs, thalidomide (Thalomid) and 
lenalidomide (Revlimid) and the proteasome inhibitor (PI) bortezomib (Velcade) 
(Kumar 2008).  Since then, these 3 agents have been used in combination with 
corticosteroids, and with chemotherapy agents (e.g., alkylating agents) (National 
Comprehensive Cancer Network 2014; Harousseau 2010).   
Despite improvements in progression free survival (PFS) and overall survival (OS), 
patients who have received several lines of prior therapy experience progressively lower 
rates and durations of response as resistance emerges (Kumar 2004; Durie 2012; 
Kumar 2012); and current therapeutic options for patients who have multiply relapsed 
and refractory disease, especially those refractory to both IMiDs and bortezomib, are 
limited.  A recent retrospective review of 286 patients from treatment centers in the US, 
Europe, and Asia with a median of 4 prior therapies and 3.3 years since initial diagnosis 
of multiple myeloma, revealed that such patients with multiply relapsed multiple 
myeloma can anticipate a median OS of approximately 9 months (Kumar 2012).  
2.3 
PROTEASOME BACKGROUND 
The proteasome is a multicatalytic proteinase complex that is responsible for degradation 
of a wide variety of protein substrates within normal and malignant cells.  Intracellular 
proteins targeted for degradation by the proteasome are first ubiquitinated via the 
ubiquitin conjugation system.  Ubiquitinated proteins are cleaved within the proteasome 
by 1 or more of 3 separate N-terminal threonine protease activities: a chymotrypsin-like 
(CT-L) activity, a trypsin-like activity, and a caspase-like activity. 
2.3.1 
CARFILZOMIB BACKGROUND (NONCLINICAL) 
Carfilzomib (formerly known as PR-171) is a tetrapeptide epoxyketone-based inhibitor of 
the 20S proteasome, primarily of the CT-L activity, and at higher concentrations, 
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of multiple 20S proteolytic activities.  Carfilzomib is a synthetic small molecule peptide 
bearing the chemical name (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl) 
-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido) 
-4-phenylbutanamido)-4-methylpentanamide.  The molecular formula is C40H57N5O7 and 
the molecular weight is 719.91.  Carfilzomib, which is structurally and mechanistically 
different from the dipeptide boronic acid PI bortezomib, showed less off-target activity 
when measured against a broad panel of proteases including metallo-, aspartyl-, and 
serine proteases compared to bortezomib; the latter showed off-target inhibitory activity 
in the nanomolar range against several serine proteases (Arastu-Kapur 2009).  This 
selectivity may be responsible for the reductions in myelosuppression and neuropathy 
observed in clinical and nonclinical studies comparing carfilzomib with bortezomib. 
Carfilzomib primarily inhibits the CT-L activity of both the constitutive proteasome and 
the immunoproteasome (Kuhn 2007; Demo 2007).  The importance for co-inhibition of 
multiple proteasome active sites for cytotoxicity (CT-L, trypsin-like, and/or caspase-like) 
has been demonstrated against multiple myeloma cell lines (Britton 2009; Geurink 2013). 
Nonclinical work supported improved tolerability with increased infusion time, possibly 
because of the reduced maximum concentration (Cmax) with a 30-minute IV infusion 
(Yang 2011).  Correlative clinical pharmacodynamics (PDn) studies have confirmed that 
longer infusion times and higher doses of carfilzomib resulted in increased proteasome 
inhibition (Papadopoulos 2014; Lee 2012).  Clinical evidence for carfilzomib dose 
response has been observed in a multivariable modeling analysis comparing 20 mg/m2 
with 27 mg/m2, (Lonial 2011; Squifflet 2011) suggesting that more effective inhibition of 
proteasome activity may improve efficacy.  An increased infusion time of 30 minutes 
enabled carfilzomib to be administered at a higher dose, with a maximum tolerated dose 
(MTD) of 56 mg/m2 in Study PX-171-007, compared to 27 mg/m2 over a 2 to 10-minute 
infusion as discussed in Section 2.3.2.  
2.3.2 
CARFILZOMIB BACKGROUND (CLINICAL) 
As of 10 July 2015, approximately 2921 individual subjects have been treated with 
carfilzomib as participants in Onyx-sponsored clinical studies, and 89 subjects have been 
enrolled in studies in Japan sponsored by Ono Pharmaceutical Company.  Approximately 
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3549 subjects have been treated with carfilzomib through the 76 completed or actively 
enrolling investigator-sponsored trials (ISTs) (Carfilzomib IB). 
There are five Phase 3 studies in multiple myeloma: PX-171-009 (ASPIRE), PX-171-011 
(FOCUS), 2011-003 (ENDEAVOR), 2012-005 (CLARION), and this study, 20140355 
(A.R.R.O.W.).  Additionally, 137 subjects with solid tumors have been treated with 
carfilzomib. 
These trials have explored various doses of carfilzomib either as monotherapy or in 
combination with other agents and in the majority of studies conducted to date, 
carfilzomib has been administered on 2 consecutive days for 3 weeks in a 28-day cycle.  
Carfilzomib clinical activity has been demonstrated in these studies along with an 
acceptable safety profile. 
Higher doses of carfilzomib administered on a twice-weekly schedule have been studied.  
PX-171-007, a Phase 1b/2 study, was the first to establish the MTD of single agent 
carfilzomib administered as a 30-minute infusion in subjects with relapsed and/or 
refractory multiple myeloma (Papadopolous 2014).  Subjects received carfilzomib 
monotherapy on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.  Cycle 1 Day 1 and Day 2 
doses were 20 mg/m2 followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2.  
Carfilzomib was administered later with low-dose dexamethasone (40 mg/week) at the 
45 mg/m2 and 56 mg/m2 dose levels.  Thirty-three subjects were treated, and there were 
dose-limiting toxicities (DLTs) in 2 subjects dosed at 70 mg/m2 of renal tubular necrosis 
(Grade 3) and proteinuria (Grade 3).  The MTD was determined to be 56 mg/m2. 
In the 56 mg/m2 cohort (n = 24), the most common treatment-related adverse events 
(AEs) of any grade were nausea (54.2%), dyspnea (50.0%), fatigue (45.8%), pyrexia 
(41.7%), and thrombocytopenia and chills (both 37.5%); a majority were Grade 1 or 2.  
At this dose, hematologic AEs of thrombocytopenia (37.5%) and anemia (16.7%) were 
the most common treatment-related AEs of ≥ Grade 3.  When carfilzomib at 56 mg/m2 
was combined with dexamethasone (n = 8), nausea (25%), fatigue (25%), and dyspnea 
and chills (each 12.5%) occurred less frequently than with carfilzomib alone.  The overall 
response rate (ORR) was 50% in the 56 mg/m2 cohort where the majority of subjects 
were refractory to IMiDs and bortezomib.  The Phase 2 PX-171-003 – Part 2 (A1) study 
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with single agent carfilzomib at 20/27 mg/m2 in a similar population had an ORR 
of 22.9% in the Safety population. 
As evidenced by Study PX-171-007, higher doses of carfilzomib on a twice-weekly 
schedule administered over 30 minutes were well tolerated and efficacious with an 
acceptable safety profile.  This led the sponsor to investigate whether higher doses of 
carfilzomib could be tolerated and be efficacious on a more convenient weekly dosing 
schedule in the CHAMPION 1 study as discussed in Section 2.5. 
Additional information on the safety and activity of carfilzomib is described in the 
Carfilzomib IB. 
2.4 
STUDY RATIONALE 
Based on the aspiration of improving the convenience of the currently approved 
carfilzomib dosing regimen and the recognition that higher doses appeared active and 
tolerable when given over a longer infusion time, a Phase 1b/2 Study CHAMPION 1 was 
initiated to evaluate the safety and efficacy of once-weekly carfilzomib with 
dexamethasone in subjects with relapsed myeloma, who had received 1 to 3 prior 
therapies.  The dose-escalation portion of the study has identified an MTD of 70 mg/m2 
administered once-weekly over 30 minutes on Days 1, 8, and 15 of a 28-day cycle.  
Preliminary results from the ongoing Phase 2 portion of this multicenter, single-arm 
study suggested that the dose and regimen of 70 mg/m2 once-weekly appeared to be well 
tolerated, highly active, and able to offer a more convenient treatment regimen for 
subjects as discussed in Section 2.5. 
The rationale for this study is to compare carfilzomib administered once weekly in 
combination with dexamethasone, based on the CHAMPION 1 results, to twice-weekly 
carfilzomib in combination with dexamethasone in subjects with relapsed and refractory 
multiple myeloma, previously treated with a proteasome inhibitor and an IMiD.  The 
hypothesis is that this regimen will have superior efficacy with an acceptable safety 
profile and a more convenient dosing regimen when compared with the US approved 
dose and schedule of carfilzomib administered at 20/27 mg/m2 twice weekly. 
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The primary endpoint in this study is PFS.  Response rates, especially high-quality 
responses of substantial duration, are important indicators of benefit in relapsed and 
refractory multiple myeloma (Anderson 2008).  A number of studies have shown an 
association between deeper responses and improved survival in patients with multiple 
myeloma (Lonial 2014).  For these reasons, this study was originally designed with 
ORR as the primary endpoint and PFS as a key secondary endpoint.  Although 
ORR remains a meaningful clinical endpoint, recent advances in antimyeloma 
therapy have altered the landscape such that PFS is now considered to be the more 
relevant regulatory endpoint in this setting.  To support regulatory interactions and 
protect the integrity of the the PFS data, the primary endpoint has been amended to 
PFS, with ORR as a key secondary endpoint. 
2.5 
DOSE RATIONALE 
Carfilzomib 20/27 mg/m2 twice-weekly is an approved monotherapy dose 
and 20/70 mg/m2 once-weekly is the MTD that was determined in the CHAMPION 1 
study described in Section 2.5.1. 
In the proposed study, dexamethasone will be administered prior to carfilzomib 
administration at 40 mg weekly on Days 1, 8, and 15 in both arms during all Cycles and 
on Day 22 in both arms during Cycle 1 to 9 only.  This dose and schedule of therapeutic 
dexamethasone was part of the once-weekly treatment regimen in Study CHAMPION 1.  
The equivalent weekly doses of dexamethasone in both treatment arms will enable a clear 
interpretation of the study’s primary comparison between high-dose once-weekly 
carfilzomib and standard-dose twice-weekly carfilzomib. 
Carfilzomib study treatment administration will use a step-up approach in which the first 
dose level for all subjects will be 20 mg/m2 (Cycle 1 Day 1 for the once-weekly regimen 
and Cycle 1 Days 1 and 2 for the twice-weekly regimen) and the dose level will then 
increase to 70 mg/m2 or 27 mg/m2 respectively, beginning on Day 8 of Cycle 1. 
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The dose levels of carfilzomib and dexamethasone being evaluated in this study are: 
Arm A: Once-weekly  
• Carfilzomib 20 mg/m2 
o Study Day 1 (Cycle 1) 
• Carfilzomib 70 mg/m2  
o Study Days 8 and 15 (Cycle 1) 
• Carfilzomib 70 mg/m2 
o Study Days 1, 8, and 15 (Cycles 2+) 
• Dexamethasone  
o 40 mg (IV or PO [orally]) on Study Days 1, 8, and 15 (all Cycles) 
o 40 mg (IV or PO) Study Day 22 (Cycles 1 to 9 only) 
Arm B: Twice-weekly  
• Carfilzomib 20 mg/m2  
o Study Days 1 and 2 (Cycle 1) 
• Carfilzomib 27 mg/m2  
o Study Days 8, 9, 15, and 16 (Cycle 1) 
• Carfilzomib 27 mg/m2 
o Study Days 1, 2, 8, 9, 15, and 16 (Cycles 2+) 
• Dexamethasone  
o 40 mg (IV or PO) on Study Days 1, 8, and 15 (all Cycles) 
o 40 mg (IV or PO) on Study Day 22 (Cycles 1 to 9 only) 
2.5.1 
RATIONALE FOR ONCE-WEEKLY DOSING 
CHAMPION 1, a Phase 1b/2 study in subjects with relapsed multiple myeloma who had 
received 1 to 3 prior therapies was initiated to investigate higher doses of carfilzomib 
given once-weekly in combination with dexamethasone, and preliminary results indicated 
that these modifications were well tolerated and active.  In the Phase 1b dose-escalation 
portion of the study, all subjects received 20 mg/m2 carfilzomib on Cycle 1 Day 1 and 
then received the cohort-assigned test dose on Cycle 1 Days 8 and 15.  The initial dose 
level evaluated was 45 mg/m2, with escalation to 56 mg/m2, 70 mg/m2, and 88 mg/m2 in 
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successive cohorts.  Subjects received 40 mg dexamethasone on Days 1, 8, 15, and 22 of 
Cycles 1 through 8 and on Days 1, 8, and 15, from Cycle 9 onward. 
No DLTs were observed during dose escalation at the dose levels of 45 mg/m2, 
56 mg/m2, or 70 mg/m2.  At the carfilzomib dose level of 88 mg/m2, 2 DLTs were 
observed during Cycle 1: 
• Dyspnea (Grade 3, Days 9 to 11)  
• Vomiting (Grade 3, Day 15)  
Per protocol, an expansion cohort of 9 additional subjects was enrolled at the 70 mg/m2 
dose.  There was 1 DLT in the 70 mg/m2 expansion cohort: Grade 3 dyspnea (Days 16 to 
18).  The MTD of once-weekly carfilzomib in combination with dexamethasone was 
determined to be 70 mg/m2. 
A total of 27 subjects were enrolled in the Phase 1 portion of the study with a median of 
1 prior therapy.  Fifteen subjects received study treatment at a dose of 70 mg/m2.  
The majority of the 27 subjects (85%) received prior bortezomib and 63% of those were 
refractory to bortezomib.  The ORR in the Phase 1 population was 81% with a clinical 
benefit rate (CBR) of 93%.  The once-weekly treatment regimen of 70 mg/m2 showed 
promising activity with an ORR of 93% (95% [confidence interval] CI:  68.1 to 99.8%), 
4 subjects achieved a complete response (CR) and the CBR was 100% (95% CI:  78.2 
to 100%).  The median treatment duration was 8.3 months in this cohort (Berenson 2014). 
All 27 subjects (100%) experienced at least 1 AE.  The most common (≥ 20% of 
subjects) AEs were upper respiratory tract infection, fatigue (each 52%), insomnia (44%), 
diarrhea, nausea, headache (each 41%), anemia, decreased hematocrit (each 37%), 
pyrexia (33%), constipation (30%), back pain, cough, muscle spasms, dyspnea, decreased 
red blood cell count (each 26%), arthralgia, dizziness, and pain in extremity (each 22%). 
Five serious adverse events (SAEs) were reported in the Phase 1 part of this ongoing 
study: 
• One subject at 45 mg/m2 had 2 SAEs; increased blood creatinine (Grade 3), and 
hyponatremia (Grade 4).   
• One subject at 70 mg/m2 had pneumonia (Grade 3).   
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• One subject at 88 mg/m2 had dyspnea (Grade 3).   
• One subject at 70 mg/m2 had chronic obstructive pulmonary disease (Grade 3).   
All SAEs were determined to be unrelated to carfilzomib and dexamethasone, except for 
the Grade 3 dyspnea event, a DLT in a subject receiving the 88 mg/m2 dose. 
As of 01 May 2015, 104 subjects (Phase 1 n = 15, Phase 2 n = 89) have received at least 
1 dose of carfilzomib at the MTD.  The majority of subjects (82%) had received prior 
bortezomib.  A total of 48% of subjects were bortezomib-refractory, 28% were 
lenalidomide-refractory, and 16% were refractory to both.  The ORR to date was 77% 
(95% CI:  68% to 85%) with a CBR of 84% (95% CI:  75% to 90%).  Median PFS was 
10.6 months (95% CI:  9.0 to 16.1).  Preliminary median carfilzomib treatment duration 
in the ongoing study is 8.3 months (range:  > 1 to 20) for the Phase 1 portion of the 
study and 7.2 months (range: 0.03 to 22.6) for the Phase 2 portion of the study 
(Berenson 2015). 
All 104 subjects experienced at least 1 AE.  The most common AEs (≥ 15% of subjects) 
were fatigue (52%), nausea (35%), headache, diarrhea (each 31%), insomnia, upper 
respiratory tract infection (each 30%), cough (26%), dyspnea (25%), anemia (24%), 
thrombocytopenia, pyrexia (each 22%), peripheral edema (20%), and back pain (17%).  
A total of 64 subjects (62%) experienced at least 1 Grade 3 or higher AE.  The most 
common (≥ 5% of subjects) Grade 3 or higher AEs were fatigue (11%), pneumonia (7%), 
thrombocytopenia, hypertension, acute renal failure (each 6%), dyspnea, anemia, back 
pain, asthenia, and chronic obstructive pulmonary disease (each 5%) (Carfilzomib IB). 
The preliminary results from CHAMPION 1 demonstrated that once-weekly carfilzomib 
at 70 mg/m2 administered as a 30-minute infusion in combination with dexamethasone in 
subjects with relapsed and refractory multiple myeloma had an acceptable safety and 
tolerability profile and promising efficacy.  Eighty-nine subjects were enrolled into the 
Phase 2 portion of the study.   
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2.5.2 
PHARMACOKINETICS AND PHARMACODYNAMICS DATA FOR 
ONCE-WEEKLY DOSING 
Pharmacokinetics (PK) and pharmacodynamics (PDn) results from CHAMPION 1 are 
supportive of the proposal to study the once-weekly 70 mg/m2 regimen as an effective 
alternative regimen for carfilzomib. 
Preliminary PK results from CHAMPION 1 indicated that a once-weekly 30-minute 
infusion of carfilzomib had a mean terminal half-life similar to the half-life of ≤ 1 hour 
following the approved twice-weekly dosing regimen (20/27 mg/m2 over 2 to10 minutes). 
In addition, the data showed a dose-proportional increase in the mean Cmax and area under 
the curve (AUC) from 20 to 88 mg/m2, as indicated by the similar dose normalized values 
for Cmax and AUC (refer to Table 1).  The AUC following a 70 mg/m2 dose was 
1045 ng⋅h/mL, which is higher than the total weekly AUC following the twice-weekly of 
27 mg/m2 dose (758 ng⋅h/mL, refer to Table 2).  The mean Cmax following the 70 mg/m2 
dose administered as a 30-minute infusion is 2640 ng/mL, which is lower than the mean 
Cmax of 4232 ng/mL in Study PX-171-003 – Part 2 (A1), following the IV infusion of 
27 mg/m2 over 2 to 10 minutes (Carfilzomib IB). 
Table 1 
Summary of Pharmacokinetic Parameters from CHAMPION 1 
Dose 
(mg/m2) 
n 
t1/2 (%CV) 
Cmax 
(%CV) 
Cmax/Dose 
(ng/mL)/ 
mg/m2 
AUC0-last 
(%CV) 
AUC/Dose 
(h.ng/mL)/m
g/m2 
20 
11 
0.77 hr 
(37.4%) 
703 ng/mL 
(16.0%) 
35.0 
283 ng⋅h/mL 
(17.6%) 
14.2 
70 
5 
0.91 hr 
(24.3%) 
2640 ng/mL 
(24.9%) 
37.7 
1045 ng⋅h/mL 
(22.1%) 
14.9 
88 
5 
0.84 hr 
(11.3%) 
3172 ng/mL 
(24.9%) 
36.0 
1247 ng⋅h/mL 
(31.3%) 
14.2 
AUC0-last = AUC from time 0 to last time measurable concentration, CV = coefficient of variation, 
t1/2 = terminal half-life, Cmax = maximum plasma concentration, AUC = area under the curve. 
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Table 2 
Pharmacokinetic Parameters Comparison of CHAMPION 1 and 
PX-171-003 – Part 2 (A1) 
Study 
Cycle/Dose/Days 
Infusion 
Duration 
Total 
dose/week 
(mg/m2) 
Total AUC 
per week 
(ng⋅hr/mL) 
Maximal 
concentration 
(ng/mL) 
PX-171-003 
– Part 2 (A1) 
Cycle 1:  20 mg/m2 
Days 1, 2, 8, 9, 15, and 
16 
2–10 minutes 
40 
566a 
3060 
Cycle 2:  27 mg/m2 
Days 1, 2, 8, 9, 15, and 
16  
2–10 minutes 
54 
758a 
4232 
2012-002 
(CHAMPION 1) 
Cycle 1 Day 1: 20 mg/m2 
Cycle 1 Days 8 and 15: 
70 mg/m2  
30 minutes 
70 
1045b 
2640 
Cycle 2:  70 mg/m2 
Days 1, 8, and 15  
30 minutes 
AUC = area under the curve. 
a AUC following a single 20 and 27 mg/m2 dose (2–10 minutes infusion) is 283 and 379 ng⋅hr/mL, 
respectively.  Total AUC per week is calculated by multiplying the single dose AUC by 2 
(e.g., 379 × 2 = 758 ng⋅h/mL).  
b Represents total AUC per week starting on Day 8. 
An exploratory exposure response analysis indicates a statistically significant relationship 
between the carfilzomib average AUC during Cycle 1 and response rates (ORR and 
CBR) with higher AUC exposures associated with improved responses in subjects with 
multiple myeloma (TR-1092-171).  No statistically significant relationships between Cmax 
and efficacy or safety endpoints were found.   
Preliminary PDn data from CHAMPION 1 revealed that in blood and peripheral blood 
mononuclear cells (PBMCs) the 70 mg/m2 dose level resulted in a greater depth of 
proteasome inhibition, at 1-hour post dose, compared to 1 hour after the Cycle 2 Day 1 
dose in a twice-weekly schedule of 27 mg/m2 and 56 mg/m2 (as observed in the 
Phase 1b/2 PX-171-007 study).  Chymotrypsin-like subunits (Beta 5 and latent membrane 
protein 7 [LMP7]) were inhibited most strongly, followed by trypsin-like (Beta 2 and 
multicatalytic endopeptidase complex-like 1 [MECL-1]), and caspase-like (Beta 1 and 
latent membrane protein 2 [LMP2]) subunits, respectively (refer to Figure 1). 
Together, PK and PDn results from CHAMPION 1 support the investigation of 
once-weekly 70 mg/m2 regimen as a potentially effective alternative regimen for 
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carfilzomib.  The PK results from this study indicate that the total AUC per cycle 
delivered by the 70 mg/m2 dose is expected to be higher compared to those of the 
20/27 mg/m2 regimen, consistent with the high ORR observed in the study 
(Berenson 2014) and exploratory exposure response analysis for carfilzomib 
(TR-1092-171).  Pharmacodynamics data are consistent with a greater depth of 
proteasome inhibition with 70 mg/m2 compared to those at 27 mg/m2 and 56 mg/m2 (as 
observed in the Phase 1b/2 PX-171-007 study).  
Figure 1
Proteasome Percent Activity in Peripheral Blood Mononuclear Cells
% Activity or Subunit Occupancy
(Relative to Cycle 1 Day 1 Predose)
C1D1 = Cycle 1 Day 1; CT-L = Chymotrypsin-like; LMP2 = latent membrane 
protein 2; LMP7 = latent membrane protein 7; MECL-1 = multicatalytic 
endopeptidase complex-like 1; PBMCs = peripheral blood mononuclear cells.
27 mg/m2 (n = 3); 56 mg/m2 (n = 5–13) and 70 mg/m2 (n = 4).  Values (relative to 
Cycle 1 Day 1 pre-dose) are presented as mean (±SEM).  Chymotrypsin-like and 
relative active subunit concentration (LMP7, MECL-1, LMP2) were assessed from 
PBMCs 1 hour following the carfilzomib dose.  27 mg/m2 and 56 mg/m2 samples 
are from the PX-171-007 study, while 70 mg/m2 data samples are preliminary data 
from the 2012-002 study. Chymotrypsin-like activity was measured by the 
fluorescent enzymatic Suc-LLVY-AMC assay, while subunit occupancy was 
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3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to compare the PFS of once-weekly carfilzomib 
dosing in combination with dexamethasone to the PFS of twice-weekly carfilzomib 
dosing in combination with dexamethasone in subjects with relapsed and refractory 
multiple myeloma who have received prior treatment with a proteasome inhibitor and an 
IMiD. 
3.2 
SECONDARY OBJECTIVES  
The secondary objectives of the study are to compare the following between treatment 
groups:  
• ORR 
• Overall survival (OS) 
• Safety and tolerability 
• Pharmacokinetics (PK) of carfilzomib using sparse sampling  
3.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives are to evaluate the following between treatment groups: 
• Intensive pharmacokinetics (PK) and pharmacodynamics (PDn) of carfilzomib in 
a subset of subjects (substudy) 
• All subscales of the European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Core Module (QLQ-C30), and the EORTC Quality of 
Life Multiple Myeloma Module 20 (QLQ-MY20) 
• European Quality of Life-5 Dimensions (EQ-5D-5L); a standardized measure of 
health status developed by the European Quality of Life (EuroQol) Group  
• Patient reported convenience and satisfaction with the carfilzomib dosing 
schedule 
• Healthcare resource utilization 
4 
EXPERIMENTAL PLAN 
4.1 
STUDY DESIGN 
This is an open-label, multicenter, Phase 3 study.  The study design is illustrated in 
Figure 2. 
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Figure 2 Study 20140355 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG = Eastern Cooperative Oncology Group; IMiD = immunomodulatory agents; IV = intravenous(ly); 
ORR = overall response rate; OS = overall survival; PD = progressive disease; PFS = progression-free 
survival; PI = proteasome inhibitor; PO = orally. 
Subjects with relapsed and refractory multiple myeloma will be screened for eligibility.  
Subjects must have had 2 or 3 prior therapies for multiple myeloma and received 
treatment with a proteasome inhibitor and an IMiD.  Eligible subjects will be randomized 
in a 1:1 ratio to receive a regimen consisting of either once-weekly or twice-weekly 
carfilzomib in combination with dexamethasone.   
Randomization will be stratified by: 
• International Staging System (ISS) Stage at study entry (Stage 1 versus Stage 2 or 
3) per International Myeloma Working Group (Greipp 2005).  See Appendix H. 
• Refractory to bortezomib treatment (Yes versus No) 
• Age (< 65 versus ≥ 65 years) 
The primary endpoint is PFS. 
Study treatment will be administered in 28-day cycles.  Subjects will receive the study 
treatment determined by randomization until disease progression, unacceptable toxicity, 
Long-Term Follow-up for Survival 
Arm B: Twice-weekly Carfilzomib with Dexamethasone  
Carfilzomib 20 mg/m2 Study Days 1 and 2 (Cycle 1)  
Carfilzomib 27 mg/m2 Study Days 8, 9, 15, and 16 (Cycle 1), Study 
Days 1, 2, 8, 9, 15, and 16 (Cycles 2+) 
Dexamethasone 40 mg (IV or PO) Study Days 1, 8, and 15 (all Cycles) 
Dexamethasone 40 mg (IV or PO) Study Day 22 (Cycles 1-9 only)  
Baseline 
Screening 
Randomization 1:1 
Eligibility: 
• 
Relapsed and 
 
refractory 
• 
2-3 prior therapies 
• 
ECOG 0 or 1 
• 
PI and IMiD 
 
exposure 
Primary Endpoint 
• PFS 
Key Secondary Endpoints 
• ORR 
• OS 
Follow-up for Disease Status Until 
Confirmed PD 
Arm A: Once-weekly Carfilzomib with Dexamethasone  
Carfilzomib 20 mg/m2 Study Day 1 (Cycle 1)  
Carfilzomib 70 mg/m2 Study Days 8 and 15 (Cycle 1), Study Days 1, 8, 
and 15 (Cycles 2+)  
Dexamethasone 40 mg (IV or PO) Study Days 1, 8, and 15 (all Cycles) 
Dexamethasone 40 mg (IV or PO) Study Day 22 (Cycles 1-9 only)  
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withdrawal of consent, or death (whichever occurs first).  No crossover between the 
2 treatment groups before progression will be allowed. 
Disease assessments will be conducted at Screening (within 21 days before 
randomization) and then every 28 days ± 4 days after Cycle 1 Day 1, End of Treatment 
(EOT), and during LTFU every 28 days ± 4 days, until PD and/or administration of 
subsequent antimyeloma therapy.  Response will be evaluated using the International 
Myeloma Working Group-Uniform Response Criteria (IMWG-URC). 
Following termination of study treatment, all subjects will be followed for disease status 
(if PD has not been reached), subsequent antimyeloma treatment, and survival. 
All subjects will be followed for AEs for at least 30 additional days after the last study 
treatment administration.  All treatment-related AEs and SAEs will be followed until 
resolution or stabilization.   
4.2 
NUMBER OF CENTERS 
Approximately 150 sites worldwide will participate. 
4.3 
NUMBER OF SUBJECTS 
Approximately 460 subjects (230 subjects per treatment group) will take part in this 
study. 
4.4 
ESTIMATED STUDY DURATION AND CLOSURE  
The total study accrual period is expected to be approximately 15 months.  The interim 
analysis of PFS will occur when approximately 263 PFS events are observed.  If the 
interim analysis crosses the boundary, the trial may stop early for efficacy; 
otherwise subjects will be followed for disease and survival status until approximately 
350 PFS events are observed or by end of year 2018, whichever is earlier. 
4.4.1 
END OF STUDY 
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 
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the primary endpoint(s), for the purposes of conducting the primary analysis, 
whether the study concluded as planned in the protocol or was terminated early.   
The primary completion is anticipated to occur when approximately 350 PFS events 
occur or end of year 2018, whichever is earlier.  The primary completion date is the 
date when data for the primary endpoint are last collected for the purposes of 
conducting the primary analysis or the end of year 2018, whichever is earlier.   
If the study concludes prior to the primary completion date originally planned in 
the protocol (i.e., 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 (i.e., 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 (i.e., 
last subject last visit), following any additional parts in the study (e.g., long-term 
follow-up), as applicable. 
5 
SUBJECT ELIGIBILITY 
5.1 
INCLUSION CRITERIA 
101. Age ≥ 18 years 
102. Able to provide written informed consent in accordance with federal, local, 
and institutional guidelines 
103. Relapsed multiple myeloma 
104. Refractory multiple myeloma, defined as meeting 1 or more of the following: 
a. Nonresponsive to most recent therapy (stable disease or progressive disease 
[PD] while on treatment), or 
b. Disease progression within 60 days of discontinuation from most recent 
therapy 
105. At least 2, but no more than 3, prior lines of therapy for multiple myeloma 
106. Prior exposure to an IMiD 
107. Prior exposure to a proteasome inhibitor (PI) 
108. Documented response of at least partial response (PR) to at least 1 prior line of 
therapy  
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109. Measurable disease, with at least 1 of the following assessed at a central 
laboratory within the 21 days prior to randomization: 
a. Serum M-protein ≥ 0.5 g/dL 
b. Urine M-protein ≥ 200 mg/24 hours  
c. In subjects without measurable serum or urine M-protein, serum free light 
chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum 
kappa:lambda ratio 
110. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 
111. Left ventricular ejection fraction (LVEF) ≥ 40% within the 21 days prior to 
randomization  
112. Adequate organ and bone marrow function performed at a central laboratory 
within the 21 days prior to randomization, defined by: 
a. Bilirubin < 1.5 times the upper limit of normal (ULN) 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
< 3 times the ULN 
c. Absolute neutrophil count (ANC) ≥ 1 × 109/L (screening ANC must be 
independent of growth factor support for ≥ 7 days) 
d. Hemoglobin ≥ 8 g/dL (Use of erythropoietic stimulating factors and red blood 
cell [RBC] transfusions per institutional guidelines are allowed; however the 
most recent RBC transfusion may not have been done within 7 days prior to 
obtaining the screening hemoglobin.) 
e. Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the 
bone marrow is > 50%.  Subjects must not have received platelet transfusions 
for at least 7 days prior to obtaining the screening platelet count.) 
f. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min.  
Calculation must be based on the Cockcroft and Gault formula:   
[(140 – Age) × Mass (kg) / (72 × Creatinine mg/dL)]; multiply result by 0.85 
if female 
113. Females of childbearing potential (FCBP) must have a confirmed negative serum 
pregnancy test performed at a central laboratory, within the 21 days prior to 
randomization, and must not be breastfeeding.  
114. Females of childbearing potential must agree to use highly effective method(s) of 
contraception, during the study and for 30 days following the last study drug 
administration.  (Refer to Appendix K for specific contraceptive requirements). 
115. Male subjects who are sexually active with an FCBP must agree to use condoms 
(unless they have had a vasectomy with medical confirmation of surgical 
success), during treatment and for an additional 90 days following the last study 
drug administration.   
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116. Male subjects must agree to not donate sperm, during treatment and for an 
additional 90 days following the last study drug administration. 
5.2 
EXCLUSION CRITERIA 
201. Waldenström macroglobulinemia 
202. Multiple myeloma of Immunoglobulin M (IgM) subtype 
203. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes) 
204. Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard 
differential) 
205. Myelodysplastic syndrome 
206. Second malignancy within the past 5 years except: 
a. Adequately treated basal cell or squamous cell skin cancer 
b. Carcinoma in situ of the cervix 
c. Prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA) 
over 12 months 
d. Ductal breast carcinoma in situ with full surgical resection (i.e., negative 
margins) 
e. Treated medullary or papillary thyroid cancer 
f. Similar condition with an expectation of > 95% five-year disease-free survival 
207. History of or current amyloidosis 
208. Cytotoxic chemotherapy or other antineoplastic therapy, aside from 
immunotherapy or proteasome inhibitors, within the 28 days prior to 
randomization  
209. Immunotherapy, such as an IMiD, or a proteasome inhibitor, within the 21 days 
prior to randomization  
210. Glucocorticoid therapy exceeding a cumulative dose of 160 mg dexamethasone or 
equivalent, within the 14 days prior to randomization 
211. Radiation therapy: 
a. Focal therapy within the 7 days prior to randomization  
b. Extended field therapy within the 21 days prior to randomization  
212. Prior treatment with either carfilzomib or oprozomib 
213. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize 
carfilzomib) 
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214. Contraindication to dexamethasone or any of the required concomitant 
medications or supportive treatments 
215. Active congestive heart failure (New York Heart Association [NYHA] Class III 
or IV, refer to Appendix F), symptomatic ischemia, conduction abnormalities 
uncontrolled by conventional intervention, acute diffuse infiltrative pulmonary 
disease, pericardial disease, or myocardial infarction within 6 months prior to 
randomization 
216. Active infection requiring systemic treatment within the 14 days prior to 
randomization 
217. Pleural effusions requiring thoracentesis within the 14 days prior to randomization  
218. Ascites requiring paracentesis within the 14 days prior to randomization  
219. Ongoing graft-versus-host disease 
220. Uncontrolled hypertension or diabetes mellitus  
221. Significant neuropathy (≥ Grade 3) within the 14 days prior to randomization 
222. Known cirrhosis 
223. Known human immunodeficiency virus (HIV) seropositivity, hepatitis C 
infection, or hepatitis B infection. Subjects with past hepatitis B virus infection, 
defined as having a negative HBsAg test and a positive antibody to hepatitis B 
core antigen (anti-HBc) antibody test, are eligible. Subjects positive for hepatitis 
C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is 
negative for HCV RNA. 
224. Participation in another interventional study within the 28 days prior to 
randomization  
225. Major surgery (except kyphoplasty) within the 28 days prior to randomization  
227. Any other clinically significant medical disease or social condition that, in the 
investigator’s opinion, may interfere with protocol adherence or a subject’s ability 
to give informed consent, be compliant with study procedures, or provide accurate 
information.   
6 
SUBJECT SCREENING 
A signed and dated informed consent form (ICF) must be obtained before any screening 
procedures or study-specific tests are performed.  Evaluations obtained as part of routine 
medical care prior to signing of the ICF may be used to satisfy the screening 
requirements, provided that these evaluations were obtained within the required screening 
period and do not require analysis at a central laboratory. 
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All subjects who provide consent will be assigned a unique study number.  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 Screening period commences when the subject or a legally-authorized representative 
signs the ICF. Screening must be completed within the 21 days prior to randomization. 
7 
SUBJECT RANDOMIZATION 
The primary investigator will determine the subject’s eligibility, ensuring that the results 
of the required screening procedures are consistent with all of the eligibility criteria 
presented in Section 5.  No eligibility waivers will be permitted.  Randomization will be 
carried out centrally through an interactive voice and web response (IVR/IWR) system.  
Please refer to the separate study reference manual.   
Eligible subjects will be randomized in a 1:1 ratio to either:  
• Arm A:  Once-weekly carfilzomib with dexamethasone regimen 
• Arm B:  Twice-weekly carfilzomib with dexamethasone regimen  
The randomization will be stratified by the following factors:  
• International Staging System (ISS) at study entry (Stage 1 versus Stage 2 or 3) 
(Appendix H) 
• Refractory to bortezomib treatment (Yes versus No) 
• Age (< 65 versus ≥ 65 years) 
Within each stratum defined by the stratification factors, subjects will be randomized 
according to a randomly permuted blocked randomization scheme. 
Study treatment will ideally commence on the day of randomization, but at least within 
5 calendar days of randomization.  Initiation of study treatment (Cycle 1 
Day 1) > 5 calendar days after randomization must be approved by the study medical 
monitor. 
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Page 44 of 165 
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.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
9 
DOSAGE AND TREATMENT ADMINISTRATION 
9.1 
TREATMENT REGIMEN 
Carfilzomib and dexamethasone will be administered in 28-day cycles.  All cycles will 
start 28 days (± 2 days) after the start of the prior cycle. 
In the once-weekly carfilzomib arm, intra-cycle doses of carfilzomib and dexamethasone 
may be administered within ± 2 days of the scheduled dose. However, carfilzomib must 
not be administered within the 5 days following a previous carfilzomib infusion.  Dose 
delays > 2 days are only permitted during the start of a new cycle. 
In the twice-weekly carfilzomib arm, every effort should be made to maintain the Days 1, 
2, 8, 9, 15, and 16, every 28-day schedule.  If this is not possible, then priority should be 
to maintain consecutive dosing days.  For example, if Day 1 of a new cycle is started 
2 days later than originally scheduled, the entire cycle should shift by 2 days, such that 
the new Days 1, 2, 8, 9, 15, and 16 of the next cycle are maintained.  Dosing on 
nonconsecutive days should only occur under exceptional circumstances, such as 
interruptions due to national holidays.  There must always be at least 5 days between the 
second dose of 1 week and the first dose of the following week (ie, between Days 2 and 
8, and Days 9 and 15).  Mid-cycle doses that are missed should not be made up, unless 
these parameters are maintained. 
The reasons for all cycle delays, schedule changes, missed doses, and dose interruptions 
will be reported. 
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9.2 
INTRAVENOUS PREHYDRATION 
Subjects will receive IV prehydration prior to each carfilzomib infusion during Cycle 1.  
Prehydration will consist of 250 to 500 mL normal saline or other appropriate IV fluid.  
Thereafter, carfilzomib prehydration should only be administered if the subject’s 
condition and/or risk factors require it.  The total volume of prehydration and the reason 
for prehydration after Cycle 1 will be recorded. 
9.2.1 
STUDY TREATMENT ADMINISTRATION 
Carfilzomib and dexamethasone will be administered in 28-day cycles in regimens of 
either once-weekly carfilzomib or twice-weekly carfilzomib as described in detail below 
in Figure 3 
.
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Figure 3 Arm A and Arm B Carfilzomib with Dexamethasone Regimens 
Arm A: Once-weekly Carfilzomib with Dexamethasone Regimen (28-day Cycles) 
Week 
1 
2 
3 
4 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
CFZ 
20a 
 
 
 
 
 
 
70 
 
 
 
 
 
 
70 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dex 
40 
 
 
 
 
 
 
40 
 
 
 
 
 
 
40 
 
 
 
 
 
 
40c 
 
 
 
 
 
 
Arm B: Twice-weekly Carfilzomib with Dexamethasone Regimen (28-day Cycles) 
Week 
1 
2 
3 
4 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
CFZ 
20b 
20b 
 
 
 
 
 
27 
27 
 
 
 
 
 
27 
27 
 
 
 
 
 
 
 
 
 
 
 
 
Dex 
40 
 
 
 
 
 
 
40 
 
 
 
 
 
 
40 
 
 
 
 
 
 
40c 
 
 
 
 
 
 
CFZ = carfilzomib, Dex = dexamethasone; PO = oral(ly). 
a Cycle 1 Day 1 carfilzomib dose level will be 20 mg/m2; all other dose levels will be 70 mg/m2. 
b Cycle 1 Days 1 and 2 carfilzomib dose levels will be 20 mg/m2; all other dose levels will be 27 mg/m2. 
c Dexamethasone on Day 22 in both treatment arms will be administered only during Cycles 1 to 9 and should be given PO, whenever possible. 
 
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9.2.1.1 
Carfilzomib 
Carfilzomib will be administered as an IV infusion over approximately 30 minutes in the 
once-weekly arm and over approximately 10 minutes in the twice-weekly arm. 
Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use 
vials.  The lyophilized product is reconstituted with Sterile Water for Injection (SWI), 
United States Pharmacopeia (USP), to a final carfilzomib concentration of 2 mg/mL. 
Mechanical infusion pumps are recommended, but gravity-dependent infusions are 
permitted, if the infusion duration can be reliably maintained.  Carfilzomib infusion must 
occur at a facility capable of managing hypersensitivity reactions.  Subjects will remain at 
the investigational site under observation for at least 1 hour following each infusion of 
carfilzomib in Cycle 1.  Carfilzomib should be administered via a dedicated IV line, 
whenever possible.  Refer to the IPIM for detailed information regarding equipment and 
flush requirements. 
9.2.1.2 
Dexamethasone 
Dexamethasone will be taken PO or administered by IV infusion.  Dexamethasone will 
be administered at least 30 minutes (but no more than 4 hours) prior to carfilzomib 
infusion on Days 1, 8, and 15 in both treatment arms.  Dexamethasone on Day 22 should 
be taken PO, whenever possible.  Note: Dexamethasone on Day 22 in both treatment 
arms will only be administered during Cycles 1 to 9. 
9.3 
DOSE MODIFICATION RULES  
In the event of a possible study treatment-related AE, the clinical investigator should 
assess, to the best of his/her ability, its relationship to carfilzomib and/or dexamethasone.  
Dose reduction rules for carfilzomib are presented in Table 4 and Table 5 and are often 
event-specific.   
• If a subject requires interruption of carfilzomib for more than 28 days, the subject 
should be removed from study treatment.  Exceptions must first be approved by 
the study medical monitor.   
• If a subject requires carfilzomib dose reduction, the reduced dose level will be 
continued for at least 1 complete cycle.  After that, if the reduced dose level has 
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been well tolerated, the previous dose level may be resumed at the investigator’s 
discretion. 
• If carfilzomib is temporarily held due to an AE, dexamethasone should be 
continued, unless the investigator determines that criteria for interrupting 
dexamethasone have also been met. 
• If carfilzomib is permanently discontinued due to toxicity, dexamethasone must 
also be discontinued and the subject will be followed for disease progression per 
the guidelines in Section 10.10.1. 
• If dexamethasone is permanently discontinued due to toxicity, the subject may 
continue to receive study treatment with carfilzomib at the investigator’s 
discretion. 
9.3.1 
CARFILZOMIB: RULES FOR DOSE MODIFICATION 
Dose decrements for carfilzomib are provided in Table 3. 
Table 3 
Carfilzomib Dose Decrements 
Dose a 
Carfilzomib Dose Decrements 
First Dose Reduction 
Dose -1 
Second Dose Reduction 
Dose -2 
Third Dose Reduction 
Dose -3 
70 mg/m2  
56 mg/m2  
45 mg/m2  
36 mg/m2  
27 mg/m2  
20 mg/m2  
15 mg/m2  
11 mg/m2  
a Note: If dose reduction of carfilzomib is required on C1D1 (Arm A) or C1D1 or D2 (Arm B), the 
investigator should contact the medical monitor to discuss the situation, before any additional doses of 
carfilzomib are administered. 
The requirements for carfilzomib dose modification for specific hematologic and 
nonhematologic toxicities are outlined in Sections 9.3.1.1 and 9.3.1.2, respectively. 
9.3.1.1 
Hematologic Toxicity 
Requirements for dose modification of carfilzomib in the events of thrombocytopenia, 
neutropenia, or neutropenic fever are summarized in Table 4. 
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Table 4 
Carfilzomib Dose Modification Rules for Treatment-emergent 
Hematologic Toxicity  
Hematologic Toxicity 
Required Actiona 
Thrombocytopenia 
• 
Platelets ≤ 10 × 109/L, 
OR  
• 
Platelets ≤ 30 × 109/L 
with evidence of 
bleeding/bruising  
1st episode 
• 
Withhold doses 
• 
Resume at the same dose level when 
platelets ≥ 10 × 109/L and bleeding is 
controlled 
Subsequent episodes 
• 
Withhold doses 
• 
Resume at 1 dose decrement when 
platelets ≥ 10 × 109/L and bleeding is 
controlled 
Neutropenia   
• 
ANC < 0.5 × 109/L  
1st episode 
• 
Withhold doses 
• 
Resume at the same dose level when 
ANC  ≥ 0.5 × 109/L 
Subsequent episodes 
• 
Withhold doses 
• 
Resume at 1 dose decrement when ANC 
≥ 0.5 × 109/L  
Febrile neutropenia   
• 
ANC < 0.5 x 109/L 
and oral temperature 
either: 
o 
> 38.5°C, OR 
o 
 > 38.0°C on 
2 consecutive 
measurements 
over 2 hours 
1st and subsequent episodes • 
Withhold doses 
• 
Resume at the same dose level when 
ANC returns to baseline grade and fever 
resolves 
ANC = absolute neutrophil count; NA = not applicable. 
9.3.1.2 
Nonhematologic Toxicity 
Requirements for dose modification of carfilzomib in the event of nonhematologic 
toxicities are summarized in Table 5. 
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Table 5 
Carfilzomib Dose Modifications for Nonhematologic Toxicity 
Nonhematologic Toxicity 
Required Actiona 
Renal Dysfunction 
• 
Serum creatinine ≥ 2 × 
baseline, OR 
• 
CrCl < 15 mL/min, OR  
• 
CrCl decreases to ≤ 50% 
of baseline, OR 
• 
Requirement for dialysis 
• Withhold doses while the cause of renal dysfunction is being 
assessed 
• If attributable to carfilzomib, resume at 1 dose decrement when CrCl 
has recovered to within 25% of baseline 
• If not attributable to carfilzomib, resume the same dose or reduce by 
1 dose decrement, at the investigator’s discretion, when CrCl has 
recovered to within 25% of baseline 
• For patients on dialysis receiving carfilzomib, the dose is to be 
administered after the dialysis procedure 
Hepatic Dysfunction 
• Mild to moderate liver 
dysfunction: defined as 
2 consecutive values, at 
least 28 days apart, of: 
(1) Total bilirubmin 
(> 33% direct) 
> 1 x ULN to 
< 3 x ULN 
OR 
(2) An elevation of 
AST and/or ALT 
with normal 
bilirubin 
• 25% dose reduction. 
• Dose may be re-escalated if liver function tests return to normal 
and drug-induced hepatotoxicity is excluded. 
• Grade 3 elevation in ALT 
and/or AST (> 5 x ULN) 
• Hold carfilzomib until resolution to baseline. 
• Monitor any abnormality weekly.  Resume carfilzomib with a 
25% dose reduction if drug-induced hepatoxicity is excluded. 
• Grade 3 elevation in total 
bilirubin 
• Hold carfilzomib until resolution to baseline.  Monitor total 
bilirubin and direct bilirubin weekly. 
• Upon resolution of total bilirubin to normal, resume carfilzomib 
dosing with at 25% dose reduction if drug-induced 
hepatotoxicity is excluded. 
• Drug-induced 
hepatoxicity attributable 
to carfilzomib 
• Discontinue carfilzomib. 
Infection 
• ≥ Grade 3 Infection 
• Withhold doses 
• Resume at the same dose level, when the infection is controlled 
 
 
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Nonhematologic Toxicity 
Required Actiona 
Cardiovascular Dysfunction 
• Congestive Heart Failure 
• Withhold doses for any subject with symptomatic heart failure, 
whether or not it is attributed to carfilzomib 
• Resume at 1 dose decrement, when symptoms have resolved or 
returned to baseline 
• LVEF < 40%, OR 
• LVEF < 55%, if decreased 
> 20% from baseline 
• Withhold doses 
• Resume at 1 dose decrement, when LVEF returns to ≥ 40%, or to 
within 15% of baseline, if carfilzomib was held due to a drop to 
< 55% 
• ≥ Grade 2 Pulmonary 
Hypertension 
• Withhold doses  
• Carfilzomib may be resumed at 1 dose decrement when pulmonary 
hypertension resolves to grade ≤ 1 
Thrombotic Microangiopathy 
• Thrombotic 
thrombocytopenic 
purpura/hemolytic uremic 
syndrome (TTP/HUS) 
• Withhold doses when TTP/HUS is suspected 
• If the diagnosis is excluded, resume at the same dose level 
• If the diagnosis is confirmed, discontinue carfilzomib.  Subjects 
should not be rechallenged. 
• Manage symptoms per standard of care including, plasma exchange as 
clinically indicated b 
Venous Thrombosis 
• ≥ Grade 3 
• 
Hold carfilzomib and adjust anticoagulation regimen. 
• 
Resume at full dose once anticoagulation has been optimized per 
treating investigator’s discretion. 
Encephalopathy 
• Posterior reversible 
encephalopathy syndrome 
(PRES) 
• Withhold doses  
• Consider evaluation with neuroradiological imaging for onset of 
visual or neurological symptoms suggestive of PRES 
• If the diagnosis is excluded, resume at the same dose level 
• If the diagnosis is confirmed, discontinue carfilzomib.  Subjects 
should not be rechallenged. 
Other Nonhematologic Toxicity 
• ≥ Grade 3 and attributed to 
carfilzomib 
• Withhold doses 
• Resume at 1 dose decrement, when toxicity has resolved to Grade ≤ 2 
or to baseline 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
CrCl = creatinine clearance; eCRF = electronic Case Report Form; IB = Investigator’s Brochure; 
IMWG = International Myeloma Working Group; LFTs = liver function tests; LVEF = left ventricular 
ejection fraction; mL = milliliter(s); PRES = posterior reversible encephalopathy syndrome; ULN = upper 
limit of normal. 
Note: Carfilzomib dose schedule does not need to be adjusted for baseline renal dysfunction. 
a The maximum allowed dose interruption is 4 weeks, except with approval by the medical monitor. 
b Subjects requiring plasma exchange must be withdrawn from study treatment.  Every effort should be 
made to assess disease status in accordance with IMWG criteria, before plasma exchange is initiated. 
 
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9.3.2 
DEXAMETHASONE: GUIDELINES FOR TOXICITIES AND DOSE 
MODIFICATION  
Dose decrements for dexamethasone are provided in Table 6.  
Table 6 
Dose Decrements for Dexamethasone 
Nominal Dose 
Dexamethasone Dose Decrements 
Dose -1 
Dose -2 
40 mg 
20 mg 
12 mg 
Dexamethasone will be permanently discontinued, if toxicity persists following 2 dose 
level reductions.  At the investigator’s discretion, dexamethasone may be tapered, prior to 
complete discontinuation, according to institutional practice.  The requirements for dose 
modification due to dexamethasone-related toxicities are summarized in Table 7. 
 
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Table 7 
Treatment Rules for Dexamethasone-related Toxicities 
Toxicity 
Required Action 
Edema 
≥ Grade 3: 
• 
Limb edema 
• 
Truncal edema 
• Withhold doses and diurese as needed 
• Resume at 1 dose decrement when Grade ≤ 1 or baseline 
Gastrointestinal Distress 
Grade 1 or 2: 
• 
Dyspepsia, OR 
• 
Gastritis, OR 
• 
Gastric or duodenal ulcer 
• Continue doses while attempting medical management 
• If symptoms persist, reduce by 1 dose decrement 
≥ Grade 3: 
• 
Dyspepsia, OR 
• 
Gastritis, OR 
• 
Gastric or duodenal ulcer 
• Withhold doses 
• Resume at 1 dose decrement, when symptoms return to baseline 
• If symptoms recur despite appropriate medical management, discontinue dexamethasone 
permanently 
• 
Acute pancreatitis 
• Discontinue dexamethasone permanently 
Psychiatric Disorders 
≥ Grade 2: 
• 
Confusion, OR  
• 
Mood alteration  
• Withhold doses 
• Resume at 1 dose decrement, when symptoms return to baseline 
Other Toxicities 
• 
≥ Grade 3 and attributed to dexamethasone 
• Withhold doses 
• Resume at 1 dose decrement, when toxicity has resolved to ≤ Grade 2 
 
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9.3.3 
CONDITIONS NOT REQUIRING DOSE REDUCTION 
The following conditions are exceptions to the requirements presented above.  
Carfilzomib and dexamethasone do not require dose modification in the following cases: 
• Grade 3 nausea, vomiting, or diarrhea (unless persisting more than 3 days despite 
appropriate use of antiemetics or antidiarrheal agents)  
• Grade 3 hyperglycemia 
• Grade 3 fatigue (unless persisting for > 14 days) 
• Alopecia 
9.4 
CONCOMITANT MEDICATIONS AND THERAPIES 
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements.  For all randomized subjects, all administered 
concomitant medications and therapies, from signing of the informed consent until 
30 days after the last dose of study treatment, must be recorded in the designated 
electronic case report form (eCRF). 
Concomitant medications required for the study or used prophylactically should be 
described as such in the designated eCRF.  Concomitant medications prescribed for “prn” 
or “as needed” use should not be reported, unless actually administered. 
Blood and blood products are not considered concomitant medications and must be 
recorded on the appropriate eCRF. 
9.4.1 
REQUIRED CONCOMITANT MEDICATIONS 
Required prophylactic medications should be initiated at least 1 day prior to the first 
administration of carfilzomib. 
9.4.1.1 
Gastrointestinal Prophylaxis 
Lansoprazole or other oral proton-pump inhibitor, dosed according to institutional 
practice, is required to prevent peptic ulcer disease throughout the duration of treatment 
with dexamethasone. 
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9.4.1.2 
Pregnancy and Contraception 
Contraception must continue during study, during drug dose interruption intervals, and 
until 30 days (females) or 90 days (males) after the last study drug administration.  If 
applicable, refer to the Country Specific Pregnancy and Contraceptive Supplement 
(refer to Appendix K). 
If a subject thinks she may be pregnant (e.g., if a menstrual period in an FCBP does not 
occur at the anticipated time), study drug treatment must be interrupted, and a urine or 
serum pregnancy test must be performed locally.  Study drug administration may resume 
after documentation of a nonpregnant state. 
9.4.2 
RECOMMENDED CONCOMITANT MEDICATIONS 
9.4.2.1 
Antiviral Prophylaxis 
Valacyclovir (or an equivalent antiviral agent) is recommended for prophylaxis against 
herpes zoster reactivation. 
9.4.2.2 
Uric Acid-lowering Agents 
Allopurinol or other approved uric acid-lowering agent are recommended for subjects at 
high risk for tumor lysis syndrome (TLS) due to high tumor burden.  Refer to the current 
Carfilzomib IB for safety guidance regarding TLS. 
9.4.2.3 
Mycostatin or Oral Fluconazole  
Mycostatin or oral fluconazole may be given to prevent oral thrush throughout the 
duration of treatment with dexamethasone. 
9.4.2.4 
Antiemetics and Antidiarrheal Agents 
Antiemetics and antidiarrheal agents are recommended for prophylaxis and/or 
management of treatment-related gastrointestinal symptoms.  
9.4.2.5 
Thrombophrophylaxis 
Venous thromboembolism has been observed in patients receiving carfilzomib.  
Thromboprophylaxis may be considered on the basis of a benefit-risk assessment. 
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9.4.3 
EXCLUDED CONCOMITANT MEDICATIONS AND THERAPIES 
If an investigator deems that use of an excluded concomitant medication or therapy is 
required but does not believe that withdrawal from study treatment is indicated, he/she 
must contact the study medical monitor to determine if continued study treatment is 
acceptable. 
9.4.3.1 
Anticancer Agents 
Therapy with a marketed or investigational anticancer agent that is not required per this 
protocol is prohibited, while subjects remain on study treatment, and should be avoided 
prior to documentation of disease progression.   
9.4.3.2 
Radiation Therapy 
Radiation to large marrow reserves is prohibited; however, focal palliative radiation is 
allowed with permission from the study medical monitor. 
9.4.3.3 
Myeloid Growth Factors 
Prophylactic use of myeloid growth factors is prohibited, but they may be used for 
management of neutropenia, in accordance with American Society of Clinical Oncology 
(ASCO) Guidelines (Smith 2006). 
9.4.3.4 
Corticosteroids  
Corticosteroids should not be used to treat concurrent medical conditions, unless the dose 
remains less than the equivalent of 4 mg/day of dexamethasone.  Short term use of higher 
doses may be permitted to treat acute exacerbations of concurrent medical conditions, but 
this must be discussed with the study medical monitor as soon as is possible. 
9.4.3.5 
Plasmapheresis 
Plasmapheresis is not permitted at any time during the Screening period or while the 
subject is receiving study treatment.  If a subject who has started screening procedures 
requires plasmapheresis or is anticipated to require plasmapheresis during or after the 
Screening period, this subject will be considered ineligible. 
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For subjects requiring plasmapheresis while on study treatment, every attempt should be 
made to document disease status by IMWG criteria first.  Study treatment must be 
discontinued and the subject will enter LTFU. 
9.4.3.6 
Novel Agents for Non-neoplastic Conditions 
The use of novel agents for non-neoplastic conditions is prohibited throughout the 
duration of treatment and for 30 days following the last dose of study treatment. 
10 
STUDY ASSESSMENTS AND PROCEDURES 
All protocol-required tests and observations, along with their chronology, are outlined in 
the Schedule of Assessments (refer to Appendix A).  Protocol-specified assessments and 
procedures are summarized below. 
10.1 
STUDY SPECIFIC PROCEDURES 
10.1.1 
MULTIPLE MYELOMA HISTORY AND PRIOR LINES OF 
THERAPY ASSESSMENT 
When documenting prior therapies 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, PD (even if the level of progression has not yet 
met IMWG criteria for PD), relapse, or toxicity.  A new therapy is also 
considered to start when a planned period of observation off-therapy is 
interrupted by a need for additional lines of therapy.  
• An increase in treatment administration, with the intention of recapturing 
response in a patient with evidence of disease progression on that line of 
therapy, is considered to be a new line of therapy.   
Examples of a 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)  
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If available, historical FISH data should be entered into the eCRF.  The following results 
should be captured: 
o t(4;14) 
o t(6;14) 
o t(11;14) 
o t(14;16) 
o t(14;20) 
o Del 17p 
o Del 13 
o Chromosome 1 abnormalities 
10.1.2 
VITAL SIGNS 
Vital signs will include heart rate, blood pressure, respiratory rate, and temperature and 
will be assessed at Screening, prior to each administration of carfilzomib, EOT, and as 
needed to assess potential AEs.  Clinically significant abnormal vital signs will be 
reported as AEs. 
10.1.3 
COMPLETE PHYSICAL EXAMINATION 
A physical examination will be performed during Screening, prior to dosing on Day 1 of 
each cycle, and at the EOT.  For Cycle 1 Day 1, the screening physical examination may 
be used if performed within 7 days prior to Cycle 1 Day 1.  Physical exam may be 
completed up to 3 days prior to Day 1 of each cycle.  At a minimum, the physical exam 
should include constitutional, abdominal, cardiovascular, and respiratory assessments. 
Clinically significant abnormal findings identified after the signing of informed consent 
must be reported as AEs and examined more frequently, as clinically indicated.  Note: 
Clinically significant abnormal physical examination findings identified prior to the 
signing of informed consent should be reported as part of Medical History, not as AEs. 
BSA is to be determined by a standard formula, such as the Mosteller Formula 
(Mosteller 1987): body surface area (BSA) (m²) = ([Height (cm) × Weight (kg)]/ 
3600 )½.  Body surface area must be recalculated and used for subsequent dose 
determinations, if the subject experiences a weight change of ≥ 20%.  Recalculations of 
BSA must be made using the same technique as used at baseline. 
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10.1.4 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS 
Eastern Cooperative Oncology Group Performance Status will be assessed at Screening 
and at the EOT visit.  Eastern Cooperative Oncology Group Performance Status grades 
and descriptions are tabulated in Appendix E. 
10.1.5 
INTERNATIONAL STAGING SYSTEM STAGE DETERMINATION 
Beta-2 microglobulin and albumin will be assessed at the central laboratory during 
Screening to determine ISS Stage (refer to Appendix B and Appendix H).  These results 
must be available, prior to randomization. 
10.2 
MULTIPLE MYELOMA DISEASE ASSESSMENTS 
Disease response and progression assessments include (but are not limited to): SPEP, 
urine protein electrophoresis (UPEP), immunofixation, SFLC, bone marrow sample 
evaluation, serum calcium, plasmacytoma evaluation, and skeletal survey.  Multiple 
myeloma assessment should be based on calendar day, regardless of cycle delay.  SPEP, 
UPEP, immunofixation, SFLC, bone marrow evaluation, and serum calcium will all be 
conducted at the central laboratory. 
The following disease assessments must be performed at Screening: 
• SPEP, UPEP (24-hour assessment, no substitute method is acceptable), 
and immunofixation 
• SFLC 
• Quantitative immunoglobulins 
• Beta-2 microglobulin 
Cycle 1 Day 1 before treatment begins (Screening values may be used if obtained within 
7 days prior to Cycle 1 Day 1), and every 28 days (± 4 days) thereafter, at EOT, and 
during LTFU if disease progression has not already been documented (every 28 days ± 4 
days, until PD and/or started a subsequent antimyeloma therapy): 
•  SPEP, immunofixation 
• UPEP (24-hour assessment, no substitute method is acceptable), 
and immunofixation: post-Cycle 1 Day 1 measurements required only if Cycle 1 
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Day 1 UPEP ≥ 200 mg/24 hours or to confirm a disease response (for very good 
partial response [VGPR] or better) or progression (if applicable) 
• SFLC: post-Cycle 1 Day 1 measurements required only for SFLC measurable 
disease or to confirm stringent complete response (sCR) 
• Quantitative immunoglobulins 
Subjects will be instructed to collect 24-hour urine samples for assessment of UPEP at 
Screening and as required during the study.  This collection will occur over 2 days and 
will be assessed at the central laboratory.  For further instructions, refer to the Central 
Laboratory Services Manual.   
Radiological disease assessments at baseline are collected after subject eligibility is 
confirmed and may be done after randomization (as long as they are done before the start 
of treatment).  Radiological disease assessments that were done per standard of care 
within 30 days before Cycle 1 Day 1 can be used as study baseline disease assessments.  
They include: 
Extramedullary Plasmacytoma Assessment 
• A plasmacytoma evaluation will be conducted at baseline, only if a lesion is 
suspected clinically. 
• If an extramedullary plasmacytoma is detected, evaluation will be repeated during 
treatment to confirm a response of PR or better or to assess for PD based on 
plasmacytoma. 
• Plasmacytomas are considered measurable if they have a longest diameter of at 
least 1 cm and the product of cross diameter measurements is at least 1 cm2.  
Plasmacytomas of lesser size are considered unmeasurable.  Bidimensional 
measurements must be recorded in the designated eCRF.  The same technique 
must be used to evaluate plasmacytomas throughout the duration of study 
participation and may include: palpation, ultrasound, x-ray, computed 
tomography (CT) scan, magnetic resonance imaging (MRI), positron emission 
tomography (PET), or any other technique that is considered to be standard of 
care. 
Skeletal Survey 
• Skeletal survey will include lateral radiograph of the skull, anteroposterior and 
lateral views of the spine, and anteroposterior views of the pelvis, ribs, femora, 
and humeri.  The skeletal survey will be conducted at baseline and will be 
repeated if worsening clinical symptoms suggest PD, or as clinically indicated. 
• Other radiologic modalities for performing skeletal assessment (eg, low-dose CT 
scan) are acceptable, in accordance with regional standards. 
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10.3 
MULTIPLE MYELOMA RESPONSE ASSESSMENTS 
10.3.1 
DISEASE RESPONSE AND PROGRESSION ASSESSMENTS 
Determination of disease response must be based on the reported values from the central 
laboratory.  Local laboratory results may be used for hypercalcemia (corrected calcium 
based on albumin), but a confirmatory sample should be collected and sent to the central 
laboratory for documentation. 
Investigator-determined responses must be based on results from the central laboratory 
and must be consistent with the IMWG-URC (see definitions in Appendix G).  
10.3.2 
TUMOR RESPONSE ASSESSMENT 
The following confirmatory assessments are required for all response categories (sCR, 
CR, VGPR, PR, minimal response [MR] and PD; refer to definitions in Appendix G: 
• All laboratory-based PD (except bone marrow sample) and all response categories 
require 2 consecutive assessments made at any time before initiation of new 
therapy. 
• All response categories require that there be no evidence of disease progression, 
including confirmation of no new bone lesions, if radiographic studies were 
performed. 
• The preferred method of confirming CR or sCR is a bone marrow biopsy; 
however, a bone marrow aspirate is also acceptable for confirmation of CR. 
• Extramedullary plasmacytoma evaluation (if present at Screening).  Two 
consecutive radiographic tests are not required to confirm response or 
progression of extramedullary plasmacytoma. 
• In the case where a patient does not have measurable M-protein by UPEP at 
baseline (i.e., baseline UPEP < 200 mg/24 hours), when SPEP is consistent with 
response (i.e., ≥ PR), 2 consecutive UPEP measurements must be performed to 
confirm response. 
10.3.3 
DISEASE PROGRESSION 
Disease progression will be documented in an eCRF intended to capture PD information 
and will be analyzed as a study endpoint.  Signs and symptoms related to disease 
progression (e.g., pathologic fracture in a subject with progressive multiple myeloma) 
should be reported in the appropriate eCRF as an AE or as an SAE (if the event in 
question meets the criteria for seriousness).  Verbatim terms such as “disease 
progression,” “progressive disease,” etc. should not be reported as AEs or SAEs unless 
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the investigator considers the progression to be atypical, accelerated, or caused by the 
study drug.  Similarly deaths occurring as a result of disease progression should be 
reported on the eCRF intended to capture death information and should not be reported as 
SAEs. 
Study treatment should not be discontinued on the basis of disease progression, until PD 
has been appropriately confirmed per IMWG-URC.  Disease progression during LTFU 
must also be confirmed by these same criteria.  Confirmation of PD will require 
2 consecutive central laboratory evaluations that indicate PD, except in cases where PD is 
based on extramedullary lesions or hypercalcemia that is attributed solely to PD.  These 
assessments should be separated in time by at least 1 calendar day, but no more than 
28 ± 4 calendar days.  Local laboratory results may not be used to determine or confirm 
disease progression, except when PD is based on hypercalcemia.  The assessments 
outlined in Appendix B are required for PD determination. 
10.4 
LABORATORY TESTS  
Laboratory tests for efficacy and safety during scheduled and unscheduled study visits, 
including screening will be performed at a central laboratory.  Additional safety 
laboratory samples must also be collected and analyzed by local laboratories if the results 
are necessary to determine the appropriateness of dose administration.  In rare 
circumstances, when the central laboratory is unable to provide results for tests that are 
needed to determine eligibility, the study medical monitor may grant permission for local 
laboratory results to be applied to the screening requirements.  Local labs may also be 
required for management of treatment-emergent adverse events (TEAEs).  Laboratory 
tests for disease assessment are described in Section 10.2. 
Safety samples must be obtained within the 1 day prior to carfilzomib administration and 
the results must be reviewed prior to the start of the carfilzomib infusions on Days 1, 8, 
and 15 of Cycles 1 to 4.  Beyond Cycle 4, these labs are only required on Days 1 and 15 
of each cycle. 
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10.4.1 
HEMATOLOGY 
Hematology assessments (Table 8) will be performed during Screening, on Days 1, 8, and 
15 for Cycles 1 to 4 and EOT.  Beyond Cycle 4 labs will be performed on Days 1 and 15 
of each cycle.  For Cycle 1 Day 1, hematology assessments from Screening can be used, 
if they were obtained within 3 days prior to carfilzomib administration.  For subsequent 
visits, hematology assessments may be completed up to 1 day prior to the scheduled dose. 
Table 8 
Laboratory Tests:  Hematology  
Hematology Panel 
Hemoglobin 
Hematocrit 
WBC count with complete differential to include: a 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC count 
Platelet count 
RBC = red blood cells; WBC = white blood cells. 
a 
Absolute counts or percentage will be acceptable. 
10.4.2 
SERUM CHEMISTRY 
A serum chemistry panel (Table 9) will be performed during Screening, on Days 1, 8, and 
15 for Cycles 1 to 4 and EOT.  Beyond Cycle 4, labs will be performed on Days 1 and 15 
of each cycle.  For Cycle 1 Day 1, serum chemistry assessments from Screening can be 
used, if performed within 3 days prior to carfilzomib administration.  For subsequent 
visits, serum chemistries may be completed up to 1 day prior to the scheduled carfilzomib 
dose. 
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Table 9 
Laboratory Tests:  Chemistry Panel 
Chemistry Panel  
Albumin 
Glucose 
Alkaline Phosphatase 
LDH 
ALT 
Magnesium 
AST 
Phosphorus 
Bicarbonate 
Potassium 
BUN 
Sodium 
Calcium 
Total Bilirubin  
Chloride 
Total Protein 
Creatinine 
Uric Acid 
ALT= alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, eCRF = 
electronic Case Report Form; LDH = lactate dehydrogenase; ULN = upper limit of normal 
10.4.3 
COAGULATION 
Coagulation tests will be performed at a central laboratory at Screening and at EOT:  
• Prothrombin time (PT) 
• Activated partial thromboplastin time (PTT) 
• International normalized ratio (INR) 
10.4.4 
PREGNANCY TESTING 
For FCBP, a serum pregnancy test that is confirmed negative is required for eligibility 
determination and is to be performed at the central laboratory; FCBP is defined in 
Appendix K.  In addition to the pregnancy tests conducted for eligibility, a serum or urine 
pregnancy test must be confirmed negative locally on Day 1 of each cycle and at EOT.  
A negative pregnancy test result must be available prior to the first dose of study 
treatment.  More frequent pregnancy tests may be conducted if required per local 
regulations or investigational sites. 
10.5 
ELECTROCARDIOGRAM 
Twelve-lead electrocardiograms (ECGs) including corrected QT-interval (QTc; 
representing the corrected duration of ventricular electrical activity) will be performed 
locally.  Electrocardiograms will be required from all subjects at Screening and EOT.  
Additional ECG assessment is only required if clinically indicated. 
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10.6 
ECHOCARDIOGRAM 
A 2-D transthoracic echocardiogram (ECHO) is required to assess LVEF during 
Screening and will also serve as the baseline ECHO.  If transthoracic ECHO is not 
available, multigated acquisition (MUGA) will be acceptable for LVEF evaluation. 
Any subject with a clinically significant cardiac AE should be evaluated by a cardiologist 
and must have a follow-up ECHO, if medically indicated.   
10.7 
PATIENT REPORTED OUTCOMES 
Patient reported outcomes (PRO) are based on the following questionnaires 
(refer to Appendix J). 
All questionnaires should be collected on Day 1 of Cycle 1, then every second cycle 
(Cycle 1, 3, 5, etc) during treatment.  The questionnaires listed below should be 
completed by the subject prior to drug administration during treatment cycles:  
• EORTC QLQ-C30
• EORTC QLQ-MY20
• EQ-5D-5L
• Patient reported convenience and satisfaction (collected Day 1 Cycle 2 and EOT
only) 
Health-related Quality of Life (HRQL) will be assessed by the EORTC 30-item 
QLQ-C30 questionnaire and by the 20-item QLQ-MY20 module specifically designed to 
address the quality of life for those with multiple myeloma (Aaronson 1993; Fayers 2001; 
Cocks 2007).  The primary constructed scales from the QLC-C30 are: 
• Global Health Status/Quality of Life
• Physical functioning
• Role functioning
• Emotional functioning
• Cognitive functioning
• Social functioning
• Nine additional scales can be derived:
• Fatigue
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• Nausea and vomiting 
• Pain  
• Dyspnea 
• Insomnia  
• Appetite loss  
• Constipation  
• Diarrhea 
• Financial difficulties 
The primary scales from the QLQ-MY20 include disease symptoms, side effects of 
treatment, body image and future perspectives. 
The EQ-5D-5L is a standardized measure of health status developed by the EuroQol 
Group in order to provide a simple, generic measure of health for clinical and economic 
appraisal (EuroQol Group 1990).  The EQ-5D-5L version will be used in this study.  The 
EQ-5D-5L consists of a 1-page descriptive system and a 1-page EQ Visual Analogue 
scale (EQ VAS).  The descriptive system comprises 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression).  Each dimension is then scored 
on 5 levels: no problems, slight problems, moderate problems, severe problems, and 
extreme problems.  The respondent is asked to indicate his/her health state by ticking (or 
placing a cross) in the box against the most appropriate statement in each of the 
5 dimensions.  The EQ VAS records the respondent’s self-rated health on a 20 cm 
vertical, visual analogue scale with endpoints labelled ‘the best health you can imagine’ 
and ‘the worst health you can imagine’.  This information can be used as a quantitative 
measure of health as judged by the individual respondents. 
Patient reported convenience and satisfaction with the carfilzomib dosing schedule will 
be provided as a 1-page questionnaire on the tablet.  Subjects will be instructed to fill out 
the questionnaires to the best of his/her abilities.  The study coordinator will be 
responsible for signing off that the subject has completed the questionnaires. 
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10.8 
HEALTHCARE RESOURCE UTILIZATION  
Healthcare resource utilization data related to AEs will be collected for each subject.  
These data may include inpatient care, outpatient care, surgery, and use of other 
medications and therapeutic procedures related to AEs.  Details on hospitalizations (not 
related to AEs) will also be collected. 
10.9 
CORRELATIVE STUDIES 
Samples for correlative studies will be collected only after confirmation of study 
eligibility.  Intensive PK and PDn will be conducted as a substudy at selected sites.  
Sparse PK samples will be collected at all other sites from subjects who consent to the 
additional testing.   
10.9.1 
INTENSIVE PHARMACOKINETICS/PHARMACODYNAMICS 
SUBSTUDY  
Approximately 15 evaluable subjects in each arm will participate in the intensive PK/PDn 
substudy at select sites.  On both arms, whole blood and PBMCs will be collected from 
all subjects on Days 1, 15, 16, 17, and 22 of Cycle 1 at the timepoints (summarized in 
Table 10).  Directions for collection, processing, and shipping of PDn blood samples are 
provided in the Central Laboratory Services Manual.  The actual time of when the PDn 
sample was collected will be recorded. 
Table 10 Study 20140355 Pharmacodynamics Sampling Timepoints  
 
Arm A 
Once-weekly carfilzomib 
Arm B 
Twice-weekly carfilzomib 
Cycle 1 Day 1 
Predose 
Predose 
Cycle 1 Day 15 
Predose and 1 hour after the end of 
infusion 
Predose and 1 hour after the end of 
infusion 
Cycle 1 Day 16 
24 hours ± 2 hours after the end of the 
Day 15 infusion 
Predose and 1 hour after the end of 
infusion 
Cycle 1 Day 17 
48 hours ± 2 hours after the end of the 
Day 15 infusion 
24 hours ± 2 hours after the end of the 
Day 16 infusion 
Cycle 1 Day 22 
168 hours ± 2 hours after the end of 
the Day 15 infusion 
144 hours ± 2 hours after the end of 
the Day 16 infusion 
 
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For both treatment arms, PK samples will be collected from all subjects for determination 
of plasma concentrations of carfilzomib on treatment Day 15 of Cycle 1 at the following 
time points: 
• Predose (within 5 minutes before the start of infusion) 
• 15 minutes (± 5 minutes) after the start of infusion for Arm A only (once-weekly 
carfilzomib) 
• Immediately prior to (within 2 minutes before) the end of infusion 
• 15 minutes (± 5 minutes) after the end of infusion 
• 60 minutes (± 5 minutes) after the end of infusion 
• 2 hours (± 5 minutes) after the end of infusion  
The actual time of PK sample collection will be recorded.  Samples will be collected 
within ± 5 minute time windows around the nominal time points (except for the time 
point immediately prior to the end of infusion, for which the PK collection needs to occur 
prior to the end of infusion).  Directions for collection, processing, and shipping of PK 
samples are provided in the Central Laboratory Services Manual. 
10.9.2 
SPARSE PHARMACOKINETIC SAMPLING  
Sparse PK samples will be collected from subjects who do not participate in the intensive 
PK/PDn substudy and who consent to the additional testing.  The actual time of the PK 
sample collection will be recorded.  These samples will be assessed at a central 
laboratory.  Directions for collection, processing, and shipping of PK samples are 
provided in the Central Laboratory Services Manual.   
The sparse PK samples will be collected on Cycle 2 Day 1 at the following time points: 
• Predose (within 5 minutes before the start of infusion) 
• 15 minutes (± 5 minutes) after the start of infusion for Arm A only (once-weekly 
carfilzomib) 
• Immediately prior to (within 2 minutes before) the end of infusion 
• 30 minutes (± 5 minutes) after the end of infusion 
10.10 
LONG-TERM FOLLOW-UP 
There are 2 criteria which mark when subjects may enter LTFU.  Subjects may enter into 
LTFU when discontinuing treatment before disease progression occurs (refer to 
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Section 10.10.1, below), or, subjects may enter into LTFU when discontinuing due to 
disease progression (outlined in Section 10.10.2).   
10.10.1 
LONG-TERM FOLLOW-UP BEFORE DISEASE PROGRESSION 
For subjects who discontinue treatment before disease progression occurs, disease 
assessments will be performed (using the central laboratory results) every 
28 days ± 4 days until the subject has PD or until withdrawal of consent (Appendix B).  
Confirmatory PD results (refer to Appendix G) must be obtained prior to the initiation of 
new antimyeloma therapy.  Subject reported outcomes (PROs) including the EORTC 
QLQ-C30 and QLQ-MY20, EQ-5D-5L and Healthcare Resource Utilization will be 
collected for these subjects who discontinue therapy prior to progression; assessments 
will be conducted every 12 weeks (every 84 days ± 4 days) until progression, or 
withdrawal of consent during LTFU (Appendix A).  Long-term follow-up will continue 
until the subject has withdrawn consent for further participation, is lost to follow-up, has 
died, or the sponsor makes a decision to close the study.  For any subject who is lost to 
follow-up, the study site will attempt to ascertain survival information via public database 
search. 
10.10.2 
LONG-TERM FOLLOW-UP AFTER DISEASE PROGRESSION 
(FOR SURVIVAL) 
After completion of the EOT visit, subjects who have discontinued due to disease 
progression will be followed for survival status, queried by telephone contact or other 
method, approximately every 12 weeks ± 28 days, or as needed until study closure. 
11 
STUDY DISCONTINUATION 
11.1 
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
Subjects may withdraw from study treatment at any time.  Reasons for discontinuation 
include, but are not limited to: 
• Adverse event 
• Pregnancy 
• Death 
• Lost to follow-up 
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• Non-compliance with study requirements 
• Withdrawal of consent by subject 
• Study termination by Sponsor 
• Investigator decision 
• Progression of disease 
The primary reason for study treatment discontinuation will be documented in the eCRF.  
Investigators will be instructed to interview subjects to obtain the most accurate reason 
for study treatment discontinuation, while respecting the privacy of the subject. 
If the reason for study treatment discontinuation is the occurrence of an AE, the subject 
will be followed by the investigator until such event(s) resolves, stabilizes, or, according 
to the investigator’s judgment, no longer requires follow-up.   
Study treatment discontinuation due to PD should be recorded as “disease progression.”  
All subjects who are withdrawn from study treatment will be encouraged to complete all 
relevant safety assessments and continue in the LTFU period.  Subjects who discontinue 
study treatment will be followed for survival and disease status (if discontinuation is prior 
to progression) until study closure (refer to Appendix B, footnote d). 
11.2 
WITHDRAWAL OF SUBJECTS FROM STUDY 
Reasons for complete withdrawal from study (treatment and all follow-up) before 
documentation of subject death include: 
• Withdrawal of consent by subject for all study procedures and study participation 
• Lost to follow-up 
• Sponsor decision 
The reason for complete withdrawal from the study will be documented in the eCRF. 
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11.3 
STUDY TERMINATION 
Sponsor has the right to terminate this study or to terminate a study site from 
participating in the study at any time.  Reasons for study or site termination may include, 
but are not limited to: 
• The incidence or severity of AEs in this or other carfilzomib studies indicates a 
potential health hazard to subjects 
• Subject enrollment is unsatisfactory 
• Data recording is inaccurate or incomplete 
• Investigator does not adhere to the protocol or applicable regulatory requirements 
in conducting the study 
• Investigational site non-compliance with International Conference on 
Harmonisation/Good Clinical Practice (ICH/GCP) 
12 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
An AE is any untoward medical occurrence in a subject administered a study drug and 
which is not necessarily caused by the study drug.  An AE can therefore be any 
unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, combination product, 
or medical device, whether or not considered related to the product.  In addition to new 
events, any worsening of a pre-existing condition that occurs after the subject signs the 
ICF for participation is considered an AE.  Worsening indicates that the pre-existing 
medical condition or underlying disease has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  This includes any side effect, injury, toxicity, or 
sensitivity reaction.  All reported AEs will be coded using the current version of Medical 
Dictionary for Regulatory Activities (MedDRA). 
12.1 
ADVERSE EVENT REPORTING 
12.1.1 
ADVERSE EVENT TERMINOLOGY 
When reporting an AE, accurate and standard medical terminology should be used that 
clearly identifies the event and the affected body system.  Use of non-standard 
terminology and/or abbreviations should be avoided to ensure accurate and complete 
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reporting of AEs.  Individual signs and symptoms should be reported unless they result in 
a definitive diagnosis of an event or represent a well-recognized syndrome.   
12.1.2 
SEVERITY 
Whenever possible, the National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) Version 4.03 should be used to describe the event and to 
assess the severity of AEs (NCI 2010).  For AEs not adequately addressed in the 
NCI-CTCAE Version 4.03, the following criteria should be used (see Table 11). 
Table 11 Grading for Adverse Events not Covered in the NCI-CTCAE 
Severity 
Description 
GRADE 1 – Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
GRADE 2 – Moderate 
Minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)  
GRADE 3 – Severe 
Medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL 
GRADE 4 – Life-threatening 
Life-threatening consequences; urgent intervention indicated 
GRADE 5 – Fatal 
Death 
NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events. 
An AE or suspected adverse reaction (ADR) is considered “unexpected” if it is not listed 
in the current Carfilzomib IB or is not listed at the specificity or severity that has been 
observed.  Adverse events or suspected ADRs that are mentioned in the IB as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with particular study drug are considered 
“unexpected.”  For example, an event more specific or more severe than described in the 
IB would be considered “unexpected.”  Any condition, laboratory abnormality, or 
physical finding with an onset date prior to the subject signing the ICF is considered to be 
pre-existing in nature and part of the subject’s medical history and should not be 
considered an AE. 
Abnormal laboratory findings should be reported as AEs if medical intervention or 
corrective action (e.g., transfusions, initiation of antibiotics or other treatment regimens, 
hydration, study drug placed on hold) is required or the event is deemed clinically 
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significant by the treating physician.  Where applicable, clinical sequelae (not the 
laboratory abnormality) are to be recorded as the AE. 
12.1.3 
DURATION 
The start and stop dates for all AEs will be recorded.  The start date is the first date that 
the subject was aware of the AE and the end date is the date that the event has changed in 
grade, totally resolved, or returned to baseline.  Any changes in grade should be recorded 
as a separate event.  Terms such as “intermittent” or “occasional” are not appropriate 
descriptions of AEs; each time a full calendar day elapses without the subject 
experiencing the event should result in the event stop date recorded and a new event 
reported if the event recurs.   
12.1.4 
CAUSALITY 
A relationship between study drug and an adverse event is considered causal if there is at 
least a reasonable possibility the adverse event was caused by carfilzomib administration, 
i.e., the relationship cannot be ruled out.  The relationship of the AE to the study drug 
should be assessed by the investigator taking into account the totality of the evidence and 
in considering the variables listed below. 
The following criteria should be considered and would support a positive assessment of 
causality:  
• Time to onset plausible: There is a clinically plausible time sequence between the 
AE onset and administration of study treatment. 
• Biologic plausibility: There is a biologically plausible mechanism for the study 
treatment to cause or contribute to the AE.  Biologic plausibility should be 
evaluated but is not required for a positive causality assessment.  For example, if 
there is lack of an alternative explanation for the adverse event, then a causal 
relationship may be positive pending a complete causality assessment. 
• Positive dechallenge or rechallenge: The event improves or diminishes upon 
withdrawal of the study drug without the initiation of any specific treatment for 
the event (dechallenge) and/or recurs or worsens with rechallenge (when 
clinically feasible). 
• Alternative explanation or confounding factors do not suggest another etiology for 
the AE: The role of concurrent or underlying illness, co-medication, procedures 
or other events need to be evaluated as possible causes of or contributing to the 
adverse event. 
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The following criteria should be considered and would support a non-causal association 
between drug administration and the adverse event. 
• The AE is more likely to be explained by the subject’s clinical state, underlying 
disease, concomitant medication, study or non-study procedure. 
• The amount, duration of exposure, or time of last dose prior to the event suggests 
the AE is not reasonably related to administration of study treatment. 
12.2 
ADVERSE EVENTS REPORTING PROCEDURES 
12.2.1 
GENERAL 
All AEs (e.g., any new event or worsening in severity or frequency of a pre-existing 
condition or laboratory finding) with an onset date after the subject signs the informed 
consent for participation in the clinical trial must be promptly documented on the AE 
eCRF via the electronic data capture (EDC) system.  Details of the event must include 
severity, relationship to study drug(s), duration, action taken, and, for SAEs only, 
outcome.  Whenever possible, reporting specific diagnoses is preferred when reporting 
AEs in the AE eCRF rather than reporting individual signs and symptoms. 
All AEs will be collected from the time the subject signs informed consent through 
30 days after receiving the last dose of study drug(s).  If initiation of new anticancer 
therapy occurs within 30 days following the last dose of study drug(s), the date of new 
anticancer therapy will be recorded on the appropriate eCRF.  In addition, the 
investigator should report any AEs that may occur after this time period which are 
assessed to have a reasonable possibility of being associated with study drug. 
All AEs that are considered related to study drug and all SAEs regardless of relationship 
to study drug must be followed to resolution or stabilization if improvement is not 
expected.  Adverse events which completely resolve and then recur should be recorded as 
new AEs.  For subjects who complete the EOT visit less than 30 days following the last 
dose of study drug, a follow-up of ongoing AEs should be documented in the subject’s 
source file.  Adverse events continuing at 30 days after the last dose of study treatment 
should have a comment in the source file by the investigator that the event has stabilized 
or is not expected to improve. 
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The investigator is responsible for evaluating all AEs, obtaining supporting source 
documents, and determining that documentation of the event is adequate.  The 
investigator may delegate these duties to subinvestigators and must ensure that these 
subinvestigators are qualified to perform these duties under the supervision of the 
investigator and that they are listed on the FDA Form 1572. 
12.3 
SERIOUS ADVERSE EVENT DEFINITION 
An SAE is an AE that meets 1 or more of the following criteria: 
• Death  
• Life-threatening experience defined as any adverse experience that places the 
subject, in the view of the Sponsor or investigator, at immediate risk of death at 
the time of occurrence (i.e., it does not include a reaction that, had it occurred in 
a more severe form, might have caused death). 
• Requires in-subject hospitalization or prolongation of an existing hospitalization 
(except scheduled hospitalizations for a nonacute, unrelated cause such as 
elective surgery). 
• Results in persistent or significant disability/incapacity (i.e., substantial disruption 
in a subject’s ability to conduct normal activities of daily living [ADL]). 
• Is a congenital anomaly/birth defect in the offspring of an exposed female subject 
or offspring of a female partner of a male subject. 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered a SAE when, based upon appropriate 
medical judgment, jeopardizes the subject and may require medical or surgical 
intervention to prevent 1 of the outcomes listed in this definition. 
12.4 
SERIOUS ADVERSE EVENT REPORTING AND DOCUMENTATION 
REQUIREMENTS 
Amgen Global Patient Safety must be notified of the occurrence of any SAE within 
24 hours of the investigator, designee, or site personnel’s knowledge of the event.  The 
SAE will be reported by completing and submitting the SAE report form through the 
EDC system.  In the event that the EDC system is not available, paper SAE report forms 
may be used to report the SAE to Amgen Global Patient Safety (Appendix L).  Please 
refer to the SAE Reporting Guidelines in the study reference manual.   
Follow-up reports must be submitted in a timely fashion as additional information 
becomes available. 
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The investigator is responsible for notifying the Institutional Review Board (IRB) or 
Independent Ethics Committees (IEC), in accordance with local regulations, of all SAEs.  
The Sponsor may request for additional source documentation pertaining to the SAE 
from the investigational site.  If a subject is permanently withdrawn from the study due to 
an SAE, this information must be included in the initial or follow-up SAE report in the 
eCRF. 
The Sponsor is responsible for notifying the appropriate global health authorities of 
SAEs, when required, in accordance with applicable laws and regulations. 
Properly anonymized and de-identified documents (e.g., hospital discharge summaries, 
autopsy reports, and/or death certificates), as available will be provided to Amgen Global 
Patient Safety. 
12.5 
PREGNANCY AND LACTATION EXPOSURE REPORTING 
Pregnancy, although not considered an SAE, must be reported to Amgen Global Patient 
Safety within 24 hours of the investigator’s awareness, if the pregnancy has occurred 
within 30 days of study treatment (for female participants) or within 90 days of study 
treatment (for female partners of male participants).  The pregnancy will be reported on a 
Pregnancy Notification Worksheet (APPENDIX M).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested. 
If a subject becomes pregnant while taking an Amgen drug, the study treatment will be 
immediately discontinued.  The investigator will discuss the risks and concerns of 
investigational drug exposure to a developing fetus and counsel the subject and/or 
pregnant partner (or ensure that such counseling is provided). 
Pregnancies will be followed through the outcome of the pregnancy. 
If the outcome of the pregnancy meets a criterion for immediate classification as an SAE 
(e.g., spontaneous abortion, stillbirth, neonatal death, fetal or neonatal congenital 
anomaly), the investigator will report the event as an SAE. 
With authorization of the subject or female partner, newborns should be followed-up at 6 
and 12 months of age.   
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If a female subject breastfeeds during treatment with carfilzomib or up to 30 days 
following the last dose of study drug administration, the investigator will notify Amgen 
Global Patient Safety within 24 hours of learning of her breastfeeding.  The investigator 
will discuss the risks and concerns of breastfeeding while taking an IP.  The subject will 
be required to either discontinue breastfeeding or study treatment.  The investigator will 
complete a Lactation Notification Worksheet (APPENDIX N).  Amgen Global Patient 
Safety will follow-up with the investigator regarding additional information that may be 
requested. 
12.6 
DEATH REPORTING 
All deaths that occur from signing of informed consent until 30 days after the last dose of 
study drug are to be reported as SAEs (unless due to PD - refer to Section 12.4).  
Deaths occurring after the EOT visit do not need to be reported as SAEs.  Additional 
details of the event (such as the primary and contributory causes of death) should be 
reported on the end of study eCRF. 
13 
STATISTICAL CONSIDERATIONS 
This section describes the statistical considerations of the study design and summarizes 
the statistical analyses that will be conducted to assess the efficacy and safety endpoints 
in the study.  Further details will be provided separately in the Statistical Analysis Plan 
(SAP).  If, after the study has begun, but prior to the final analysis, important changes are 
made to the primary or key secondary analyses, then the changes will be reflected in the 
SAP or its amendment where applicable.  The study protocol may be amended as 
appropriate.  Any other changes made to the planned analyses after the protocol and SAP 
have been finalized, along with an explanation as to when and why they occurred, will be 
described in the clinical study report, in which any post hoc exploratory analyses also 
will be clearly identified.  Any changes made in the analysis plan, after the primary 
inferential comparisons between treatment groups are performed, will be exploratory in 
nature. 
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13.1 
STUDY ENDPOINTS 
13.1.1 
PRIMARY ENDPOINTS 
The primary endpoint is PFS, which is defined as the time in months from 
randomization to the earlier of disease progression or death due to any cause. 
13.1.2 
SECONDARY ENDPOINTS 
The secondary endpoints of the study are as follows: 
• ORR, defined as the proportion of subjects who achieved a confirmed PR, 
VGPR, CR, or sCR, according to the IMWG-URC. 
• OS defined as the time in months from randomization to death due to any cause. 
• Safety and tolerability  
• Sparse PK 
13.2 
STUDY POPULATIONS 
13.2.1 
INTENT-TO-TREAT POPULATION 
The Intent-to-Treat (ITT) Population consists of all randomized subjects.  It will be the 
basis for the analysis of efficacy endpoints in this study.  Subjects in the analysis based 
on the ITT Population will be included in the treatment group to which they were 
randomized. 
13.2.2 
SAFETY ANALYSIS POPULATION 
The Safety Population is defined as all randomized subjects who received at least 1 dose 
of any study drug (i.e., carfilzomib, dexamethasone).  Subjects in the analysis based on the 
Safety Population will be included in the treatment group corresponding to the actual 
treatment received. 
13.3 
STATISTICAL METHODS 
13.3.1 
ANALYSIS OF THE CONDUCT OF THE STUDY 
The number of subjects screened, randomized, and treated will be presented.  The number 
and percentage of subjects excluded from each analysis population will be summarized 
with reasons for exclusion.  The number of subjects who discontinue study treatment will 
be tabulated, along with the reason for discontinuation.   
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Subjects’ demographics and baseline characteristics, disease characteristics, prior and 
concomitant medications, and study drug exposure and treatment compliance will be 
summarized descriptively for each treatment group. 
The number and percentage of subjects with important protocol deviations will be 
summarized by treatment group. 
13.3.2 
EFFICACY ANALYSES 
All efficacy analyses will be based on the ITT Population, which consists of all subjects 
randomized. 
13.3.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS.  Progression-free survival will be calculated 
from the time of randomization until disease progression or death due to any cause, 
whichever occurs first.  If a subject is alive or lost to follow-up without experiencing 
documented disease progression by the data cutoff date, the PFS data for the subject 
will be censored at the date of last valid disease and response assessment.  Detailed 
PFS data censoring rules will be described in the SAP. 
The distribution of PFS, including median, will be estimated using the 
Kaplan-Meier method.  Progression-free survival rates at selected time points will 
be reported by treatment group.  The 95% CI for the median and other percentiles 
of PFS will be constructed using the method of Klein and Moeschberger (1997) with 
log-log transformation.  The 95% CIs for PFS rates were estimated using the 
method by Kalbfleisch and Prentice (1980) with log-log transformation.  The 
inferential comparison between treatment groups will be made using the log-rank 
test stratified by the randomization stratification factors specified in Section 7.  The 
hazard ratio (HR) and its 95% CI will be estimated using a Cox proportional 
hazards model stratified by the same randomization stratification factors.  Duration 
of follow up for PFS will be estimated using the reverse Kaplan-Meier method 
(Schemper 1996; Smith 2006). 
Response and disease progression will be determined using a validated computer 
algorithm (Onyx Response Computational Assessment; [ORCA]), as well as by local 
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Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 81 of 165 
median, will be estimated using the Kaplan-Meier method on the basis of subjects 
who achieve overall response. 
13.3.2.2.2 
Overall Survival 
Overall Survival will be analyzed using the same methods as for PFS. 
Overall Survival data will be right-censored at the earlier of last known alive date or data 
cutoff date for subjects who are still alive.   
The analysis of OS will be conducted at the time of the PFS analysis (interim or 
final), only if both PFS and ORR analyses are positive, per hierarchical testing 
procedures.  There will be no interim analysis for OS.  Additional follow-up for OS 
may be performed. 
13.3.2.3 
Control of Family-wise Type I Error Rate 
The null hypotheses for the primary efficacy endpoint, PFS, and secondary efficacy 
endpoints (ORR and OS) will be tested using a fixed sequence hierarchical testing 
procedure to control the family-wise Type I Error rate below 1-sided 0.025 level.  The 
family of hypotheses is ordered as follows: 1) PFS, 2) ORR, and 3) OS.  Starting with 
the hypothesis of PFS, if any hypothesis in the sequence is rejected at a 1-sided 
significance level of 0.025, then the subsequent hypothesis will be tested; if any 
hypothesis is accepted, then the subsequent hypotheses will not be tested. 
13.3.3 
SAFETY ANALYSIS 
Safety analyses will be based on the Safety Population (defined as all randomized 
subjects who have received at least 1 dose of study treatment). 
13.3.3.1 
Adverse Events 
Treatment-emergent adverse events are defined as AEs that start on or after the first day 
study treatment is administered and within 30 days of the last administration of study 
treatment.  The reported AE term will be coded using MedDRA and will be graded for 
severity using NCI-CTCAE Version 4.03.  The causal relationship between the 
occurrence of an AE and each treatment will be assessed by the investigator as related or 
not related. 
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Treatment-emergent adverse events will be summarized based on the number and 
percentage of subjects experiencing events by treatment group and by MedDRA system 
organ class (SOC) and preferred term.  In the event that a patient experiences repeated 
episodes of the same AE, the subject will be counted once within each SOC 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. 
Tabular summaries of the following will be provided: 
• All TEAEs by SOC 
• All TEAEs in decreasing order of frequency 
• TEAEs by causal relationship to study drug  
• TEAEs by maximum severity grade 
• All SAEs by SOC 
• All SAEs in decreasing order of frequency 
• TEAEs resulting in modification (i.e., dose reduction or dose interruption) of 
study treatment  
• TEAEs resulting in discontinuation of study treatment 
• Deaths within 30 days of the last administration of study treatment  
• All AEs, including TEAEs, will be included in individual patient listings. 
13.3.3.2 
Safety Laboratory Values 
For hematology, chemistry, and other laboratory values, the baseline values, changes 
from baseline by visit, the minimum, maximum, and last observed values will be 
summarized descriptively. 
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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All available laboratory data, including those excluded from summary tabulations, will be 
included in individual patient listings. 
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 by assessing the maximum increase and/or decrease observed 
during the course of study treatment relative to the baseline toxicity grade. 
The subject incidence of Grade 3 and 4 hematological laboratory abnormalities 
(including neutropenia, thrombocytopenia, and anemia) will be provided by treatment 
group. 
The subject incidence of Grade 3 and 4 nonhematological laboratory abnormalities 
(including liver function test [LFT], CrCl) will be provided by treatment group.  Similar 
analyses will be done for selected chemistry tests. 
13.3.3.3 
Vital Signs 
Vital sign results (systolic and diastolic blood pressure, pulse, respiratory rate, and 
temperature) will be summarized descriptively for baseline values and changes from 
baseline to the minimum, maximum, and last observed values.   
For the summary of changes from baseline by visit, subjects without a baseline and/or 
past-baseline value will be excluded; values from unscheduled assessments will be 
excluded.  Vital sign results taken > 30 days after the last administration of protocol 
therapy will be excluded from all vital sign summaries. 
13.3.4 
SPARSE PHARMACOKINETIC ANALYSES  
A sparse PK sampling strategy will be employed in this study, at a subset of study sites.  
Blood samples will be collected at specified times, processed and stored until analysis.  
Concentrations of carfilzomib will be measured in plasma using a validated assay 
method. 
The population pharmacokinetic analysis will be a cumulative analysis that will include 
population pharmacokinetic data obtained from previous Phase 2 and Phase 3 studies that 
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used intensive or sparse PK sampling.  The analysis plan as well as a stand-alone 
pharmacokinetic analysis report will be prepared separately.  The population modeling 
program may be used to fit a nonlinear mixed effects model to estimate PK parameters, 
including clearance and volume of distribution, the inter- and intra-subject variability, 
and the population variability in the parameter estimates.  The PK concentrations 
obtained from subjects who participate in the sparse PK sampling, along with results 
from the intensive PK/PDn substudy and other carfilzomib studies, will be used in the 
development of a structural model.  The best model will be evaluated by goodness-of-fit 
statistics and reduction in the objective function and posterior predictive checks.  Subject 
characteristics such as age, gender, body weight, BSA, and race will be included in the 
model to identify potential covariates affecting PK of carfilzomib. 
Additional analyses may be performed to evaluate the relationship between the estimated 
PK parameters and selected safety or clinical effect endpoints. 
13.3.5 
EXPLORATORY ANALYSES  
Exploratory analyses will be performed for the following endpoints: 
• PDn and PK endpoints 
o To characterize the PK and PDn of proteasome inhibition in both treatment 
groups in a subset of subjects.  Actual collection times will be recorded and 
used in the analysis.  For the intensive PK/PDn substudy, individual and 
mean plasma concentration versus time data will be tabulated and plotted by 
dose level.  The PK parameter will be estimated based on noncompartmental 
methods.  The PK parameter estimates for carfilzomib will be summarized, 
including total plasma exposure (AUC, Cmax, time to maximum plasma 
concentration [tmax], total plasma clearance, and t1/2 [as appropriate for 
data collected]).  Estimates for these parameters will be tabulated and 
summarized (i.e., mean, standard deviation).  These estimates will be 
summarized descriptively by each arm.   
• Patient-reported outcomes 
o All subscales of the EORTC QLQ-C30, and the EORTC QLQ-MY20 
o EQ-5D-5L: a standardized measure of health status developed by the 
EuroQol Group  
o Patient-reported convenience and satisfaction  
• Healthcare resource utilization  
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13.4 
HANDLING OF DATA 
13.4.1 
HANDLING MISSING DATA IN DESCRIPTIVE ANALYSES 
When summarizing categorical variables, subjects with missing data are generally not 
included in calculations of percentages unless otherwise specified.  When needed, the 
category of “Missing” is created and the number of subjects with missing data is 
presented. 
When summarizing continuous variables, subjects with missing data are not included in 
calculations.  No imputations are made. 
13.4.2 
HANDLING MISSING OR PARTIALLY MISSING DATES 
Missing or partially missing dates will not be imputed at data level.  However, 
assumptions for missing or partially missing dates for important variables will be made to 
allow inclusion of appropriate data records in the analyses.  In general, the assumptions 
about the missing or partially missing dates, when needed, are made conservative to 
avoid overestimation of treatment effect and underestimation of adverse effects. 
If a medication date or time is missing or partially missing, and it cannot be determined 
whether it was taken prior or concomitantly, it will be considered as a prior, concomitant, 
and a post-treatment medication. 
If the partial AE onset date information does not indicate whether the AE started prior to 
treatment or after the TEAE period, the AE will be classified as treatment-emergent. 
If the start day of subsequent anticancer therapy is missing, it will be assumed to be the 
first day of the month. 
If only the day of a death date is missing, the death will be assumed to be on the first day 
of the month if the last known alive date is earlier.  If the last known alive date is later 
than the first day of the month, then the death date will be assumed to be the last known 
alive date plus 1 day. 
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Onyx Therapeutics, Inc. 
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Carfilzomib 
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including the roles and responsibilities of the involved parties, will be described in 
the IRC Charter. 
13.7 
DATA MONITORING COMMITTEE  
An independent Data Monitoring Committee (DMC) will be convened for this study and 
will act in an advisory capacity to the sponsor with respect to safeguarding the interests 
of study subjects through periodic safety data reviews, assessments of interim safety and 
efficacy data, and monitoring of the overall conduct of the study.  To enhance the 
integrity of the study, the DMC may also formulate recommendations relating to the 
selection, recruitment, and retention of subjects, their management, improving adherence 
to protocol treatment, and the procedures for data management and quality control.   
An Independent Statistical Reporting Group (ISRG) will function independently of the 
Sponsor study team, in support of the DMC.  The ISRG will conduct unblinded analyses, 
generate the open and closed reports to be reviewed at the DMC meetings, and serve as 
the liaison between the Sponsor and the DMC. 
The details of the DMC, including the roles and responsibilities of the involved parties, 
will be described in the DMC Charter.   
The DMC will meet to review safety data on a periodic basis, including after 
approximately 40 subjects have completed ≥ 1 cycle and no less frequently than 
approximately every 6 months thereafter.  Unplanned safety review meetings of the DMC 
may be called at any time, if warranted, for an earlier review of safety data.  The DMC 
will also review the interim PFS analysis results and recommend whether the study 
should stop early for efficacy. 
13.8 
INTERIM ANALYSIS  
Periodic safety review will be conducted by the DMC. 
One interim analysis will be conducted for PFS when approximately 263 (75% of total 
350) PFS events are observed.  The objective of the interim analysis is to monitor for 
differences between treatment arms for evidence of a substantial benefit in the 
carfilzomib once-weekly with dexamethasone arm. 
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will review the ICF for approval.  A copy of the approved form must be submitted to the 
sponsor or its designated representative prior to initiation of the study. 
Before implementing any study procedure, informed consent will be documented in the 
subject’s case history and by the use of a written ICF approved by the IRB/IEC and 
signed and dated by the subject or the subject’s legally authorized representative at the 
time of consent.  A copy of the signed informed consent will be given to the subject or 
subject’s legally authorized representative.  The original signed consent must be 
maintained by the investigator and available for inspection by the Sponsor, its designated 
representative, or regulatory authority at any time. 
14.2 
COMPLIANCE WITH LAWS AND REGULATIONS 
The study will be conducted in accordance with US FDA and International Conference 
on Harmonisation (ICH) Good Clinical Practice (GCP), the Declaration of Helsinki, any 
applicable local health authority, and IRB or IEC requirements. 
This study must have the approval of a properly constituted IRB/IEC.  Before the 
investigational drug is shipped to the investigator, the investigator or designee will 
provide the Sponsor with a copy of the IRB/IEC approval letter stating that the study 
protocol and any subsequent amendments and the ICF have been reviewed and approved. 
The investigator or designee will be responsible for obtaining annual IRB/IEC 
re-approval throughout the duration of the study.  Copies of the investigator’s annual 
report to the IRB/IEC and copies of the IRB/IEC continuance of approval must be 
submitted to the Sponsor or designee. 
The investigator is also responsible for notifying their IRB/IEC of any significant AEs 
that are serious and/or unexpected. 
The Sponsor will provide study sites with any Investigational New Drug (IND) safety 
reports, changes to the IB, and any safety updates.  The investigator is responsible for 
immediately notifying their IRB/IEC of any such updates. 
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14.3 
SUBJECT CONFIDENTIALITY 
Subject medical information obtained as part of this study is confidential, and must not be 
disclosed to third parties, except as noted below.  The subject may request in writing that 
medical information be given to his/her personal physician. 
The investigator/institution will permit direct access to source data and documents by the 
Sponsor, its designee, the US FDA, and other applicable regulatory authorities.  The 
access may consist of study-related monitoring, audits, IRB/IEC reviews, and US 
FDA/regulatory authority inspections. 
Release of research results should preserve the privacy of medical information and must 
be carried out in accordance with US Department of Health and Human Services 
Standards for Privacy of Individually Identifiable Health Information, 45 CFR 164.508 
and, if and to the extent applicable, the principles set out in Directive 95/46/EC of the 
European Parliament and of the Council of 24 October 1995 on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data, and national legislation with regard to data privacy. 
15 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
15.1 
PROTOCOL AMENDMENTS  
The Sponsor will implement in writing any substantive changes to this protocol as a 
protocol amendment.  The amendment will be submitted to the applicable local 
regulatory health authority and IRB/IEC, together with a revised ICF, if applicable.  
Amendments must be submitted to the applicable local regulatory health authority and 
IRB/IEC approval must be received, signed, and dated by the subject or the subject’s 
legally authorized representative at the time of consent before the amendment is 
implemented.  The investigator or designee must send a copy of the approval letter from 
the IRB/IEC, along with the revised ICF, to the Sponsor or designee.  Upon completion 
of the study, the investigator must provide the IRB/IEC with a summary of the study’s 
outcome. 
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15.2 
STUDY TERMINATION 
The Sponsor reserves the right to terminate the study at any time.  The investigator or 
designee should notify the IRB/IEC in writing of the study’s completion or early 
termination and send a copy of the notification to the Sponsor or designee. 
15.3 
STUDY DOCUMENTATION AND ARCHIVES 
15.3.1 
SOURCE DOCUMENTS 
Source records are original documents, data, and records (e.g., medical records, raw data 
collection forms, pharmacy dispensing records, recorded data from automated 
instruments, laboratory data) that are relevant to the clinical study.  The investigator will 
prepare and maintain adequate and accurate source documents.  These documents are 
designed to record all observations and other pertinent data for each subject randomized 
in this clinical study.  Source records must be adequate to reconstruct all data entered in 
the designated eCRF.   
15.3.2 
ARCHIVAL OF RECORDS 
According to 21 CFR 312.62(c), the investigators will retain records required to be 
maintained under this part for a period of 2 years following the date a marketing 
application is approved for the drug for the indication for which it is being investigated.  
If no application is to be filed or if the application is not approved for such indication, the 
investigator will retain these records until 2 years after the investigation is discontinued 
and the US FDA or applicable regulatory authorities are notified. 
The investigator must retain protocols, amendments, IRB/IEC approvals, copies of the 
Form FDA 1572 or Canadian Quality Investigator Undertaking, signed and dated consent 
forms, medical records, eCRFs, drug accountability records, all correspondence, and any 
other documents pertaining to the conduct of the study. 
15.4 
DATA COLLECTION AND STUDY MONITORING 
15.4.1 
ELECTRONIC CASE REPORT FORMS 
As part of the responsibilities assumed by participating in the study, the investigator 
agrees to maintain adequate case histories for the subjects treated as part of the research 
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under this protocol.  The investigator agrees to maintain accurate eCRFs and source 
documentation as part of the case histories.  These source documents may include subject 
diaries, laboratory reports, etc. (refer to Section 15.3.1).  The Sponsor will supply the 
eCRF, which must be completed in English. 
The investigator or designee must enter all results collected during the clinical study into 
eCRFs.  Guidelines for completion of eCRFs will be reviewed with study site personnel 
at the site initiation visits.  Investigators are responsible for approval of the 
entered/corrected data; however, they can authorize listed sub-investigators to 
sign/approve the data. 
15.4.2 
STUDY MONITORING 
The clinical research associate or study monitor, as a representative of the sponsor, has 
the obligation to follow the study closely.  In doing so, the monitor will visit the 
investigator(s) and study facility at periodic intervals, in addition to maintaining 
necessary telephone and letter contacts.  The monitor will maintain current personal 
knowledge of the study through observation, review of study records and source 
documentation, discussion of the conduct of the study with the investigators and study 
site personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, 
for compliance with applicable government regulation with respect to current GCP and 
current SOPs. 
15.4.3 
DATA QUALITY ASSURANCE  
The clinical research associates will visit each study site, at a frequency documented in 
the monitoring plan, to review eCRFs for completeness and accuracy.  Any discrepancies 
noted between source documents and completed eCRFs will be entered as a discrepancy 
in the EDC system by the clinical research associate, which will then be addressed by the 
study site personnel.  Uniform procedures for eCRF correction (queries) will be discussed 
at the investigator meeting, and during the study site initiation visits.  Data from eCRFs 
and other external data sources will be entered into a clinical database as specified in the 
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data management plan.  Quality control and data validation procedures will be applied to 
ensure the validity and accuracy of the clinical database. 
15.5 
PUBLICATION POLICY 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors [ICMJE]) Recommendations 
for the Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical 
Journals, which states: 
• Authorship credit should 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 should meet conditions 1, 2, 3, and 4. 
• When a large, multicenter group has conducted the work, the group should 
identify the individuals who accept direct responsibility for the manuscript.  These 
individuals should 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 should qualify for authorship, and all those who 
qualify should be listed. 
• Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
[Additional information on the current guidelines for publications can be found at the 
following location:  http://www.icmje.org/.] 
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. 
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16 
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Amgen/Onyx. Carfilzomib Investigator’s Brochure, version 16.1. Onyx Therapeutics, 
Inc. (a wholly owned subsidiary of Onyx Pharmaceuticals, Inc., an Amgen Inc. 
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Anderson KC, Kyle RA, Rajkumar SV, et al. Clinically relevant end points and new drug 
approvals for myeloma. Leukemia. 2008;22(2):231–39. 
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inhibitors bortezomib and carfilzomib. Haematologica. 2009:94(s2). 14th Congress of the 
European Hematology Association. Abstract 0939. 
Berenson J, Cartmell A, Bessudo A, et al. Updated results from CHAMPION-1, a phase 
1/2 study investigating weekly carfilzomib with dexamethasone for patients (pts) with 
relapsed or refractory multiple myeloma (RRMM). J Clin Oncol. May 29–June 2, 2015. 
ASCO Annual Meeting 2015. Abstract accepted. 
Berenson J, Klein L, Rifkin R, et al. Results of the dose-escalation portion of a phase 1/2 
study (CHAMPION-1) investigating weekly carfilzomib in combination with 
dexamethasone for patients with relapsed or refractory multiple myeloma. J Clin Oncol. 
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Cancer. 2007;43(11):1670–78. 
Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible 
inhibitor of the proteasome. Cancer Res. 2007;67(13):6383–91. 
Durie BG, Moreau P, Sonneveld P, et al. Regional differences in the treatment 
approaches for relapsed multiple myeloma: an IMF study. J Clin Oncol. 
2012;30(15_suppl). ASCO Annual Meeting 2012. Abstract 8095. 
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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. Errata in: Leukemia 2006;20(12):2220 and Leukemia 2007;21(5):1134. 
EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of 
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Fayers PM, Aaronson NK, Bjordal K, et al., on behalf of the EORTC Quality of Life 
Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Brussels, Belgium: 
European Organisation for Research and Treatment of Cancer; 2001. 
Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality 
in Europe in 2008. Eur J Cancer. 2010;46(4):765–81. 
Geurink PP, van der Linen WA, Mirabella AC, et al. Incorporation of non-natural amino 
acids improves cell permeability and potency of specific inhibitors of proteasome 
trypsin-like sites. J Med Chem. 2013;56(3):1262–1275. 
Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple 
myeloma. J Clin Oncol. 2005;23(15):3412–20.  
Harousseau JL, Dreyling M, ESMO Guidelines Working Group. Multiple myeloma: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 
2010; 21 Suppl 5:v155−57. 
Kalbfleisch JD and Prentice RL. The Statistical Analysis of Failure Time Data, 
Hoboken, New Jersey: John Wiley & Sons; 1980. 
Klein, JP and Moeschberger, M L. 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):3281–90. 
Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple 
myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international 
myeloma working group study. Leukemia. 2012;26(1):149−57. 
Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma 
and the impact of novel therapies. Blood. 2008;111(5):2516–20. 
Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with relapsed 
multiple myeloma. Mayo Clin Proc. 2004;79(7):867–74. 
Lee S, Arastu-Kapur S, Kellerman S, et al. Potent inhibition of select proteasome 
subunits by carfilzomib in multiple myeloma and solid tumor patients is associated with 
patient response. Haematologica. 2012;97(s1). 17th Congress of the European 
Hematology Association. Abstract 840. 
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Lonial, S. and K. C. Anderson. Association of response endpoints with survival outcomes 
in multiple myeloma. Leukemia 2014;28(2):258–68. 
Lonial S, Mitsiades CS, Richardson PG. Treatment options for relapsed and refractory 
multiple myeloma. Clin Cancer Res. 2011;17(6):1264–77. 
Mosteller RD. Simplified calculation of body surface area. N Engl J Med 1987;317(17): 
1098 (letter). 
National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. May 
29, 2009 (v4.03 June 14, 2010). NCI, NIH, DHHS. NIH publication # 09-7473. 
National Comprehensive Cancer Network (NCCN) Guidelines 2014. Clinical Practice 
Guidelines in Oncology:  Multiple Myeloma . Version 2.2014. 
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):649−55. 
Papadopoulos KP, Siegel DS, Vesole DH, et al. Phase I Study of 30-Minute Infusion of 
Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in 
Patients With Relapsed and/or Refractory Multiple Myeloma J Clin Oncol. Sep 2014. 
Epub ahead of print. 
Parlati F, Lee SJ, Aujay M, et al. Carfilzomib can induce tumor cell death through 
selective inhibition of the chymotrypsin-like activity of the proteasome. Blood. 
2009;114(16): 
3439–47. 
Rajkumar SV, Harousseau J-L, 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):4691–95. 
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. 
Control Clin Trials. 1996;17(4):343–46. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the 
use of white blood cell growth factors: an evidence-based clinical practice guideline. J 
Clin Oncol. 2006;24(19):3187–205. 
Squifflet P, Michiels S, Siegel D, et al. Multivariate modelling reveals evidence of a dose 
response relationship in phase 2 studies of single-agent carfilzomib. Blood. 
2011;118(21). ASH Annual Meeting 2011. Abstract 1877.   
Yang J, Wang, Z, Fang Y, et al. Pharmacokinetics, pharmacodynamics, metabolism, 
distribution, and excretion of carfilzomib in rats. Drug Metab Dispos. 
2011;39(10):1873-82 
 
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APPENDIX A 
SCHEDULE OF ASSESSMENTS 
Assessmenta 
Screeningb 
Baselinec 
All Cycles 
LTFU 
D1 
D2 
D8 
D9 
D15 
D16 
D22 
EOT 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical and treatment history 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
X 
Xd 
X 
Xd 
X 
Xd 
 
X 
 
Physical examinatione 
X 
 
X 
 
 
 
 
 
 
X 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
 
X 
 
12 lead ECG with QTc interval 
X 
 
 
 
 
 
 
 
 
X 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
Full hematology panelf 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Full serum chemistry panelf 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
X 
 
QLQ-C30, QLQ-MY20, EQ-5D-5L, and Patient 
Convenience and Satisfactiong 
 
 
X 
 
 
 
 
 
 
X 
X 
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APPENDIX A 
SCHEDULE OF ASSESSMENTS (CONT’D) 
Assessment 
Screeningb 
Baselinec 
All Cycles 
LTFU 
D1 
D2 
D8 
D9 
D15 
D16 
D22 
EOT 
AEs and Survival Status 
 
 
Concomitant medications 
 
 
Pregnancy Test (FCBP)h 
X 
 
X 
 
 
 
 
 
 
X 
 
Survival 
 
 
 
 
 
 
 
 
 
 
X 
AEs = adverse events; C1D1 = Cycle 1 Day 1; C2D1 = Cycle 2 Day 1; ECHO = echocardiogram; ECG = electrocardiogram; LTFU = long-term follow-up; EOT = 
End of Treatment; FCBP = females of childbearing potential; MUGA = multigated acquisition; QLQ-C30 = Quality of Life Core Module; QLQ-MY20 = Quality of 
Life Multiple Myeloma Module; QTC = corrected QT-interval; EQ-5D-5L = European Quality of Life-5 Dimensions.   
Details of Assessments are in the protocol body.  
a 
Refer to Section 9.1 for study treatment related assessment window. 
b 
Screening samples can be collected within 21 days of randomization.  Refer to Section 10.1.   
c 
Baseline samples are collected only after subject eligibility is confirmed.  Refer to Section 10.2. 
d 
Arm B only (twice-weekly regimen). 
e 
The physical examination Screening may be used if within 7 days prior to C1D1.  Refer to Section 10.1.3. 
f 
Full hematology and serum chemistry samples from Screening may be used for C1D1 if taken within 3 days prior to C1D1.  Refer to Section 10.4.1 and 
Section 10.4.2.  Beyond Cycle 4, labs will be performed on Days 1 and 15 of each cycle in both arms. 
g 
Questionnaires to be collected on Day 1 of Cycle 1, then every second cycle (Cycle 1, 3, 5, etc) during treatment and every 12 weeks (every 84 days ± 4 days) 
until progression, or withdrawal of consent during LTFU.  Questionnaires should be completed by the subject prior to drug administration during treatment cycles.  
Patient convenience and satisfaction collected at Cycle 2 and EOT only.  Refer to Sections 10.7 and 10.10.1. 
h 
Urine or serum pregnancy test must be confirmed negative locally on Day 1 of each Cycle prior to dosing and at EOT.  At Screening, a confirmed negative serum 
pregnancy test that is performed centrally is required.  Refer to Section 10.4.4.  
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APPENDIX B 
SCHEDULE OF DISEASE ASSESSMENTS 
Disease Assessment 
Screening 
(within 21 days of 
randomization) 
Baseline 
(predose-C1D1 ) 
C1D1 
Disease Assessment 
repeated every 28 days (± 
4 days) 
EOTc 
LTFU 
SPEP/UPEP/immunofixationa,b 
X 
 
Xb 
X 
X 
Xd 
SFLCa,b 
X 
 
Xb 
X 
X 
Xd 
Quantitative immunoglobulinsa,b 
X 
 
Xb 
X 
X 
Xd 
Beta-2 microglobuline 
X 
 
 
 
 
 
Plasmacytoma Evaluation  
 
Xf 
 
 
 
 
Skeletal Survey 
 
Xf 
 
 
 
 
Bone Marrow Sampleg 
 
 
 
 
 
 
C1D1 = Cycle 1 Day 1; C2D1 = Cycle 2 Day 1; LTFU = Long-Term Follow-Up; PD = progressive disease; SFLC = serum free light chain;  
SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis; EOT = End of Treatment. 
a 
C1D1 before treatment begins (Screening values may be used if obtained within 7 days prior to C1D1) and every 28 days (± 4 days) thereafter, at EOT and during 
LTFU if disease progression has not already been documented, (every 28 days ± 4 days) until PD and/or start of a subsequent antimyeloma therapy.  Refer to 
Section 10.2. 
b 
Screening values may be used if within 7 days prior to C1D1.  Refer to Section 7 for allowable window between randomization and C1D1. 
c 
EOT will be upon treatment discontinuation or early study withdrawal.  Refer to Section 11.   
d 
For subjects who did not progress during treatment, SPEP, UPEP, SFLC, and quantitative immunoglobulins will continue to be measured (by the central 
laboratory) every 4 weeks (every 28 days ± 4 days) until PD.  All subjects will be followed for survival and disease status (if discontinuation is prior to 
progression) by telephone contact or other method every 12 weeks ± 28 days for until study closure.  Refer to Sections 10.10.1, 10.10.2 and 11.1. 
e 
Must be obtained by central laboratory within 21 days prior to randomization. 
f 
Extramedullary plasmacytoma assessments will be performed if clinically indicated at baseline and repeated during treatment only to confirm a response of PR or 
better, or to confirm PD, or as clinically indicated.  A skeletal survey will be repeated if worsening clinical symptoms suggest PD, or as clinically indicated.  
Historical plasmacytoma evaluation and a skeletal survey performed within 30 days prior to C1D1 may be used for baseline assessments. 
g Bone marrow samples:  Bone marrow biopsy or bone marrow aspirate will be obtained to confirm sCR or CR, or as clinically indicated.  The preferred method for 
a confirmation of CR or sCR is bone marrow biopsy.  However, an aspirate slide is acceptable for confirmation of CR (a confirmatory bone marrow sample is not 
required). 
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APPENDIX C 
SCHEDULE OF STUDY TREATMENT ADMINISTRATION 
 
Cycle 1  
Cycles 2+  
 
D1 
D2 
D8 
D9 
D15 
D16 
D22 
D1 
D2 
D8 
D9 
D15 
D16 
D22 
Arm Aa 
Once-weekly Carfilzomib with Dexamethasone Regimen 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carfilzomib (20 mg/m2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carfilzomib (70 mg/m2) 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
Dexamethasone 40 mgb  
(Day 22 administration should be given PO, 
Cycles 1−9) 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
IV Hydration (Cycle 1 Only) 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Arm Ba  
Twice-weekly Carfilzomib with Dexamethasone Regimen 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carfilzomib (20 mg/m2) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Carfilzomib (27 mg/m2) 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Dexamethasone 40 mgb  
(Day 22 administration should be given PO, 
Cycles 1−9) 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
IV Hydration (Cycle 1 Only) 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
D = Day; IV = intravenous(ly); PO = oral(ly). 
a 
Study treatment will commence on the day of randomization or at least within 5 calendar days of randomization according to treatment group assignment.  Refer 
to Sections 7 and 9.1 for study treatment related assessment window. 
b 
Within 4 hours prior to carfilzomib on Days 1, 8, and 15 in both arms.  
 
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APPENDIX D 
SCHEDULE OF STUDY ASSESSMENTS FOR THE 
PHARMACOKINETIC SPARSE SAMPLING AND INTENSIVE 
PHARMACOKINETIC & PHARMACODYNAMIC SUB-STUDY 
INTENSIVE PK/PDn SUBSTUDY 
SAMPLING 
Optional 
Cycle 1  
D1 
D2 
D8 
D9 
D1
5 
D1
6 
D1
7 
D2
2 
Arm A 
 
 
 
 
 
 
 
 
PDn substudy/whole blood/PBMCs  
• Predose  
X 
 
 
 
X 
 
 
 
PDn substudy/whole blood/PBMCs 
• 1 hour after dose or equivalent time on 
non-dosing day   
 
 
 
 
X 
Xa 
Xb 
Xc 
PK plasma samples  
• Predose (within 5 minutes before the start of 
infusion) 
• 15 minutes after the start of infusion 
(± 5 minutes) 
• Immediately prior to (within 2 minutes 
before) the end of infusion 
• 15 minutes, 60 minutes, and 2 hours after the 
end of infusion (± 5 minutes) 
 
 
 
 
X 
 
 
 
Arm B 
 
 
 
 
 
 
 
 
PDn sub-study/whole blood/PMBCs 
• Predose 
X 
 
 
 
X 
X 
 
 
PDn sub-study/whole blood/PBMCs 
• 1 hour after dose or equivalent time on 
non-dosing day 
 
 
 
 
X 
X 
Xd 
Xe 
PK plasma samples  
• Predose (within 5 minutes before the start of 
infusion) 
• Immediately prior to (within 2 minutes 
before) the end of infusion 
• 15 minutes, 60 minutes, and 2 hours after the 
end of infusion (± 5 minutes) 
 
 
 
 
X 
 
 
 
D = Day; PBMC(s) = Peripheral blood mononuclear cell(s); PDn = Pharmacodynamics; 
PK = Pharmacokinetics. 
a. 
24 hours ± 2 hours after the end of the Day 15 infusion 
b. 
48 hours ± 2 hours after the end of the Day 15 infusion 
c. 
168 hours ± 2 hours after the end of the Day 15 infusion 
d. 
24 hours ± 2 hours after the end of the Day 16 infusion 
e. 
144 hours ± 2 hours after the end of the Day 16 infusion 
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SPARSE PK SAMPLING Optional 
(ALL SUBJECTS NOT IN THE ABOVE 
SUBSTUDY)  
Cycle 2 
D
1 
D
2 
D
8 
D
9 
D1
5 
D1
6 
D1
7 
D2
2 
Arm A  
• Predose (within 5 minutes before the start of 
infusion) 
• 15 minutes after the start of infusion (± 
5 minutes)  
• Immediately prior to (within 2 minutes before) 
the end of infusion 
• 30 minutes after the end of infusion (± 
5 minutes) 
X 
 
 
 
 
 
 
 
Arm B  
• Predose (within 5 minutes before the start of 
infusion) 
• Immediately prior to (within 2 minutes before) 
the end of infusion 
• 30 minutes after the end of infusion (± 
5 minutes) 
X 
 
 
 
 
 
 
 
D = Day; PK = Pharmacokinetics. 
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Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 104 of 165 
APPENDIX F 
NEW YORK HEART ASSOCIATION (NYHA) 
CLASSIFICATION 
Class I: 
Patients with no limitation of activities; they suffer no symptoms from ordinary 
activities. 
Class II: 
Patients with slight, mild limitation of activity; they are comfortable with rest or with 
mild exertion. 
Class III:   
Patients with marked limitation of activity; they are comfortable only at rest.  
Class IV:   
Patients who should be at complete rest, confined to bed or chair; any physical activity 
brings on discomfort and symptoms occur at rest. 
 
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APPENDIX G 
SUMMARY OF INTERNATIONAL MYELOMA WORKING 
GROUP UNIFORM RESPONSE CRITERIA (IMWG-URC) 
Summary of International Myeloma Working Group Uniform Response Criteria 
(IMWG-URC) 
Response 
Subcategorya 
Multiple Myeloma Response Criteria 
sCRb 
• 
CR as defined below and 
• 
Normal SFLC ratio and  
• 
Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescencec 
CRb, h 
• 
Negative immunofixation on the serum and urine and  
• 
Disappearance of any soft tissue plasmacytomas and 
• 
< 5% plasma cells in bone marrow  
VGPRb 
• 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis  
or  
• 
≥ 90% reduction in serum M-protein with urine M-protein level< 100 mg/24 hours 
• 
If the serum and urine M-protein are not measurable, a decrease of ≥ 90% in the 
difference between the involved and uninvolved FLC levels required in place of the 
M-protein criteria. However, documentation of VGPR requires collection and analysis 
of 24 hour urine sample for UPEP and immunofixation and confirmed to be negative. 
• 
If present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas is 
also required. 
PRb 
• 
≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 
≥ 90% or to < 200 mg/ 24 h 
• 
If the serum and urine M-protein are unmeasurable, a ≥ 50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein 
criteria. 
• 
If serum and urine M-protein are not measureable, and serum free light assay is also 
not measureable, ≥ 50% reduction in plasma cells is required in place of M-protein, 
provided baseline bone marrow cell percentage was ≥ 30% 
• 
If present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas is 
also required  
MR 
• 
25%–49% reduction in the level of serum M-protein and a 50%–89% reduction in 24 
hour urinary M-protein, which still exceeds 200 mg per 24 hours 
• 
If the serum and urine M-protein are not measurable, a decrease of 25%–49% in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria. 
• 
If present at baseline, a 25%–49% reduction in the size of soft tissue plasmacytomas is 
also required 
Stable disease 
• 
Not meeting criteria for sCR, CR, VGPR, PR, MR, or PD 
 
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Summary of International Myeloma Working Group Uniform Response Criteria 
(IMWG-URC) (cont’d) 
Response 
Subcategorya 
Multiple Myeloma Response Criteria 
PDb 
Any one or more of the following: 
• 
Increase of ≥ 25% from lowest response value in: 
o 
Serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL)  
o 
Urine M-component and/or (the absolute increase must be ≥ 200 mg/24 h) 
o 
Only in patients without measurable serum and urine M-protein levels; the 
difference between involved and uninvolved FLC levels.  The absolute increase 
must be >10 mg/dL 
o 
Bone marrow plasma cell percentages (absolute percentage must be ≥ 10%) 
• 
Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomase, f, g 
• 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 
2.65mmol/L) that can be attributed solely to the plasma cell proliferative disorder 
Source: Durie 2006; Rajkumar 2011 (modified for protocol purposes). 
CR = complete response; sCR = stringent complete response; FLC = serum light chain; PD = progressive 
disease; PR = partial response; SFLC = serum free light chain; VGPR = very good partial response. 
Note: For patients without measurable protein on UPEP at baseline, UPEP will need to be repeated to confirm a 
response of VGPR or better. 
a 
Patients with measurable disease in both serum (SPEP) and urine (UPEP) at study entry are required to 
meet response criteria in both UPEP and SPEP in order to qualify for a MR or better.  Conversely, it should 
be noted that criteria for PD only needs to be met, and confirmed, in one parameter. 
b All response categories (CR, sCR, VGPR, PR) require 2 consecutive assessments made at any time before 
the institution of any new therapy, as well as no known evidence of progressive or new bone lesions if 
radiographic studies were performed.  Radiographic studies are not required to satisfy these response 
requirements.  Bone marrow, plasmacytoma, and skeletal survey assessments are not required to be 
confirmed by repeat testing.  SD requires a duration of ≥ 6 weeks. 
c 
Presence/absence of clonal cells is based upon the κ/λ ratio.  An abnormal κ/λ ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis.  
An abnormal ratio reflecting presence of an abnormal clone is κ/λ of > 4:1 or < 1:2. 
d Determination of PD while on study requires 2 consecutive assessments made at any time before 
classification of PD and/or the institution of new therapy.  Serum M-component increases of ≥ 1 g/dL from 
nadir are sufficient to define progression if nadir M-component is ≥ 5 g/dL.   
e 
Plasmacytomas: A definite increase in the size is defined as a ≥ 50% increase as measured serially by the 
sum of the products of the cross-diameters of the measurable lesion.  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.   
f 
The requirement for bi-directional measurements applies only to plasmacytomas. 
g The plasmacytoma specifications for PD are based on the Sponsor’s interpretation of the IMWG-URC and 
practical considerations for study execution. 
h In patients with sFLC measurable disease only, normal sFLC ratio is required for CR. 
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APPENDIX H 
INTERNATIONAL STAGING SYSTEM 
The International Staging System (ISS) for myeloma was published by the International 
Myeloma Working Group (Greipp 2005):  
Stage 
Criteria 
I 
Serum beta-2 microglobulin < 3.5 mg/L and serum albumin ≥ 3.5 g/dL 
II 
Serum beta-2 microglobulin < 3.5 mg/L and serum albumin < 3.5 g/dL 
or 
Serum beta-2 microglobulin 3.5–5.5 mg/L irrespective of the serum albumin 
III 
Serum beta-2 microglobulin ≥ 5.5 mg/L 
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APPENDIX I NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI-CTCAE) GRADING SCALE 
 
Common Terminology Criteria for Adverse Events (CTCAE) of the 
National Cancer Institute (NCI), Version 4.03 
 
Published:  28 May 2009 (v4.03: June 14, 2010) 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06 
-14_QuickReference_8.5x11.pdf 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


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APPENDIX K 
COUNTRY SPECIFIC PREGNANCY AND 
CONTRACEPTIVE SUPPLEMENT 
A woman of childbearing potential (WOCBP) is defined as: 
Any woman who has experienced menarche and is not postmenopausal or permanently 
sterilized.  Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
A postmenopausal woman is defined as: 
• Age > 55 years with cessation of menses for 12 or more months 
• Age < 55 years but no spontaneous menses for at least 2 years 
• Age < 55 years and spontaneous menses within the past 1 year, but currently 
amenorrheic (e.g., spontaneous or secondary to hysterectomy), and with 
postmenopausal gonadotropin levels (luteinizing hormone and 
follicle-stimulating hormone levels > 40 IU/L) or postmenopausal estradiol 
levels (< 5 ng/dL) or according to the definition of "postmenopausal range" for 
the laboratory involved. 
• Underwent a bilateral oophorectomy 
Pregnancy Prevention Information 
Female Subjects 
Highly effective methods of birth control are defined as methods that achieve a failure 
rate of less than 1% per year when used consistently and correctly. 
WOCBP must use a highly effective method of birth control during treatment and for an 
additional 30 days after the last dose of protocol-required therapies.  Highly effective 
methods of birth control for female participants or their male partner include: 
• Combined (estrogen and progestogen) hormonal methods:  pills, vaginal ring, or 
skin patch. 
• Single hormonal methods (progestogen to stop the release of the egg from the 
ovary): pills, shots/injections, implants (placed under the skin by a healthcare 
provider) 
• Intrauterine device (IUD) 
• Intrauterine hormonal-releasing system (IUS) surgery to tie both fallopian tubes 
(bilateral tubal ligation/occlusion)  
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• Vasectomised partner:  Provided the partner is the sole sexual partner of the 
WOCBP trial participant and that the vasectomized partner has received 
medical assessment of the surgical success. 
• Sexual abstinence:  Refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatment.  The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial 
and with the preferred and usual lifestyle of the subject. 
Male Subjects 
If the male subjects sole female partner has received medical confirmation that she is 
postmenopausal or she has had a permanent sterilization method (hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy) or the male subject has had a vasectomy with 
medical confirmation of surgical success, or his sole female partner has had a bilateral 
tubal ligation/occlusion, additional contraceptive methods are not required during this 
study.  Otherwise, if the male subject’s female partner could become pregnant, the male 
must:  
• Practice true sexual abstinence.  (Refraining from heterosexual intercourse during 
treatment and for an additional 90 days following the last dose of study drug 
administration.  The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and be the preferred and usual 
lifestyle of the subject.) 
Or 
• Use a condom with spermicide during treatment and for an additional 90 days 
following the last dose of study drug administration.  (Note a condom without 
spermicide is acceptable in countries where spermicide is not commercially 
available.)  
The female partner should also consider using an acceptable method of effective 
contraception such as: 
• Intrauterine device (IUD) 
• Intrauterine hormonal-releasing system (IUS) 
• Hormonal birth control method: pill, shots/injections, implants (placed under the 
skin by a healthcare provider), skin patches, or a vaginal ring 
• Female barrier method: diaphragm, cervical cap, or contraceptive sponge (a 
female condom is not an option because there is a risk of tearing when both 
partners use a condom) 
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Male subjects must not donate sperm during treatment and for an additional 90 days 
following the last dose of study drug administration. 
Males with pregnant partners must practice true sexual abstinence or wear a condom 
during vaginal sex to prevent exposure to the embryo/fetus through semen.  
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APPENDIX L 
SAMPLE SERIOUS ADVERSE EVENT REPORT FORM 
 
 
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APPENDIX M 
PREGANCY NOTIFICATION FORM 
 
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APPENDIX N 
LACTATION NOTIFICATION FORM 
 
Superseding Amendment 4: 07 March 2017 
 
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APPENDIX O 
SUMMARY OF CHANGES FOR PROTOCOL 
AMENDMENT 4 AND FOR SUPERSEDING PROTOCOL AMENDMENT 4 
Protocol Title:  A Randomized, Open-label, Phase 3 Study in Subjects with Relapsed 
and Refractory Multiple Myeloma Receiving Carfilzomib in Combination with 
Dexamethasone, Comparing Once-weekly versus Twice-weekly Carfilzomib Dosing 
 
Amgen Protocol Number 20140355 (formerly CFZ014) 
 
Amendment Date: 
07 March 2017 
Rationale: 
In Protocol Amendment 4, the protocol is amended to: 
• Switch progression-free survival (PFS) from a key secondary objective/endpoint 
to the primary objective/endpoint and overall response rate (ORR) from the 
primary objective/endpoint to a key secondary objective/endpoint 
Rationale: This study was originally designed with ORR as the primary endpoint 
because response rates, especially high-quality responses of substantial duration, 
are important indicators of benefit in relapsed and refractory multiple myeloma.  
However, recent advances in antimyeloma therapy have altered the landscape 
such that PFS is now considered to be the more relevant regulatory endpoint in 
this setting.  To support regulatory interactions and protect the integrity of the 
PFS data, the primary endpoint has been amended to PFS, with ORR as a key 
secondary endpoint. 
• Change the purpose and timing of the interim PFS analysis 
Rationale: The purpose and timing of the interim PFS analysis were amended to 
monitor efficacy and allow the possibility of stopping the trial early for efficacy. 
• Revise statistical language to align with changes in objectives/endpoints and 
purpose and timing of the interim PFS analysis 
• Update Table 12 (Stopping Boundaries for Progression-free Survival) 
• Allow the possibility for long-term follow-up for overall survival 
• Add Section 4.4.1 (End of Study) 
• Add Section 8.4 (Product Complaints) 
• Update Table 5 (Carfilzomib Dose Modifications for Nonhematologic Toxicity) 
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• Add Section 9.4.2.5 (Thromboprophylaxis) 
• Add the following forms in the Appendices 
o Sample Serious Adverse Event Report Form 
o Pregnancy Notification Form 
o Lactation Notification Form 
• Update Section 2 (Background Information) 
• Correct an error in the study schema inserted into Protocol Amendment 4 (thereby 
creating a Superseding Amendment 4) 
• Make minor text clarifications, additions, corrections, and edits throughout the 
protocol 
In Superseding Protocol Amendment 4, the protocol is amended to: 
• Correct an error in the dexamethasone dosing in the study schema inserted into 
Protocol Amendment 4 
• Make minor edits throughout the protocol 
 
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Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: Global, Footer 
Replace: 
Amendment 3: 22 April 2016 
With: 
Superseding Amendment 4: 07 March 2017 
Administrative change 
Section: Title Page 
 
 
Add: 
Date of Protocol Amendment 4.0: 08 
February 2017 
Administrative change 
Section: Title Page 
 
Add: 
Date of Superseding Protocol Amendment 4.0: 
07 March 2017 
Administrative change 
Section: Protocol Acceptance 
Page, Issue/Date 
Replace: 
20140355 (Protocol Amendment 3.0)/22 April 
2016 
With:  
20140355 (Superseding Protocol 
Amendment 4.0)/07 March 2017 
Administrative change 
Section: Synopsis, Study 
objective(s), Primary Objective 
Replace: 
To compare the overall response rate (ORR) of 
once-weekly carfilzomib dosing in combination 
with dexamethasone to the ORR of twice- weekly 
carfilzomib dosing in combination with 
dexamethasone in subjects with relapsed and 
refractory multiple myeloma who have received 
prior treatment with a proteasome inhibitor and 
an IMiD (immunomodulatory agent). 
With: 
To compare the progression-free survival (PFS) 
of once-weekly carfilzomib dosing in 
combination with dexamethasone to the PFS of 
twice-weekly carfilzomib dosing in combination 
with dexamethasone in subjects with relapsed and 
refractory multiple myeloma who have received 
prior treatment with a proteasome inhibitor and 
an IMiD (immunomodulatory agent). 
Primary/secondary 
objective switch 
Section: Synopsis, Study 
objective(s), Secondary 
Objectives, Bullet 1 
Replace: 
Progression-free survival (PFS) 
With: 
Overall response rate (ORR) 
Primary/secondary 
objective switch 
Section: Synopsis, Study 
design, Line 5 
Replace: 
The primary endpoint is ORR. 
With: 
The primary endpoint is PFS. 
Primary/secondary 
endpoint switch 
 
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Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: Synopsis, Study 
design, Study Schema 
Replace: 
Original Study 20140355 Schema below 
With: 
Revised Study 20140355 Schema below 
Alignment with 
Primary/secondary 
objective switch 
 
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Page 124 of 165 
Original Study 20140355 Schema: 
 
ECOG = Eastern Cooperative Oncology Group; IMiD = immunomodulatory agents; IV = intravenous(ly); ORR = overall response rate; OS = overall survival; PD = disease 
progression; PFS = progression-free survival; PI = proteasome inhibitor; PO = orally. 
 
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Clinical Study Protocol No. 20140355 
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Revised Study 20140355 Schema: 
 
ECOG = Eastern Cooperative Oncology Group; IMiD = immunomodulatory agents; IV = intravenous(ly); ORR = overall response rate; OS = overall survival; PD = progressive 
disease; PFS = progression-free survival; PI = proteasome inhibitor; PO = orally. 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


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Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: Synopsis, Statistical 
methods and analyses, 
Paragraph 2 
Replace: 
The primary endpoint, ORR, is defined as the 
proportion of subjects achieving a best overall 
response of partial response (PR), very good 
partial response (VGPR), complete response (CR) 
or stringent complete response (sCR) based on 
the IMWG-URC. 
With: 
The primary endpoint, PFS, will be calculated 
from the time of randomization until PD or 
death due to any cause, whichever occurs first.  
If a subject is alive or lost to follow-up without 
experiencing documented disease progression 
by the data cutoff date, the PFS data for the 
subject will be censored at the date of last valid 
disease and response assessment.  The 
distribution of PFS will be estimated using the 
Kaplan-Meier method.  The inferential 
comparison between treatment groups will be 
made using the log-rank test stratified by the 
randomization stratification factors.  The HR 
and its 95% CI will be estimated using a Cox 
proportional hazards model stratified by the 
same randomization stratification factors.   
Statistical revision to align 
with primary 
objective/endpoint change 
Section: Synopsis, Statistical 
methods and analyses, 
Paragraph 3 
Delete: 
The inferential comparison of ORR between 
treatment groups will be conducted using a 
logistic regression model-based test against the 
null hypothesis that the odds ratio is ≤ 1 at a 1-
sided significance level of 0.025.   
 
Statistical revision to align 
with primary 
objective/endpoint change 
Section: Synopsis, Statistical 
methods and analyses, 
Paragraph 4, Line 1 
Replace: 
The randomization stratification factors will be 
included as covariates in the model: 
With: 
The following randomization stratification factors 
will be included as covariates in the model: 
Statistical revision to align 
with primary 
objective/endpoint change 
 
 
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Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: Synopsis, Statistical 
methods and analyses, after 
Paragraph 4 
 
Add: 
Response and disease progression will be 
determined using a validated computer 
algorithm (Onyx Response Computational 
Assessment [ORCA]), as well as by local 
investigators and by an Independent Review 
Committee (IRC).  The primary analysis of 
PFS will be based on ORCA-assessed 
outcomes.  The PFS outcomes assessed by the 
investigator will serve as a supportive analysis 
of PFS, as will IRC-assessed outcomes. 
Statistical revision to align 
with primary 
objective/endpoint change 
Section: Synopsis, Statistical 
methods and analyses, 
Paragraph 5 
Replace: 
The ORR will be calculated by treatment group 
and the associated 95% confidence interval [CI] 
will be estimated using the Clopper-Pearson 
method.  The odds ratio (and its 95% CI) will be 
estimated using the logistic regression model.   
With: 
The secondary endpoint ORR is defined as the 
proportion of subjects achieving a best overall 
response of PR, very good partial response 
(VGPR), complete response (CR), or stringent 
complete response (sCR), based on the 
IMWG-URC.  The ORR will be calculated by 
treatment group, and the associated 95% 
confidence interval [CI] will be estimated using 
the Clopper-Pearson method.  The odds ratio 
(and its 95% CI) will be estimated using the 
logistic regression model.   
Clarification 
 
 
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Page 129 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: Synopsis, Statistical 
methods and analyses, 
Paragraph 6 
Delete: 
Response and disease progression will be 
determined using a validated computer algorithm 
(Onyx Response Computational Assessment 
[ORCA]) as well as by local investigators.  The 
primary analysis of ORR will be based on the 
ORCA-assessed responses.  Investigator-assessed 
responses will be analyzed as part of a supportive 
ORR analysis, as will IRC-assessed responses, if 
an Independent Review Committee (IRC) is 
convened.   
 
Statistical revision to align 
with primary 
objective/endpoint change 
Section: Synopsis, Statistical 
methods and analyses, 
Paragraph 8 
Delete: 
The secondary endpoints of PFS and OS will be 
analyzed using the log-rank test stratified by the 
randomization stratification factors.  The 
corresponding hazard ratios (HRs) will be 
estimated using a stratified Cox proportional 
hazards model.  The distribution of PFS and OS 
including medians will be summarized using the 
Kaplan-Meier method.   
 
Statistical revision to align 
with secondary 
objective/endpoint change 
 
 
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Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: Synopsis, Statistical 
methods and analyses, 
Paragraph 9 
Replace: 
The hypotheses for the primary efficacy endpoint, 
ORR, and secondary efficacy endpoints (PFS and 
OS) will be tested using a fixed sequence 
hierarchical testing procedure to control the 
family-wise Type I error rate below 1-sided 0.025 
level.  The family of hypotheses is ordered as 
follows: ORR, PFS, and OS.  Starting with the 
hypothesis of ORR, if any hypothesis in the 
sequence is rejected at a 1-sided significance 
level of 0.025, then the subsequent hypothesis 
will be tested; if any hypothesis is accepted, then 
the subsequent hypotheses will not be tested.   
With: 
The hypotheses for the primary efficacy endpoint, 
PFS, and secondary efficacy endpoints (ORR 
and OS) will be tested using a fixed sequence 
hierarchical testing procedure to control the 
family-wise Type I error rate below 1-sided 0.025 
level.  The family of hypotheses is ordered as 
follows: PFS, ORR, and OS.  Starting with the 
hypothesis of PFS, if any hypothesis in the 
sequence is rejected at a 1-sided significance 
level of 0.025, then the subsequent hypothesis 
will be tested; if any hypothesis is accepted, then 
the subsequent hypotheses will not be tested.   
Statistical revision to align 
with primary/secondary 
objective/endpoint switch 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


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Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 132 of 165 
 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 2.4 STUDY 
RATIONALE, Paragraph 3 
Replace: 
The primary endpoint in this study is ORR.  
Response rates, especially high-quality responses 
of substantial duration, are important indicators of 
benefit in relapsed and refractory multiple 
myeloma (Anderson 2008).  A number of studies 
have shown an association between deeper 
responses and improved survival in patients with 
multiple myeloma (Lonial 2014) 
With: 
The primary endpoint in this study is PFS.  
Response rates, especially high-quality responses 
of substantial duration, are important indicators of 
benefit in relapsed and refractory multiple 
myeloma (Anderson 2008).  A number of studies 
have shown an association between deeper 
responses and improved survival in patients with 
multiple myeloma (Lonial 2014).  For these 
reasons, this study was originally designed 
with ORR as the primary endpoint and PFS as 
a key secondary endpoint.  Although ORR 
remains a meaningful clinical endpoint, recent 
advances in antimyeloma therapy have altered 
the landscape such that PFS is now considered 
to be the more relevant regulatory endpoint in 
this setting.  To support regulatory 
interactions and protect the integrity of the 
PFS data, the primary endpoint has been 
amended to PFS, with ORR as a key secondary 
endpoint. 
Addition of rationale for 
primary/secondary 
endpoint switch 
Section: 3.1 PRIMARY 
OBJECTIVE 
Replace: 
The primary objective of this study is to compare 
the ORR of once-weekly carfilzomib dosing in 
combination with dexamethasone to the ORR of 
twice-weekly carfilzomib dosing in combination 
with dexamethasone in subjects with relapsed and 
refractory multiple myeloma who have received 
prior treatment with a proteasome inhibitor and 
an IMiD. 
With: 
The primary objective of this study is to compare 
the PFS of once-weekly carfilzomib dosing in 
combination with dexamethasone to the PFS of 
twice-weekly carfilzomib dosing in combination 
with dexamethasone in subjects with relapsed and 
refractory multiple myeloma who have received 
prior treatment with a proteasome inhibitor and 
an IMiD. 
Primary/secondary 
objective switch 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 133 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 3.2 SECONDARY 
OBJECTIVES, Bullet 1 
Replace: 
Progression-free survival (PFS) 
With: 
ORR 
Primary/secondary 
objective switch 
Section: 4.1 STUDY DESIGN, 
Figure 2 Study 20140355 
Schema 
Replace: 
Original Study 20140355 Schema below 
With: 
Revised Study 20140355 Schema below 
Alignment with 
Primary/secondary 
objective switch 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 134 of 165 
Original Study 20140355 Schema: 
 
ECOG = Eastern Cooperative Oncology Group; IMiD = immunomodulatory agents; IV = intravenous(ly); ORR = overall response rate; OS = overall survival; PD = disease 
progression; PFS = progression-free survival; PI = proteasome inhibitor; PO = orally. 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 135 of 165 
Revised Study 20140355 Schema: 
 
ECOG = Eastern Cooperative Oncology Group; IMiD = immunomodulatory agents; IV = intravenous(ly); ORR = overall response rate; OS = overall survival; PD = progressive 
disease; PFS = progression-free survival; PI = proteasome inhibitor; PO = orally. 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 136 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: STUDY DESIGN, 
Paragraph 4 
Replace: 
The primary endpoint is ORR. 
With: 
The primary endpoint is PFS. 
Primary/secondary 
endpoint switch 
Section: 4.4 ESTIMATED 
STUDY DURATION AND 
CLOSURE 
Replace: 
The total study accrual period is expected to be 
approximately 15 months.  The data cut off date 
for the primary analysis of ORR will be 
approximately 4 months after the last subject is 
randomized.  Subjects will be followed for 
disease and survival status until approximately 
350 PFS events are observed, which is expected 
to occur approximately 25 months after the first 
subject is randomized.  These durations are 
estimated based upon the assumptions of median 
PFS of 8.2 months in the once-weekly dosing arm 
and 6 months in the twice-weekly dosing arm 
with an underlying hazard ratio (HR) of 0.73. 
With: 
The total study accrual period is expected to be 
approximately 15 months.  The interim analysis 
of PFS will occur when approximately 263 PFS 
events are observed.  If the interim analysis 
crosses the boundary, the trial may stop early 
for efficacy; otherwise subjects will be followed 
for disease and survival status until approximately 
350 PFS events are observed or by end of year 
2018, whichever is earlier. 
Statistical revision to align 
with change in primary 
objective/endpoint and 
purpose and timing of the 
interim PFS analysis. 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 137 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: after Section 4.4 
ESTMATED STUDY 
DURATION AND CLOSURE 
 
Add: 
4.4.1 
END OF STUDY 
Primary Completion: The primary completion 
date is defined as the date when the last 
subject is assessed or receives an intervention 
for the final collection of data for the primary 
endpoint(s), for the purposes of conducting the 
primary analysis, whether the study concluded 
as planned in the protocol or was terminated 
early.   
The primary completion is anticipated to occur 
when approximately 350 PFS events occur or 
end of year 2018, whichever is earlier.  The 
primary completion date is the date when data 
for the primary endpoint are last collected for 
the purposes of conducting the primary 
analysis or the end of year 2018, whichever is 
earlier.   
If the study concludes prior to the primary 
completion date originally planned in the 
protocol (i.e., 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 (i.e., 
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 (i.e., last subject last 
visit), following any additional parts in the 
study (e.g., long-term follow-up), as applicable. 
Addition of section for end 
of study definition 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 138 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: after 8.3 STUDY 
DRUG ACCOUNTABILITY 
 
Add: 
8.4 
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.   
Any product complaint(s) associated with an 
investigational product(s) or 
non-investigational product(s) or device(s) 
supplied by Amgen are to be reported 
according to the instructions provided in the 
IPIM. 
Addition of instructions for 
reporting product 
complaints 
Section: 9.3.1.2 
Nonhematologic Toxicity, 
Table 5 Carfilzomib Dose 
Modifications for 
Nonhematologic Toxicity 
Replace: 
Original Table 5 below 
With: 
Revised Table 5 below 
Update of guidelines 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 139 of 165 
Original Table 5: 
 
Nonhematologic Toxicity 
Required Actiona 
Renal Dysfunction 
• 
Serum creatinine ≥ 2 × 
baseline, OR 
• 
CrCl < 15 mL/min, OR  
• 
CrCl decreases to ≤ 50% 
of baseline, OR 
• 
Requirement for dialysis 
• Withhold doses while the cause of renal dysfunction is being 
assessed 
• If attributable to carfilzomib, resume at 1 dose decrement when CrCl 
has recovered to within 25% of baseline 
• If not attributable to carfilzomib, resume the same dose or reduce by 
1 dose decrement, at the investigator’s discretion, when CrCl has 
recovered to within 25% of baseline 
• For patients on dialysis receiving carfilzomib, the dose is to be 
administered after the dialysis procedure 
Hepatic Dysfunction 
• ≥ Grade 3 Elevations of 
AST, ALT, or total 
bilirubin 
• Withhold doses.   
• Resume at 1 dose decrement when the grade has returned to baseline 
Infection 
• ≥ Grade 3 Infection 
• Withhold doses 
• Resume at the same dose level, when the infection is controlled 
Cardiovascular Dysfunction 
• Congestive Heart Failure 
• Withhold doses for any subject with symptomatic heart failure, 
whether or not it is attributed to carfilzomib 
• Resume at 1 dose decrement, when symptoms have resolved or 
returned to baseline 
• LVEF < 40%, OR 
• LVEF < 55%, if decreased 
> 20% from baseline 
• Withhold doses 
• Resume at 1 dose decrement, when LVEF returns to ≥ 40%, or to 
within 15% of baseline, if carfilzomib was held due to a drop to 
< 55% 
• Pulmonary Hypertension 
• Withhold doses and assess the benefit: risk of resuming carfilzomib 
• If the assessment favors benefit, carfilzomib may be resumed at the 
same dose level or at 1 dose decrement, at the investigator’s 
discretion 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 140 of 165 
Nonhematologic Toxicity 
Required Actiona 
Thrombotic Microangiopathy 
• Thrombotic 
thrombocytopenic 
purpura/hemolytic uremic 
syndrome (TTP/HUS) 
• Withhold doses when TTP/HUS is suspected 
• If the diagnosis is excluded, resume at the same dose level 
• If the diagnosis is confirmed, the decision to resume or not resume 
carfilzomib is at the investigator’s discretion.  The safeness of 
resuming carfilzomib following TTP/HUS is unknown. 
• Manage symptoms per standard of care including, plasma exchange as 
clinically indicated b 
Encephalopathy 
• Posterior reversible 
encephalopathy syndrome 
(PRES) 
• Withhold doses and assess the benefit:risk of resuming carfilzomib 
• Consider evaluation with neuroradiological imaging for onset of 
visual or neurological symptoms suggestive of PRES 
• If the diagnosis is excluded, resume at the same dose level 
• If the diagnosis is confirmed, the decision to resume or not resume 
carfilzomib is at the investigator’s discretion.  The safeness of 
resuming carfilzomib following PRES is unknown. 
Other Nonhematologic Toxicity 
• ≥ Grade 3 and attributed to 
carfilzomib 
• Withhold doses 
• Resume at 1 dose decrement, when toxicity has resolved to Grade ≤ 2 
or to baseline 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 141 of 165 
Revised Table 5: 
 
Nonhematologic Toxicity 
Required Actiona 
Renal Dysfunction 
• 
Serum creatinine ≥ 2 × 
baseline, OR 
• 
CrCl < 15 mL/min, OR  
• 
CrCl decreases to ≤ 50% 
of baseline, OR 
• 
Requirement for dialysis 
• Withhold doses while the cause of renal dysfunction is being 
assessed 
• If attributable to carfilzomib, resume at 1 dose decrement when CrCl 
has recovered to within 25% of baseline 
• If not attributable to carfilzomib, resume the same dose or reduce by 
1 dose decrement, at the investigator’s discretion, when CrCl has 
recovered to within 25% of baseline 
• For patients on dialysis receiving carfilzomib, the dose is to be 
administered after the dialysis procedure 
Hepatic Dysfunction 
• Mild to moderate liver 
dysfunction: defined as 
2 consecutive values, at 
least 28 days apart, of: 
(3) Total bilirubmin 
(> 33% direct) 
> 1 x ULN to 
< 3 x ULN 
OR 
(4) An elevation of 
AST and/or ALT 
with normal 
bilirubin 
• 25% dose reduction. 
• Dose may be re-escalated if liver function tests return to normal 
and drug-induced hepatotoxicity is excluded. 
• Grade 3 elevation in ALT 
and/or AST (> 5 x ULN) 
• Hold carfilzomib until resolution to baseline. 
• Monitor any abnormality weekly.  Resume carfilzomib with a 
25% dose reduction if drug-induced hepatoxicity is excluded. 
• Grade 3 elevation in total 
bilirubin 
• Hold carfilzomib until resolution to baseline.  Monitor total 
bilirubin and direct bilirubin weekly. 
• Upon resolution of total bilirubin to normal, resume carfilzomib 
dosing with at 25% dose reduction if drug-induced 
hepatotoxicity is excluded. 
• Drug-induced 
hepatoxicity attributable 
to carfilzomib 
• Discontinue carfilzomib. 
Infection 
• ≥ Grade 3 Infection 
• Withhold doses 
• Resume at the same dose level, when the infection is controlled 
Cardiovascular Dysfunction 
• Congestive Heart Failure 
• Withhold doses for any subject with symptomatic heart failure, 
whether or not it is attributed to carfilzomib 
• Resume at 1 dose decrement, when symptoms have resolved or 
returned to baseline 
• LVEF < 40%, OR 
• LVEF < 55%, if decreased 
> 20% from baseline 
• Withhold doses 
• Resume at 1 dose decrement, when LVEF returns to ≥ 40%, or to 
within 15% of baseline, if carfilzomib was held due to a drop to 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 142 of 165 
Nonhematologic Toxicity 
Required Actiona 
< 55% 
• ≥ Grade 2 Pulmonary 
Hypertension 
• Withhold doses  
• Carfilzomib may be resumed at 1 dose decrement when pulmonary 
hypertension resolves to grade ≤ 1 
Thrombotic Microangiopathy 
• Thrombotic 
thrombocytopenic 
purpura/hemolytic uremic 
syndrome (TTP/HUS) 
• Withhold doses when TTP/HUS is suspected 
• If the diagnosis is excluded, resume at the same dose level 
• If the diagnosis is confirmed, discontinue carfilzomib.  Subjects 
should not be rechallenged. 
• Manage symptoms per standard of care including, plasma exchange as 
clinically indicated b 
Venous Thrombosis 
• ≥ Grade 3 
• 
Hold carfilzomib and adjust anticoagulation regimen. 
• 
Resume at full dose once anticoagulation has been optimized per 
treating investigator’s discretion. 
Encephalopathy 
• Posterior reversible 
encephalopathy syndrome 
(PRES) 
• Withhold doses  
• Consider evaluation with neuroradiological imaging for onset of 
visual or neurological symptoms suggestive of PRES 
• If the diagnosis is excluded, resume at the same dose level 
• If the diagnosis is confirmed, discontinue carfilzomib.  Subjects 
should not be rechallenged. 
Other Nonhematologic Toxicity 
• ≥ Grade 3 and attributed to 
carfilzomib 
• Withhold doses 
• Resume at 1 dose decrement, when toxicity has resolved to Grade ≤ 2 
or to baseline 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 143 of 165 
 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 9.4.1.2  Pregnancy and 
Contraception, Line 1 
Replace: 
Contraception must continue during study drug 
dose interruption intervals until 30 days (females) 
or 90 days (males) after the last study drug 
administration. 
With: 
Contraception must continue during study, 
during drug dose interruption intervals, and until 
30 days (females) or 90 days (males) after the last 
study drug administration. 
Edit 
Section: after Section 9.4.2.4 
 
Add: 
9.4.2.5 Thromboprophylaxis 
Venous thromboembolism has been observed 
in patients receiving carfilzomib.  
Thromboprophylaxis may be considered on 
the basis of a benefit-risk assessment. 
Addition of language for 
thromboprophylaxis 
Section: 12.4 SERIOUS 
ADVERSE EVENT 
REPORTING AND 
DOCUMENTATION 
REQUIREMENTS, 
Paragraph 1, Line 2 
Replace: 
The SAE will be reported by completing and 
submitting the SAE report form through the EDC 
system.  In the event that the EDC system is not 
available, paper SAE report forms may be used to 
report the SAE to Amgen Global Patient Safety. 
With: 
The SAE will be reported by completing and 
submitting the SAE report form through the EDC 
system.  In the event that the EDC system is not 
available, paper SAE report forms may be used to 
report the SAE to Amgen Global Patient Safety 
(Appendix L). 
Administrative addtion 
Section: 12.5 PREGNANCY 
AND LACTATION 
EXPOSURE REPORTING, 
Paragraph 1, Line 4 
Replace: 
The pregnancy will be reported on a Pregnancy 
Notification Worksheet. 
With: 
The pregnancy will be reported on a Pregnancy 
Notification Worksheet (Appendix M). 
Administrative addition 
Section: 12.5 PREGNANCY 
AND LACTATION 
EXPOSURE REPORTING, 
Paragraph 6, Line 6 
Replace: 
The investigator will complete a Lactation 
Notification Worksheet. 
With: 
The investigator will complete a Lactation 
Notification Worksheet (Appendix N). 
Administrative addition 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 144 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 13.1.1 PRIMARY 
ENDPOINTS 
Replace: 
The primary endpoint is ORR, which is defined 
as the proportion of subjects who achieved a 
confirmed PR, VGPR, CR, or sCR according to 
the IMWG URC. 
With: 
The primary endpoint is PFS, which is defined as 
the time in months from randomization to the 
earlier of disease progression or death due to 
any cause. 
Primary/secondary 
endpoint switch 
Section: 13.1.2 SECONDARY 
ENDPOINTS, Bullet 1 
Replace: 
• 
PFS, defined as the time in months from 
randomization to the earlier of disease 
progression or death due to any cause. 
With: 
• 
ORR, defined as the proportion of 
subjects who achieved a confirmed 
PR, VGPR, CR, or sCR, according to 
the IMWG-URC. 
Primary/secondary 
endpoint switch 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 145 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 13.3.2.1 Primary 
Efficacy Endpoint, Paragraphs 
1-2 
Replace: 
The primary efficacy endpoint is ORR.  The data 
cutoff date for the analysis of ORR is about 4 
months after the last subject is randomized 
(approximately 19 month after the first subject 
was randomized).  The inferential comparison of 
ORR between treatment groups will be made 
using a logistic regression model-based test 
against the null hypothesis that the odds ratio is 
≤ 1 at a 1-sided significance level of 0.025.  The 
regression model will include the randomization 
stratification factors as covariates: 
• 
ISS stage at study entry (Stage 1 versus 
Stage 2 and 3) 
• 
Refractory to bortezomib treatment (Yes 
versus No) 
• 
Age (< 65 versus ≥ 65 years) 
The ORR will be calculated by treatment group 
and the associated 95% CI will be estimated using 
the Clopper Pearson method.  The odds ratio (and 
its 95% CI) will be estimated using the logistic 
regression model. 
With: 
The primary efficacy endpoint is PFS.  
Progression-free survival will be calculated 
from the time of randomization until disease 
progression or death due to any cause, 
whichever occurs first.  If a subject is alive or 
lost to follow-up without experiencing 
documented disease progression by the data 
cutoff date, the PFS data for the subject will be 
censored at the date of last valid disease and 
response assessment.  Detailed PFS data 
censoring rules will be described in the SAP. 
The distribution of PFS, including median, will 
be estimated using the Kaplan-Meier method.  
Progression-free survival rates at selected time 
points will be reported by treatment group.  
The 95% CI for the median and other 
percentiles of PFS will be constructed using 
the method of Klein and Moeschberger (1997) 
with log-log transformation.  The 95% CIs for 
PFS rates were estimated using the method by 
Kalbfleisch and Prentice (1980) with log-log 
transformation.  The inferential comparison 
between treatment groups will be made using 
the log-rank test stratified by the 
randomization stratification factors specified 
in Section 7.  The hazard ratio (HR) and its 
95% CI will be estimated using a Cox 
proportional hazards model stratified by the 
same randomization stratification factors.  
Duration of follow up for PFS will be 
estimated using the reverse Kaplan-Meier 
method (Schemper 1996; Smith 2006). 
Statistical revision to align 
with primary 
objective/endpoint change 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


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Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 147 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 13.3.2.1 Primary 
Efficacy Endpoint, Paragraph 4 
Delete: 
The duration of response (DOR), defined as time 
in months from the start date of the response to 
the earlier date of documented PD or death, will 
be calculated for subjects who achieve sCR, CR, 
VGPR, or PR.  The DOR will be censored at date 
of the last valid assessment for responders who 
have not experienced PD or death.  The 
distribution of DOR, including the median will be 
estimated using the Kaplan-Meier method based 
on the subjects who achieve overall response. 
 
Statistical revision to align 
with primary 
objective/endpoint change 
 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 148 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 13.3.2.2.1 
Progression-Free Survival 
Replace: 
Progression-Free Survival 
The distribution of PFS, including median, will 
be estimated using the Kaplan-Meier method. 
Progression-free survival rates at selected time 
points will be reported by treatment group.  The 
95% CI for the median and other percentiles of 
PFS will be constructed using the method of 
Klein and Moeschberger (1997) with log-log 
transformation.  The 95% CIs for PFS rates were 
estimated using the method by Kalbfleisch and 
Prentice (1980) with log-log transformation.  The 
inferential comparison between treatment groups 
will be made using the log-rank test stratified by 
the randomization stratification factors specified 
in Section 7.  The HR and its 95% CI will be 
estimated using a Cox proportional hazards model 
stratified by the same randomization stratification 
factors.  Duration of follow-up for PFS will be 
estimated using the reverse Kaplan-Meier method 
(Schemper 1996; Smith 2006). 
The primary analysis of PFS will be based on 
ORCA-assessed outcomes.  The PFS outcomes 
assessed by the investigator serve as a supportive 
analysis of PFS, as will IRC-assessed outcomes, 
if an IRC is convened. 
 
With: 
Overall Response Rate 
The ORR will be analyzed at the time of the 
PFS analysis (interim or final), only if the PFS 
analysis crosses the boundary.  The inferential 
comparison of ORR between treatment groups 
will be made using a logistic regression 
model-based test against the null hypothesis 
that the odds ratio is ≤ 1 at a 1-sided 
significance level of 0.025.  The regression 
model will include the randomization 
stratification factors as covariates.  The ORR 
will be calculated by treatment group and the 
associated 95% CI will be estimated using the 
Clopper-Pearson method.  The odds ratio (and 
its 95% CI) will be estimated using the logistic 
regression model.   
The primary analysis of ORR will be based on 
the ORCA-assessed responses.  Investigator 
assessed responses will be analyzed as a 
supportive analysis of ORR, as will 
IRC-assessed responses.  
 
Statistical revision to align 
with primary and 
secondary 
objective/endpoint switch 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


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Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 150 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 13.3.2.2.2 Overall 
Survival, Paragraph 3 
Replace: 
Final analysis of OS will occur at the time of final 
PFS analysis.  Under the assumptions that the 
accrual will take about 15 months and the median 
OS is 14 months in the twice weekly dosing 
group and 17 months in the once-weekly dosing 
group (HR = 0.82), it is estimated that 
approximately 245 deaths will be observed at the 
time of the final PFS analysis (approximately 
25 months after the first subject randomized).  An 
interim analysis of OS will occur at the time of 
ORR analysis.  The details of OS interim analysis 
are in Section 13.8. 
Add: 
The analysis of OS will be conducted at the 
time of the PFS analysis (interim or final), only 
if both PFS and ORR analyses are positive, per 
hierarchical testing procedures.  There will be 
no interim analysis for OS.  Additional 
follow-up for OS may be performed. 
Statistical revision to align 
with primary 
objective/endpoint change 
and addition of language to 
allow for possible 
long-term follow-up for 
OS. 
 
Section: 13.3.2.3 Control of 
Family-wise Type I Error Rate 
Replace: 
The hypotheses for the primary efficacy endpoint, 
ORR, and secondary efficacy endpoints (PFS and 
OS) will be tested using a fixed sequence 
hierarchical testing procedure to control the 
family-wise Type I Error rate below 1-sided 
0.025 level.  The family of hypotheses is ordered 
as follows: 1) ORR, 2) PFS, and 3) OS.  Starting 
with the hypothesis of ORR, if any hypothesis in 
the sequence is rejected at a 1-sided significance 
level of 0.025, then the subsequent hypothesis 
will be tested; if any hypothesis is accepted, then 
the subsequent hypotheses will not be tested. 
Add: 
The null hypotheses for the primary efficacy 
endpoint, PFS, and secondary efficacy endpoints 
(ORR and OS) will be tested using a fixed 
sequence hierarchical testing procedure to control 
the family-wise Type I Error rate below 1-sided 
0.025 level.  The family of hypotheses is ordered 
as follows: 1) PFS, 2) ORR, and 3) OS.  Starting 
with the hypothesis of PFS, if any hypothesis in 
the sequence is rejected at a 1-sided significance 
level of 0.025, then the subsequent hypothesis 
will be tested; if any hypothesis is accepted, then 
the subsequent hypotheses will not be tested. 
Statistical revision to align 
with primary and 
secondary 
objective/endpoint switch 
 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


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Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 152 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 13.6 INDEPENDENT 
REVIEW COMMITTEE 
Replace: 
An IRC may be convened for this study, if 
required to support the ORCA-determined results. 
With: 
An IRC will be convened for this study to support 
the ORCA-determined results.  The IRC will 
centrally review the disease-related tests and 
assessments (Section 10.2) to evaluate disease 
progression and responses without knowledge 
of the randomization assignments.  The details 
of the IRC, including the roles and 
responsibilities of the involved parties, will be 
described in the IRC Charter. 
Clarification 
Section: 13.7 DATA 
MONITORING COMMITTEE, 
Paragraph 4 
Replace: 
The DMC will meet to review safety data on a 
periodic basis, including after approximately 
40 subjects have completed ≥ 1 cycle and no less 
frequently than approximately every 6 months 
thereafter.  Unplanned safety review meetings of 
the DMC may be called at any time, if warranted, 
for an earlier review of safety data. 
With: 
The DMC will meet to review safety data on a 
periodic basis, including after approximately 
40 subjects have completed ≥ 1 cycle and no less 
frequently than approximately every 6 months 
thereafter.  Unplanned safety review meetings of 
the DMC may be called at any time, if warranted, 
for an earlier review of safety data.  The DMC 
will also review the interim PFS analysis 
results and recommend whether the study 
should stop early for efficacy. 
Revision to align with 
primary objective/endpoint 
change 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 153 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 13.8 INTERIM 
ANALYSIS, Paragraphs 2-3 
Replace: 
One interim analysis will be conducted for PFS 
and OS at the time of the analysis of ORR, which 
is expected to occur approximately 19 months 
after the first subject is randomized.  It is 
estimated that approximately 262 (75% of total 
350) PFS events and 171 OS events will be 
observed at the interim analysis.  The primary 
objective of the interim analysis of PFS and OS is 
to provide necessary data to help assess the 
results from the analysis of the primary endpoint 
ORR, and it is intended that all subjects will 
continue to be followed for disease assessment 
and survival status until 350 PFS events are 
observed, given a positive result of the ORR 
analysis. 
To ensure proper control of type I error rate, the 
interim and final analysis of PFS and OS will be 
analyzed under a group sequential design 
framework with the stopping boundaries 
constructed using the alpha-spending function 
approach.  Based on the objective of the interim 
analysis and the considerations above, a 1-sided 
error level of 0.0001 is assigned to the interim 
analysis and the remaining 1-side error level of 
0.0249 is reserved for the final analysis.  The 
stopping boundaries are calculated using East 5.4 
and presented in Table 12. 
With: 
One interim analysis will be conducted for PFS 
when approximately 263 (75% of total 350) PFS 
events are observed.  The objective of the interim 
analysis is to monitor for differences between 
treatment arms for evidence of a substantial 
benefit in the carfilzomib once-weekly with 
dexamethasone arm. 
To ensure proper control of type I error rate, the 
interim and final analysis of PFS will be analyzed 
under a group sequential design framework with 
the stopping boundaries constructed using the 
O’Brien-Fleming type alpha-spending function 
approach.  The stopping boundaries in an 
example scenario are calculated using East 6.4 
and presented in Table 12.  Actual boundaries 
will be calculated on the basis of observed PFS 
events up to the data cut-off date for the 
interim analysis.  If the DMC recommends to 
stop the study for efficacy after reviewing the 
interim analysis results, the sponsor will 
consider stopping the trial and conclude that 
the carfilzomib once-weekly with 
dexamethasone arm prolongs PFS compared 
to the carfilzomib twice-weekly with 
dexamethasone arm. 
 
Clarification and statistical 
revision to align with 
primary objective/endpoint 
change 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


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CCI


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 155 of 165 
 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 16 REFERENCES, 
Reference 19 
Move order to after Reference 20 
 
Minor edit 
Section: APPENDIX L 
SUMMARY OF CHANGES 
FOR AMENDMENT 3 
Delete Appendix L 
 
Administrative  
Section: after APPENDIX K 
COUNTRY-SPECIFIC 
PREGNANCY AND 
CONTRACEPTIVE 
SUPPLEMENT 
 
Add: 
APPENDIX L SAMPLE SERIOUS 
ADVERSE EVENT REPORT FORM (shown 
below) 
Addition of Sample Serious 
Adverse Event Report 
Form 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 156 of 165 
APPENDIX L 
SAMPLE SERIOUS ADVERSE EVENT REPORT FORM 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 157 of 165 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 158 of 165 
 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 159 of 165 
 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 160 of 165 
 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 161 of 165 
 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: after APPENDIX K 
COUNTRY-SPECIFIC 
PREGNANCY AND 
CONTRACEPTIVE 
SUPPLEMENT 
 
Add: 
APPENDIX M PREGNANCY 
NOTIFICATION FORM (shown below) 
Addition of Pregnancy 
Notification Form 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 162 of 165 
APPENDIX M 
PREGANCY NOTIFICATION FORM 
 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 163 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: after APPENDIX K 
COUNTRY-SPECIFIC 
PREGNANCY AND 
CONTRACEPTIVE 
SUPPLEMENT 
 
Add: 
APPENDIX N LACTATION 
NOTIFICATION FORM (shown below) 
Addition of Lactation 
Notification Form 
 
 
 
Superseding Amendment 4: 07 March 2017 
 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 164 of 165 
APPENDIX N 
LACTATION NOTIFICATION FORM 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 165 of 165 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: after APPENDIX K 
COUNTRY-SPECIFIC 
PREGNANCY AND 
CONTRACEPTIVE 
SUPPLEMENT 
 
Add: 
APPENDIX O SUMMARY OF CHANGES 
FOR PROTOCOL AMENDMENT 4 AND 
SUPSERSEDING PROTOCOL 
AMENDMENT 4 
Addition of Summary of 
Changes for Protocol 
Amendment 4 and 
Superseding Protocol 
Amendment 4 
 
 
 
Superseding Amendment 4: 07 March 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 119 of 164 
APPENDIX O 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 4 
Protocol Title:  A Randomized, Open-label, Phase 3 Study in Subjects with Relapsed 
and Refractory Multiple Myeloma Receiving Carfilzomib in Combination with 
Dexamethasone, Comparing Once-weekly versus Twice-weekly Carfilzomib Dosing 
 
Amgen Protocol Number 20140355 (formerly CFZ014) 
 
Amendment Date: 
08 February 2017 
Rationale: 
The protocol is amended to: 
• Switch progression-free survival (PFS) from a key secondary objective/endpoint 
to the primary objective/endpoint and overall response rate (ORR) from the 
primary objective/endpoint to a key secondary objective/endpoint 
Rationale: This study was originally designed with ORR as the primary endpoint 
because response rates, especially high-quality responses of substantial duration, 
are important indicators of benefit in relapsed and refractory multiple myeloma.  
However, recent advances in antimyeloma therapy have altered the landscape 
such that PFS is now considered to be the more relevant regulatory endpoint in 
this setting.  To support regulatory interactions and protect the integrity of the 
PFS data, the primary endpoint has been amended to PFS, with ORR as a key 
secondary endpoint. 
• Change the purpose and timing of the interim PFS analysis 
Rationale: The purpose and timing of the interim PFS analysis were amended to 
monitor efficacy and allow the possibility of stopping the trial early for efficacy. 
• Revise statistical language to align with changes in objectives/endpoints and 
purpose and timing of the interim PFS analysis 
• Update Table 12 (Stopping Boundaries for Progression-free Survival) 
• Allow the possibility for long-term follow-up for overall survival 
• Add Section 4.4.1 (End of Study) 
• Add Section 8.4 (Product Complaints) 
• Update Table 5 (Carfilzomib Dose Modifications for Nonhematologic Toxicity) 
• Add Section 9.4.2.5 (Thromboprophylaxis) 
• Add the following forms in the Appendices 
Amendment 4: 08 February 2017 
 
CONFIDENTIAL 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 120 of 164 
o Sample Serious Adverse Event Report Form 
o Pregnancy Notification Form 
o Lactation Notification Form 
• Update Section 2 (Background Information) 
• Make minor text clarifications, additions, corrections, and edits throughout the 
protocol 
Amendment 4: 08 February 2017 
 
CONFIDENTIAL 


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Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 111 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: Protocol Acceptance Page 
Replace: 
Protocol Amendment 2.0 
With: 
Protocol Amendment 3.0 
Administrative change 
Section: Protocol Acceptance Page 
Replace: 
28 April 2015 
With: 
22 April 2016 
Administrative change 
Section: Synopsis, Study Objectives, 
primary objective 
Replace: 
To compare the overall response 
rate (ORR) between once-weekly 
carfilzomib dosing in combination 
with dexamethasone to 
twice-weekly carfilzomib dosing 
in combination with 
dexamethasone in subjects with 
relapsed and refractory multiple 
myeloma who have received prior 
treatment with bortezomib and an 
IMiD (immunomodulatory agent). 
With: 
To compare the overall response rate (ORR) 
of once-weekly carfilzomib dosing in 
combination with dexamethasone to the 
ORR of twice-weekly carfilzomib dosing in 
combination with dexamethasone in subjects 
with relapsed and refractory multiple 
myeloma who have received prior treatment 
with a proteasome inhibitor and an IMiD 
(immunomodulatory agent). 
Revised text for consistency within 
overall protocol 
Section: Synopsis, Study Design, 
paragraph 1, sentence 1 
Replace: 
This is an open-label, multicenter, 
randomized Phase 3 study 
comparing carfilzomib dosing in 
combination with dexamethasone 
administered once-weekly to 
twice-weekly carfilzomib dosing 
in combination with 
dexamethasone in subjects with 
relapsed and refractory multiple 
myeloma, previously treated with 
bortezomib and an (IMiD). 
With: 
This is an open-label, multicenter, 
randomized Phase 3 study comparing 
carfilzomib dosing in combination with 
dexamethasone administered once-weekly to 
twice-weekly carfilzomib dosing in subjects 
with relapsed and refractory multiple 
myeloma, previously treated with a 
proteasome inhibitor and an (IMiD). 
Revised text for consistency within 
overall protocol 
Section: Synopsis, Study Design, 
paragraph 2, bullet 1 
Replace: 
• The International Staging 
With: 
• The International Staging System (ISS) 
Revised text for clarification 


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Section   
Text in Protocol  
Amended Text  
Rationale for Change 
System (ISS) at study entry 
(Stage 1 versus Stage 2 or 3) 
at study entry (Stage 1 versus Stage 2 or 
3) per International Myeloma 
Working Group (Greipp 2005). See 
Appendix H 
Section: Synopsis, Study Design, 
paragraph 6, sentences 1 and 2 
Replace: 
Subjects will be assessed for 
response using central laboratory 
results on Day 1 of each cycle.   
With: 
Subjects will be assessed for response using 
central laboratory results every 28 days (± 
4 days). 
Updated text for disease assessment 
timepoints to align with other 
sections in protocol 
Section: Synopsis, Study Design, 
paragraph 6, sentence 3 
Replace: 
For subjects who discontinue 
treatment before disease 
progression occurred (such as for 
an adverse event, noncompliance, 
etc.), disease response assessments 
will be performed using central 
laboratory response every 4 weeks 
until disease progression. 
With: 
For subjects who discontinue treatment 
before disease progression occurred (such as 
for an adverse event, noncompliance, etc.), 
disease response assessments will be 
performed using central laboratory response 
every 28 days until disease progression. 
Updated text for disease assessment 
timepoints to align with other 
sections in protocol 
Section: Synopsis, Study Design, 
paragraph 6, sentences 1 and 2 
Replace: 
Follow-up for survival will 
continue approximately every 
3 months, or as needed, for all 
surviving subjects until study 
closure. 
With: 
Follow-up for survival will continue 
approximately every 12 weeks ±28 days, or 
as needed, for all surviving subjects until 
study closure. 
Updated text for disease assessment 
timepoints to align with other 
sections in protocol 
Section: Synopsis, Number of 
investigational sites, 4.2 Number of 
Centers 
Replace: 
Approximately 120 sites 
worldwide 
With: 
Approximately 150 sites worldwide 
Updated number of sites to include 
potential New Zealand and Australian 
sites 
Section: Synopsis, Treatment Regimen, 
paragraph 1, sentence 2 
Replace: 
Carfilzomib and dexamethasone 
will be administered in 28-day 
cycles in 1 of 2 treatment 
With: 
Carfilzomib and dexamethasone will be 
administered in 28-day cycles in 1 of 
2 treatment regimens.  All cycles will start 
Revised text for consistency within 
overall protocol 


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Section   
Text in Protocol  
Amended Text  
Rationale for Change 
regimens.  All cycles will start 
28 days (± 2) after the start of the 
prior cycle. 
28 days (± 2 days) after the start of the prior 
cycle. 
Section: Synopsis, Subject Selection, 
sentence 1, 5. Subject Selection, sentence 
1 
Replace: 
Approximately 460 subjects will 
be enrolled in this study. 
With: 
Approximately 460 subjects will be 
randomized in this study. 
Administrative change 
Section: Synopsis, Inclusion and 
Exclusion Criteria, 5.1 Inclusion Criteria, 
5.2 Exclusion Criteria 
Replace: 
Criteria Numbers 1 ,2 ,3…… 
With: 
Criteria Numbers 101, 102, 103……. 
Administrative change 
Section: Synopsis, Inclusion Criteria, 
criterion 104 a, 5.1 Inclusion Criteria, 
criterion 104 a 
Replace: 
a. Nonresponsive to most recent 
therapy (stable disease only or 
progressive disease [PD] while on 
treatment), or 
With: 
a. Nonresponsive to most recent therapy 
(stable disease or progressive disease [PD] 
while on treatment), or 
Administrative change 
Section: Synopsis, Inclusion Criteria, 
criterion 105, 5.1 Inclusion Criteria, 
criterion 105 
Replace: 
105. At least 2 but no more than 3 
prior therapies for multiple 
myeloma 
With: 
105. At least 2, but no more than 3, prior 
lines of therapy for multiple myeloma 
Revised text for clarification 
Section: Synopsis, Inclusion Criteria, 
criterion 108, 5.1 Inclusion Criteria, 
criterion 108 
Replace: 
108. Documented response of at 
least partial response (PR) to 1 
line of prior therapy 
With: 
108. Documented response of at least partial 
response (PR) to at least 1 prior line of 
therapy 
Revised text for clarification 
Section: Synopsis, Inclusion Criteria, 
criterion 109, 5.1 Inclusion Criteria, 
criterion 109 
Replace: 
109. Measureable disease with at 
least 1 of the following assessed 
within 21 days prior to 
randomization: 
With: 
109. Measurable disease, with at least 1 of 
the following assessed at a central 
laboratory within the 21 days prior to 
randomization: 
Revised text for consistency within 
overall protocol 
Section: Synopsis, Inclusion Criteria, 
criterion 109 c, 5.1 Inclusion Criteria, 
Replace: 
c. In subjects without detectable 
With: 
c. In subjects without measurable serum or 
Revised text for clarification 


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Section   
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Rationale for Change 
criterion 109 c 
serum or urine M-protein, serum 
free light chain (SFLC) 
≥ 100 mg/L (involved light chain) 
and an abnormal serum kappa 
lambda ratio 
urine M-protein, serum free light chain 
(SFLC) ≥ 100 mg/L (involved light chain) 
and an abnormal serum kappa lambda ratio 
Section: Synopsis, Inclusion Criteria, 
criterion 112, 5.1 Inclusion Criteria, 
criterion 112 
Replace: 
112. Adequate organ and bone 
marrow function within the 
21 days prior to randomization 
defined by: 
With: 
112. Adequate organ and bone marrow 
function performed at a central laboratory 
within the 21 days prior to randomization 
defined by: 
Revised text for consistency within 
overall protocol 
Section: Synopsis, Inclusion Criteria, 
criterion 112 c, 5.1 Inclusion Criteria, 
criterion 112 c 
Replace: 
c. Absolute neutrophil count 
(ANC) ≥ 1000/mm3 (screening 
ANC should be independent of 
growth factor support for 
≥ 1 week) 
With: 
c. Absolute neutrophil count (ANC) ≥ 1 
× 109/L (screening ANC must be 
independent of growth factor support for 
≥ 7 days) 
Revised text for consistency within 
overall protocol 
Section: Synopsis, Inclusion Criteria, 
criterion 112 d, 5.1 Inclusion Criteria, 
criterion 112 d 
Replace: 
d. Hemoglobin ≥ 8.0 g/dL (Use of 
erythropoietic stimulating factors 
and red blood cell [RBC] 
transfusion per institutional 
guidelines is allowed, however the 
most recent RBC transfusion may 
not have been done within 7 days 
prior to obtaining screening 
hemoglobin.) 
With: 
d. Hemoglobin ≥ 8 g/dL (Use of 
erythropoietic stimulating factors and red 
blood cell [RBC] transfusions per 
institutional guidelines are allowed, 
however the most recent RBC transfusion 
may not have been done within 7 days prior 
to obtaining the screening hemoglobin.) 
Administrative change 
Section: Synopsis, Inclusion Criteria, 
criterion 112 e, 5.1 Inclusion Criteria, 
criterion 112 e 
Replace: 
e. Platelet count ≥ 50,000/mm3 
(≥ 30,000/mm3 if myeloma 
involvement in the bone marrow is 
> 50%.  Subjects should not have 
With: 
e. Platelet count ≥ 50,000/mm3 
(≥ 30,000/mm3 if myeloma involvement in 
the bone marrow is > 50%.  Subjects must 
not have received platelet transfusions for at 
Revised text for consistency within 
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Text in Protocol  
Amended Text  
Rationale for Change 
received platelet transfusions for 
at least 1 week prior to obtaining 
the screening platelet count.) 
least 7 days prior to obtaining the screening 
platelet count.) 
Section: Synopsis, Inclusion Criteria, 
criterion 112 f, 5.1 Inclusion Criteria, 
criterion 112 f 
Replace: 
f. Calculated or measured 
creatinine clearance (CrCl) of 
≥ 30 mL/min.  Calculation should 
be based on the Cockcroft and 
Gault formula:   
[(140 – Age) × Mass (kg) / (72 × 
Creatinine mg/dL)]; multiply 
result by 0.85 if female 
With: 
f. Calculated or measured creatinine 
clearance (CrCl) of ≥ 30 mL/min.  
Calculation must be based on the Cockcroft 
and Gault formula:   
[(140 – Age) × Mass (kg) / (72 × 
Creatinine mg/dL)]; multiply result by 0.85 
if female 
Revised text for clarification 
Synopsis: Synopsis, Inclusion Criteria, 
criterion 113, 5.1 Inclusion Criteria, 
criterion 113 
Replace: 
113. Females of childbearing 
potential (FCBP) must have a 
confirmed negative serum 
pregnancy test within the 21 days 
prior to randomization (performed 
at a central laboratory) 
With: 
113. Females of childbearing potential 
(FCBP) must have a confirmed negative 
serum pregnancy test performed at a central 
laboratory, within the 21 days prior to 
randomization, and must not be 
breastfeeding. 
Revised text for consistency within 
overall protocol 
Synopsis: Synopsis, Inclusion Criteria, 
criterion 114, 5.1 Inclusion Criteria, 
criterion 114 
Replace: 
14. Females of childbearing 
potential and male subjects who 
are sexually active with FCBP 
must agree to use effective 
concomitant method(s) of 
contraception during the study and 
for 30 days following the last 
study drug treatment 
administration. 
With: 
114. Females of childbearing potential must 
agree to use highly effective concomitant 
method(s) of contraception during the study 
and for 30 days following the last study drug 
treatment administration.  (Refer to 
Appendix K for specific contraception 
requirements.) 
Revised to distinguish female and 
male contraceptive guidance 
Synopsis: Synopsis, Inclusion Criteria, 
criterion 115, 5.1 Inclusion Criteria, 
 
Add: 
115. Male subjects who are sexually active 
Updated text to align with current 
carfilzomib core safety language 


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Rationale for Change 
criterion 115 
with a FCBP must agree to use condoms 
(unless they have had a vasectomy with 
medical confirmation of surgical success), 
during treatment and for an additional 90 
days following the last study drug 
administration. 
Synopsis: Synopsis, Inclusion Criteria, 
criterion 116, 5.1 Inclusion Criteria, 
criterion 116 
 
Add: 
116. Male subjects must agree to not 
donate sperm during treatment and for 
an additional 90 days following the last 
study drug administration. 
Updated text to align with current 
carfilzomib core safety language 
Synopsis: Synopsis, Exclusion Criteria, 
criterion 208, 5.2 Exclusion Criteria, 
criterion 208 
Replace: 
08. Cytotoxic chemotherapy 
within the 28 days prior to 
randomization 
With: 
208. Cytotoxic chemotherapy or other 
antineoplastic therapy, aside from 
immunotherapy or proteasome inhibitors, 
within the 28 days prior to randomization 
Revised text for clarification 
Synopsis: Synopsis, Exclusion Criteria, 
criterion 209, 5.2 Exclusion Criteria, 
criterion 209 
Replace: 
09. Immunotherapy within the 
21 days prior to randomization 
With: 
209. Immunotherapy, such as an IMiD or a 
proteasome inhibitor within the 21 days 
prior to randomization 
Revised text for clarification 
Synopsis: Synopsis, Exclusion Criteria, 
criterion 210, 5.2 Exclusion Criteria, 
criterion 210 
Replace: 
10. Glucocorticoid therapy within 
the 14 days prior to randomization 
that exceeds a cumulative dose of 
160 mg dexamethasone or 
1000 mg prednisone 
With: 
210. Glucocorticoid therapy exceeding a 
cumulative dose of 160 mg dexamethasone 
or equivalent, within the 14 days prior to 
randomization 
Revised text for clarification 
Synopsis: Synopsis, Exclusion Criteria, 
criterion 214, 5.2 Exclusion Criteria, 
criterion 214 
Replace: 
14. Contraindication to 
dexamethasone or any of the 
required concomitant drugs or 
With: 
214. Contraindication to dexamethasone or 
any of the required concomitant 
medications or supportive treatments 
Revised text for clarification 


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supportive treatments, including 
hypersensitivity to antiviral drugs, 
or intolerance to hydration due to 
pre-existing pulmonary or cardiac 
impairment 
Synopsis: Synopsis, Exclusion Criteria, 
criterion 215, 5.2 Exclusion Criteria, 
criterion 215 
Replace: 
Active congestive heart failure 
(New York Heart Association 
[NYHA] Class III or IV, refer to 
Appendix F), symptomatic 
ischemia, conduction 
abnormalities uncontrolled by 
conventional intervention, acute 
diffuse infiltrative pulmonary 
disease, pericardial disease, or 
myocardial infarction within 
6 months prior to enrollment 
With: 
Active congestive heart failure (New York 
Heart Association [NYHA] Class III or IV, 
refer to Appendix F), symptomatic ischemia, 
conduction abnormalities uncontrolled by 
conventional intervention, acute diffuse 
infiltrative pulmonary disease, 
pericardial disease, or myocardial infarction 
within 6 months prior to randomization 
Revised text for clarification 
Synopsis: Synopsis, Exclusion Criteria, 
criterion 216, 5.2 Exclusion Criteria, 
criterion 216 
Replace: 
16. Active infection within the 
14 days prior to randomization 
requiring systemic antibiotics 
With: 
216. Active infection requiring systemic 
treatment within the 14 days prior to 
randomization 
Revised text for clarification 
Synopsis: Synopsis, Exclusion Criteria, 
criterion 220, 5.2 Exclusion Criteria, 
criterion 220 
Replace: 
20. Uncontrolled hypertension or 
uncontrolled diabetes despite 
medication 
With: 
220. Uncontrolled hypertension or diabetes 
mellitus 
Revised text for clarification 
Synopsis: Synopsis, Exclusion Criteria, 
criterion 223, 5.2 Exclusion Criteria, 
criterion 223 
Replace: 
23. Known human 
immunodeficiency virus (HIV) 
seropositivity, hepatitis C 
infection, or hepatitis B infection 
(subjects with past hepatitis B 
With: 
223. Known human immunodeficiency virus 
(HIV) seropositivity, hepatitis C infection, 
or hepatitis B infection. Subjects with past 
hepatitis B virus infection, defined as having 
a negative HBsAg test and a positive 
Administrative change 


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Amended Text  
Rationale for Change 
virus (HBV) infection or resolved 
HBV infection defined as having a 
negative HBsAg test and a 
positive antibody to hepatitis B 
core antigen [anti HBc] antibody 
test are eligible; subjects positive 
for hepatitis C virus (HCV) 
antibody are eligible only if 
polymerase chain reaction (PCR) 
is negative for HCV RNA.) 
antibody to hepatitis B core antigen (anti 
HBc) antibody test, are eligible. Subjects 
positive for hepatitis C virus (HCV) 
antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV 
RNA. 
Synopsis: Synopsis, Exclusion Criteria, 
criterion 226, 5.2 Exclusion Criteria, 
criterion 226 
 
Delete: 
226. Female subjects who are pregnant or 
lactating 
Removed text to avoid duplication 
with the inclusion criteria 
Section: Synopsis, Efficacy Variable, 
paragraph 3 
Replace: 
Disease assessments according to 
the International Myeloma 
Working Group-Uniform 
Response Criteria (IMWG-URC) 
will be conducted at baseline and 
then at Cycle 2 Day 1 (C2D1) and 
on Day 1 of every cycle thereafter 
until progression. 
With: 
Disease assessments according to the 
International Myeloma Working Group-
Uniform Response Criteria (IMWG-URC) 
will be conducted at baseline and then every 
28 days (± 4 days) thereafter until 
progression. 
Updated text for disease assessment 
timepoints to align with other 
sections in protocol 
Section: Synopsis, Intensive PK and PDn 
Substudy 
Replace: 
Intensive pharmacokinetic (PK) 
and pharmacodynamic (PDn) 
samples will be obtained as a 
substudy (approximately n = 15 in 
each arm) from subjects who 
consent to the additional testing at 
selected sites.  Pharmacokinetic 
samples will be collected on 
Day 15 of Cycle 1 and PDn 
With: 
Intensive pharmacokinetic (PK) and 
pharmacodynamic (PDn) samples will be 
obtained as a substudy (approximately 
n = 15 evaluable subjects in each arm) from 
subjects who consent to the additional 
testing at selected sites.  Pharmacokinetic 
samples will be collected on Day 15 of 
Cycle 1 and PDn samples will be collected 
Revised text for consistency within 
overall protocol 


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Rationale for Change 
samples will be collected on 
Days 1, 15, 16, 17, and 22 of 
Cycle 1. 
on Days 1, 15, 16, 17, and 22 of Cycle 1. 
Section: Synopsis, Health related Quality 
of Life (HRQL), paragraph2, sentence 1 
Replace: 
All questionnaires should be 
administered prior to study 
treatment on Day 1 of Cycle 1, 
then every other cycle during 
treatment and every 12 weeks 
(every 84 days ± 4 days) until 
progression, or withdrawal of 
consent during LTFU. 
With: 
QLQ-C30, QLQ-MY20 and EQ-5D-5L 
questionnaires should be administered prior 
to study treatment on Day 1 of Cycle 1, then 
every second cycle (Cycle 1, 3, 5, etc) 
during treatment and every 12 weeks (every 
84 days ± 4 days) until progression, or 
withdrawal of consent during LTFU. 
Revised text for clarification 
Section: Synopsis, Health related Quality 
of Life (HRQL), paragraph 2, sentence 2 
 
Add: 
Patient convenience and satisfaction 
questionnaire will be collected at Cycle 2 
and EOT only. 
Revised text for consistency within 
overall protocol 
Section: Synopsis, Health related Quality 
of Life (HRQL), paragraph 2, sentence 3 
Replace: 
Healthcare resource utilization 
data related to AEs will be 
collected for all subjects during 
the study. 
With: 
Healthcare resource utilization will be 
collected for all subjects during the study. 
Updated text for collection of 
healthcare resource utilization as 
collection will not just be for AE 
related healthcare resource utilization 
Section: Synopsis, Health related Quality 
of Life (HRQL), paragraph 2, sentence 4 
 
Add: 
Details on hospitalizations (not related to 
adverse events) will also be collected. 
Added text for collection of 
hospitalizations not related to AEs to 
align to with later section 
Section: Synopsis, Safety variables, 
sentence 3 
Replace: 
All subjects will be monitored for 
adverse events for 30 days after 
the past administration of study 
treatment. 
With: 
All subjects will be monitored for adverse 
events for at least 30 days after the past 
administration of study treatment. 
Revised text for consistency within 
overall protocol 


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Rationale for Change 
Section: Synopsis, Statistical methods and 
analyses, paragraph 4, bullet 2 
Replace: 
• Refractory to proteasome 
inhibitor ([PI] bortezomib) 
treatment (Yes versus No) 
With: 
• Refractory to bortezomib) treatment (Yes 
versus No) 
Revised text for consistency within 
overall protocol 
Section: Synopsis, Statistical methods and 
analyses, paragraph 6, sentence 3 
Replace: 
Investigator-assessed responses 
will be analyzed as part of a 
supportive ORR analysis 
With: 
Investigator-assessed responses will be 
analyzed as part of a supportive ORR 
analysis, as will IRC-assessed responses, if 
an Independent Review Committee (IRC) 
is convened. 
Added text regarding potential use of 
an IRC. 
Section: 1 List of abbreviations and 
definitions of terms 
 
Delete: 
CRO contract research organization 
Administrative change 
Section: 1 List of abbreviations and 
definitions of terms 
 
Add: 
FISH       fluorescence in situ 
hybridization 
Administrative change 
Section: 1 List of abbreviations and 
definitions of terms 
 
Add: 
IPIM        Investigational Product 
Instruction Manual 
Administrative change 
Section: 1 List of abbreviations and 
definitions of terms 
Replace: 
IWRS Interactive Web Response 
System 
With: 
IVR/IWR Interactive Voice (IVR) and Web 
Response (IWR)  
Administrative change 
Section: 2.1 Introduction, paragraph 2 
Replace: 
Per the approved label, 
carfilzomib is administered 
intravenously (IV) over 2 to 
10 minutes, on 2 consecutive days 
each week for 3 weeks (Days 1, 2, 
8, 9, 15, and 16 of a 28-day cycle).  
The recommended Cycle 1 dose is 
With: 
Per the 2012 approved label, carfilzomib is 
administered intravenously (IV) over 
10 minutes, on 2 consecutive days each 
week for 3 weeks (Days 1, 2, 8, 9, 15, and 
16 of a 28-day cycle).  The recommended 
Cycle 1 dose is 20 mg/m2/day with an 
increase to 27 mg/m2 on Cycle 2 Day 1 
Updated text to reflect new IB 
version 


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20 mg/m2/day with an increase to 
27 mg/m2 on Cycle 2 Day 1 
onwards (Carfilzomib 
Investigator’s Brochure [IB] 
Version 15, 26 February 2015). 
onwards (Carfilzomib Investigator’s 
Brochure [IB]).   
Section: 2.3.1 Carfilzomib Background 
(Nonclinical), paragraph 1, sentence 1 
Replace: 
Carfilzomib (formerly known as 
PR-171) is a tetrapeptide 
epoxyketone-based inhibitor of the 
of the 20S proteasome, primarily 
of the CT-L activity, and at higher 
concentrations, of multiple 20S 
proteolytic activities. 
With: 
Carfilzomib (formerly known as PR-171) is 
a tetrapeptide epoxyketone-based inhibitor 
0S proteasome, primarily of the CT-L 
activity, and at higher concentrations, 
of multiple 20S proteolytic activities. 
Updated text to reflect new IB 
version 
Section: 2.3.1 Carfilzomib Background 
(Nonclinical), paragraph 1, sentences 2 
and 3 
 
Add: 
Carfilzomib is a synthetic small molecule 
peptide bearing the chemical name (2S) N 
((S) 1 ((S) 4 methyl 1 ((R) 2 methyloxiran-
2-yl) 1 oxopentan 2 ylcarbamoyl) 2-
phenylethyl) 2 ((S) 2 (2 
morpholinoacetamido) 4 
phenylbutanamido) 4 
methylpentanamide.  The molecular 
formula is C40H57N5O7 and the 
molecular weight is 719.91. 
Updated text to reflect new IB 
version 
Section: 2.3.1 Carfilzomib Background 
(Nonclinical), paragraph 1, sentences 4 
Replace: 
This selectivity may be 
responsible for the reductions in 
myelosuppression and neuropathy 
observed in nonclinical studies 
comparing carfilzomib with 
bortezomib. 
With: 
This selectivity may be responsible for the 
reductions in myelosuppression and 
neuropathy observed in clinical and 
nonclinical studies comparing carfilzomib 
with bortezomib. 
Updated text to reflect new IB 
version 


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Section: 2.3.2 Carfilzomib Background 
(Clinical), paragraph 1 
Replace: 
As of 12 January 2015, 
approximately 2949 individual 
subjects have been treated with 
carfilzomib as participants in 
Onyx-sponsored clinical studies.  
Approximately 1975 subjects have 
been treated with carfilzomib 
through the 69 completed or 
actively enrolling investigator-
sponsored trials (ISTs) 
(Carfilzomib IB).  There are five 
Phase 3 studies in multiple 
myeloma:  PX-171-009 
(ASPIRE), PX-171-011 (FOCUS), 
2011-003 (ENDEAVOR), 2012-
005 (CLARION), and this study, 
CFZ014 (A.R.R.O.W.).  In 
addition, 137 subjects with solid 
tumors have been treated with 
carfilzomib in completed 
Onyx-sponsored clinical studies. 
With: 
As of 10 July 2015, approximately 
2921 individual subjects have been treated 
with carfilzomib as participants in Onyx-
sponsored clinical studies and 89 subjects 
have been enrolled in studies in Japan 
sponsored by Ono Pharmaceutical 
Company.  Approximately 3549 subjects 
have been treated with carfilzomib through 
the 76 completed or actively enrolling 
investigator-sponsored trials (ISTs) 
(Carfilzomib IB).  There are five Phase 3 
studies in multiple myeloma:  PX-171-009 
(ASPIRE), PX-171-011 (FOCUS), 2011-003 
(ENDEAVOR), 2012-005 (CLARION), and 
this study, CFZ014 (A.R.R.O.W.).  
Additionally, 137 subjects with solid tumors 
have been treated with carfilzomib in 
completed Onyx-sponsored clinical studies. 
Updated date to reflect most recent 
statistics on study drug. 
Section: 2.3.2 Carfilzomib Background 
(Clinical), paragraph 5, sentence 5 
Replace: 
The Phase 2 PX-171-003 – 
Part 2 (A1) study with single 
agent carfilzomib at 20/27 mg/m2 
in a similar population, which is 
the basis for the current label, had 
an ORR of 23.7%. 
With: 
The Phase 2 PX-171-003 – Part 2 (A1) study 
with single agent carfilzomib at 
20/27 mg/m2 in a similar population had an 
ORR of 22.9% in the Safety population. 
Updated text to reflect new IB 
version 
Section: 2.4 Study Rationale, paragraph 1, 
sentence 3 
Replace: 
Preliminary results from the 
ongoing Phase 2 portion of this 
With: 
Preliminary results from the ongoing 
Phase 2 portion of this multicenter, single-
Administrative change 


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multicenter, single-arm study 
suggested that the dose and 
regimen of 70 mg/m2 once-weekly 
appears to be well tolerated, 
highly active and could offer a 
more convenient treatment 
regimen for subjects as discussed 
in Section 2.5. 
arm study suggested that the dose and 
regimen of 70 mg/m2 once-weekly appeared 
to be well tolerated, highly active, and able 
to offer a more convenient treatment 
regimen for subjects as discussed in 
Section 2.5. 
Section: 2.4 Study Rationale, paragraph 2 Replace: 
The rationale for this study is to 
compare carfilzomib dosing in 
combination with dexamethasone 
administered once-weekly, infused 
over 30 minutes based on the 
CHAMPION 1 results to 
twice-weekly carfilzomib dosing 
in combination with 
dexamethasone in subjects with 
relapsed and refractory multiple 
myeloma, previously treated with 
bortezomib and an IMiD. The 
hypothesis is that this regimen will 
have superior efficacy with an 
acceptable safety profile and a 
more convenient dosing regimen 
when compared with the US 
approved dose and schedule. 
With: 
The rationale for this study is to compare 
carfilzomib administered once weekly in 
combination with dexamethasone, based on 
the CHAMPION 1 results, to twice-weekly 
carfilzomib in combination with 
dexamethasone in subjects with relapsed and 
refractory multiple myeloma, previously 
treated with bortezomib and an IMiD. The 
hypothesis is that this regimen will have 
superior efficacy with an acceptable safety 
profile and a more convenient dosing 
regimen when compared with the US 
approved dose and schedule of carfilzomib 
administered at 20/27 mg/m2 twice 
weekly. 
Revised text for consistency within 
overall protocol 
Section:  2.5 Dose Rationale, paragraph 1 Replace: 
Carfilzomib 20/27 mg/m2 
twice-weekly is the approved 
monotherapy dose 
and 20/70 mg/m2 once-weekly is 
With: 
Carfilzomib 20/27 mg/m2 twice-weekly is 
an approved monotherapy dose 
and 20/70 mg/m2 once-weekly is the MTD 
that was determined in the CHAMPION 1 
Administrative change 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 124 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
the MTD that was determined in 
the CHAMPION 1 study 
described in Section 2.5.1. 
study described in Section 2.5.1. 
Section:  2.5 Dose Rationale, paragraph 3 Replace: 
Carfilzomib study treatment 
administration will use a step-up 
approach in which the first dose 
level for all subjects will be 
20 mg/m2 (Cycle 1 Day 1 for the 
once-weekly regimen and Cycle 1 
Days 1 and 2 for the twice-weekly 
regimen) and increased to 
70 mg/m2 or 27 mg/m2 
respectively, beginning on Day 8 
of Cycle 1. 
With: 
Carfilzomib study treatment administration 
will use a step-up approach in which the first 
dose level for all subjects will be 20 mg/m2 
(Cycle 1 Day 1 for the once-weekly regimen 
and Cycle 1 Days 1 and 2 for the 
twice-weekly regimen) and the dose level 
will then increase to 70 mg/m2 or 27 mg/m2 
respectively, beginning on Day 8 of Cycle 1. 
Administrative change 
Section:  2.5.1 Rationale for Once-weekly 
Dosing, paragraph 1, sentence 1 
Replace: 
CHAMPION 1, a Phase 1b/2 
study in subjects with relapsed 
multiple myeloma who had 
received 1 to 3 prior therapies was 
initiated to investigate higher 
doses of carfilzomib given 
once-weekly in combination with 
dexamethasone, and results 
indicate that these modifications 
were well tolerated and active. 
With: 
CHAMPION 1, a Phase 1b/2 study in 
subjects with relapsed multiple myeloma 
who had received 1 to 3 prior therapies was 
initiated to investigate higher doses of 
carfilzomib given once-weekly in 
combination with dexamethasone, and 
preliminary results indicated that these 
modifications were well tolerated and active. 
Updated text to reflect new IB 
version statistics 
Section: 2.5.1 Rationale for Once-weekly 
Dosing, paragraphs 8, 9, and 10 
Replace: 
As of 07 January 2015, 
104 subjects (Phase 1 n = 15, 
Phase 2 n = 89) have received at 
least 1 dose of carfilzomib at the 
MTD.  The majority of subjects 
With: 
As of 01 May 2015, 104 subjects (Phase 1 
n = 15, Phase 2 n = 89) have received at 
least 1 dose of carfilzomib at the MTD.  The 
majority of subjects (82%) had received 
prior bortezomib.  A total of 48% of subjects 
Updated text to reflect new IB 
version statistics 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 125 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
(82%) had received prior 
bortezomib.  A total of 48% of 
subjects were bortezomib-
refractory, 28% were 
lenalidomide-refractory, and 16% 
were refractory to both.  The ORR 
to date was 72% (95% CI:  63% to 
81%) with a CBR of 80% (95% 
CI:  71% to 87%).  Median PFS 
was 10.6 months (95% CI:  7.2 to 
not estimable).  Preliminary 
median carfilzomib treatment 
duration in the ongoing study is 
5.3 months (range:  0.03 to 18.8) 
(Berenson 2015). 
All 104 subjects experienced at 
least 1 AE.  The most common 
AEs (≥ 15% of subjects) were 
fatigue (48%), nausea (32%), 
insomnia (30%), anemia, 
headache, diarrhea (each 24%), 
dyspnea (23%), upper respiratory 
tract infection (22%), cough 
(21%), pyrexia (19%), 
thrombocytopenia (18%), 
constipation (16%), back pain, 
peripheral edema, and dizziness 
(each 15%).  A total of 57 subjects 
(55%) experienced at least 1 
Grade 3 or higher AE.  The most 
common (≥ 5% of subjects) Grade 
3 or higher AEs were fatigue 
(9%), thrombocytopenia, dyspnea, 
back pain (each 6%), anemia, and 
were bortezomib-refractory, 28% were 
lenalidomide-refractory, and 16% were 
refractory to both.  The ORR to date was 
77% (95% CI:  68% to 85%) with a CBR of 
84% (95% CI:  75% to 90%).  Median PFS 
was 10.6 months (95% CI:  9.0 to 16.1).  
Preliminary median carfilzomib treatment 
duration in the ongoing study is 8.3 months 
(range:  > 1 to 20) for the Phase 1 portion 
of the study and 7.2 months. (range: 0.03 
to 22.6) for the Phase 2 portion of the 
study (Berenson 2015). 
All 104 subjects experienced at least 1 AE.  
The most common AEs (≥ 15% of subjects) 
were fatigue (52%), nausea (35%), 
headache, diarrhea (each 31%), insomnia, 
upper respiratory tract infection (each 30%), 
cough (26%), dyspnea (25%), anemia 
(24%), thrombocytopenia, pyrexia (each 
22%), peripheral edema (20%), and back 
pain (17%).  A total of 64 subjects (62%) 
experienced at least 1 Grade 3 or higher AE.  
The most common (≥ 5% of subjects) 
Grade 3 or higher AEs were fatigue (11%), 
pneumonia (7%), thrombocytopenia, 
hypertension, acute renal failure (each 6%), 
dyspnea, anemia, back pain, asthenia, and 
chronic obstructive pulmonary disease 
(each 5%)  (Carfilzomib IB). 
The preliminary results from CHAMPION 1 
demonstrated that once-weekly carfilzomib 
at 70 mg/m2 administered as a 30-minute 
infusion in combination with dexamethasone 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 126 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
acute renal failure (each 5%)  
(Carfilzomib IB).  
The preliminary results from 
CHAMPION 1 demonstrated that 
once-weekly carfilzomib at 
70 mg/m2 administered as a 30-
minute infusion in combination 
with dexamethasone in subjects 
with relapsed and refractory 
multiple myeloma had an 
acceptable safety and tolerability 
profile and promising efficacy.  
Ninety subjects are planned for the 
Phase 2 portion of the study. 
in subjects with relapsed and refractory 
multiple myeloma had an acceptable safety 
and tolerability profile and promising 
efficacy.  Eighty-nine subjects were 
enrolled into the Phase 2 portion of the 
study. 
Section:  2.5.2 Pharmacokinetics and 
Pharmacodynamics Data for 
Once-weekly Dosing, paragraph 2, 
sentence 4 
Replace: 
The mean Cmax following the 
70 mg/m2 dose administered as a 
30-minute infusion is 2640 ng/mL, 
which is lower than the mean Cmax 
of 4232 ng/mL in Study 
PX-71-003 – Part 2 (A1) 
following the IV infusion of 
27 mg/m2 over 2 to 10 minutes 
(Carfilzomib IB). 
With: 
The mean Cmax following the 70 mg/m2 dose 
administered as a 30-minute infusion is 
2640 ng/mL, which is lower than the mean 
Cmax of 4232 ng/mL in 
Study PX-171-003- Part 2 (A1), following 
the IV infusion of 27 mg/m2 over 2 to 
10 minutes (Carfilzomib IB). 
Administrative change 
Section:  2.5.2 Pharmacokinetics and 
Pharmacodynamics Data for 
Once-weekly Dosing, paragraph 3, 
sentence 2 
Replace: 
No statistically significant 
relationships between Cmax and 
efficacy and safety endpoints were 
found. 
With: 
No statistically significant relationships 
between Cmax and efficacy or safety 
endpoints were found. 
Administrative change 
Section: 3.1 Primary Objective 
Replace: 
The primary objective of this 
With: 
The primary objective of this study is to 
Revised text for consistency within 
overall protocol 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 127 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
study is to compare the ORR 
between once-weekly carfilzomib 
dosing in combination with 
dexamethasone to twice-weekly 
carfilzomib dosing in combination 
with dexamethasone in subjects 
with relapsed and refractory 
multiple myeloma who have 
received prior treatment with 
bortezomib and an IMiD. 
compare the ORR of once-weekly 
carfilzomib dosing in combination with 
dexamethasone to the ORR of twice-weekly 
carfilzomib dosing in combination with 
dexamethasone in subjects with relapsed and 
refractory multiple myeloma who have 
received prior treatment with a proteasome 
inhibitor and an IMiD. 
Section:  4.1 Study Design, paragraph 2, 
sentence 2 
Replace: 
Subjects must have had 2 or 3 
prior therapies for multiple 
myeloma and received treatment 
with bortezomib and an IMiD. 
With: 
Subjects must have had 2 or 3 prior therapies 
for multiple myeloma and received treatment 
with a proteasome inhibitor and an IMiD. 
Revised text for consistency within 
overall protocol 
Section:  4.1 Study Design, paragraph 3, 
bullet 1 
Replace: 
• International Staging System 
(ISS) Stage at study entry 
(Stage 1 versus Stage 2 or 3) 
With: 
• International Staging System (ISS) Stage 
at study entry (Stage 1 versus Stage 2 or 
3) per International Myeloma 
Working Group (Greipp 2005). See 
Appendix H 
Revised text for clarification 
Section: 4.1 Study Design, paragraph 5, 
sentence 1 
Replace: 
Disease assessments will be 
conducted at Screening (within 
21 days before dosing on Cycle 1 
Day 1) and then on Day 1 of every 
cycle beginning with Cycle 2 and 
each cycle thereafter, End of 
Treatment (EOT) and during 
LTFU every 4 weeks (every 
28 days ± 4 days), until PD and/or 
With: 
Disease assessments will be conducted at 
Screening (within 21 days before 
randomization) and then every 28 days 
± 4 days after Cycle 1 Day 1, End of 
Treatment (EOT) and during LTFU every 
28 days ± 4 days, until PD and/or 
administration of subsequent antimyeloma 
therapy. 
Updated text for disease assessment 
timepoints to align with other 
sections in protocol 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 128 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
administration of subsequent 
antimyeloma therapy. 
Section:  4.2 Number of Centers 
Replace: 
Approximately 120 sites 
worldwide will participate. 
With: 
Approximately 150 sites worldwide will 
participate. 
Updated number of sites to include 
potential New Zealand and Australian 
sites 
Section:  5 Subject Eligibility 
Replace: 
5 
Approximately 460 subjects will 
be enrolled in this study.  Subjects 
will be evaluated for study 
eligibility within the 21 days prior 
to randomization. 
Subject Selection 
With: 
5 
 
Subject Eligibility 
Removed text to avoid duplication in 
protocol 
Section: 6 Subject Screening, paragraph 
1, sentence 2 
Replace: 
Evaluations obtained as part of 
routine medical care that do not 
require central lab testing and are 
performed during the Screening 
period may be used as the 
study-specific protocol required 
evaluations. 
With: 
Evaluations obtained as part of routine 
medical care prior to signing of the ICF 
may be used to satisfy the screening 
requirements, provided that these 
evaluations were obtained within the 
required screening period and do not 
require analysis at a central laboratory. 
Revised text for clarification 
Section: 6 Subject Screening, paragraph 3 Replace: 
The Screening period for a 
particular subject commences at 
the point at which the subject 
signs the ICF, and must be 
completed within the 21 days prior 
to randomization. 
With: 
The Screening period commences when the 
subject or a legally-authorized 
representative signs the ICF. Screening 
must be completed within the 21 days prior 
to randomization. 
Revised text for clarification 
Section: 7 Subject Randomization, title 
Replace: 
Subject Enrollment And 
With: 
Subject Randomization 
Administrative change 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 129 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Randomization 
Section: 7 Subject Randomization, 
paragraph 1 
Replace: 
Eligibility information for each 
subject must be provided to the 
study medical monitor or designee 
and reviewed and approved prior 
to randomization (refer to separate 
study reference manual). 
The Randomization will be carried 
out centrally through an 
Interactive Web Response System 
(IWRS). 
With: 
The primary investigator will determine 
the subject’s eligibility, ensuring that the 
results of the required screening 
procedures are consistent with all of the 
eligibility criteria presented in Section 5.  
No eligibility waivers will be permitted. 
Randomization will be carried out centrally 
through an interactive voice and web 
response (IVR/IWR) system.  Please refer 
to the separate study reference manual. 
Updated text to align with the 
administrative processes followed by 
Amgen 
Section: 7 Subject Randomization, 
paragraph 5 
Replace: 
After Screening, eligibility 
determination, and randomization, 
study treatment will ideally 
commence on the day of 
randomization but at least within 5 
calendar days of randomization 
according to treatment group 
assignment.  Initiation of study 
treatment (Cycle 1 Day 1) 
delay > 5 days after randomization 
must be approved by the study 
medical monitor. 
With: 
Study treatment will ideally commence on 
the day of randomization, but at least within 
5 calendar days of randomization.  Initiation 
of study treatment (Cycle 1 
Day 1) > 5 calendar days after 
randomization must be approved by the 
study medical monitor. 
Clarified the timing of initiation of 
study treatment 
Section: 8 Study Drugs, title 
Replace: 
Study Treatment 
With: 
Study Drugs 
Revised text for consistency within 
overall protocol 
Section: 8.1.1 Physical Description 
 
Delete: 
8.1.1 Physical Description 
Carfilzomib is a synthetic small molecule 
Removed section to avoid duplication 
of IPIM 


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Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 131 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Storage, paragraph 2 
Once carfilzomib is reconstituted and 
inspected, the clear solution may be stored in 
a refrigerator (recommended) controlled 
temperature from 2°C to 8°C (36°F–46°F) 
for up to 24 hours.  Once reconstituted, 
carfilzomib must be used within 4 hours if 
not refrigerated and within 24 hours if it has 
been stored in a light-tight refrigerator (refer 
to Table 3). 
duplication of IPIM 
Section:  8.1.2 (newly renumbered) 
Storage, Table 3 Stability of 
Reconstituted Carfilzomib for Injection 
(60 mg/vial) 
 
Delete: 
Table 3 
Removed table to avoid duplication 
of IPIM 
Section:  8.1.2 (newly renumbered) 
Storage, paragraph 2 
 
Add: 
Please refer to the IPIM for further 
storage information. 
Added cross reference to IPIM to 
avoid text duplication 
Section: 8.2 Dexamethasone, paragraph 1, 
sentence 2 
Replace: 
Onyx (and/or designee) may 
provide dexamethasone, if the 
investigational site is unable to 
obtain adequate supply. 
With: 
Sponsor (and/or designee) may provide 
dexamethasone, if the investigational site is 
unable to obtain adequate supply. 
Administrative change 
Section: 8.3 Study Drug Accountability 
Replace: 
Onyx (or designee), and the 
investigator must maintain records 
of each shipment of 
investigational product (IP).  Upon 
receipt of IP, the designated 
recipient at the investigational site 
will inspect the shipment, verify 
the number and condition of the 
vials, and prepare an inventory or 
With: 
Please refer to the IPIM for details on 
study drug accountability. 
Added cross reference to IPIM to 
avoid text duplication 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 132 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
drug accountability record.  The 
records will document shipment 
dates, method of shipment, batch 
numbers, product presentation, 
quantity of vials contained in the 
shipment, and dispensation to 
individual subjects using the 
subject identification number.   
Responsibility for drug 
accountability at the study site 
rests with the investigator; 
however, the investigator may 
assign drug accountability duties 
to an appropriate pharmacist or 
designee.  Inventory and 
accountability records must be 
readily available for inspection by 
the study monitor and are open to 
inspection at any time by the 
sponsor/representative and any 
applicable regulatory authorities.   
The investigator must ensure that 
the IPs are used in accordance 
with the protocol.  
The investigator will also maintain 
records adequately documenting 
that the subjects were provided the 
treatment specified and 
reconciling all IPs. 
Remaining supplies will be 
retained by the pharmacy at the 
end of the study, and any unused 
medication will be discarded or 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 133 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
destroyed according to 
institutional Standard Operating 
Procedures (SOPs).  
Documentation of destruction of 
unused study medication will be 
maintained by the site.  For each 
subject, the site pharmacy 
personnel will be required to 
record and document proper per 
protocol dispensing of carfilzomib 
and dexamethasone. 
Additional details are provided in 
the pharmacy manual. 
Section: 9.1 Treatment Regimen, 
paragraph 1 
Replace: 
Carfilzomib and dexamethasone 
will be administered in 28-day 
cycles.  All cycles will start 
28 days (± 2) after the start of the 
prior cycle. 
With: 
Carfilzomib and dexamethasone will be 
administered in 28-day cycles.  All cycles 
will start 28 days (± 2 days) after the start of 
the prior cycle. 
Revised text for consistency within 
overall protocol 
Section: 9.1 Treatment Regimen, 
paragraph 2, sentences 1 and 2 
Replace: 
Once-weekly carfilzomib must 
never be administered within the 
5 days following a previous 
carfilzomib infusion. 
With: 
In the once-weekly carfilzomib arm, intra-
cycle doses of carfilzomib and 
dexamethasone may be administered 
within ± 2 days of the scheduled dose. 
However, carfilzomib must not be 
administered within the 5 days following a 
previous carfilzomib infusion.  Dose delays 
> 2 days are only permitted during the 
start of a new cycle. 
Revised text for clarification. 
Section: 9.1 Treatment Regimen, 
paragraph 3 
Replace: 
In the twice-weekly carfilzomib 
With: 
In the twice-weekly carfilzomib arm, every 
Revised text for clarification 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 134 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
arm, every effort should be made 
to maintain the Days 1, 2, 8, 9, 15, 
and 16, every 28-day schedule.  If 
this is not possible due to 
extenuating circumstances, then 
priority should be to maintain 
consecutive dosing days.  For 
example, if Day 1 of a new cycle 
is started 2 days later than 
originally scheduled, the entire 
cycle should shift by 2 days, such 
that the new Days 1, 2, 8, 9, 15, 
and 16 of the next cycle schedule 
is maintained.  If a mid-cycle dose 
is missed, that dosing day should 
be skipped and not made up.  
Dose delays > 2 days are only 
permitted during the start of a new 
cycle. 
effort should be made to maintain the 
Days 1, 2, 8, 9, 15, and 16, every 28-day 
schedule.  If this is not possible, then priority 
should be to maintain consecutive 
dosing days.  For example, if Day 1 of a new 
cycle is started 2 days later than originally 
scheduled, the entire cycle should shift by 
2 days, such that the new Days 1, 2, 8, 9, 15, 
and 16 of the next cycle are maintained.  
Dosing on nonconsecutive days should 
only occur under exceptional 
circumstances, such as interruptions due 
to national holidays.  There must always 
be at least 5 days between the second dose 
of one week and the first dose of the 
following week (i.e., between Days 2 and 
8, and Days 9 and 15).  Mid-cycle doses 
that are missed should not be made up, 
unless these parameters are maintained. 
Section: 9.1 Treatment Regimen, 
paragraph 4 
Replace: 
The reason for all cycle delays, 
missed doses, and dose 
interruptions will be reported. 
With: 
The reasons for all cycle delays, schedule 
changes, missed doses, and dose 
interruptions will be reported. 
Revised text for clarification 
Section: 9.2 Intravenous Hydration 
Replace: 
9.2 Intravenous Hydration 
Subjects will receive IV 
prehydration prior to each 
carfilzomib infusion during 
Cycle 1.  Prehydration will consist 
of 250 to 500 mL normal saline or 
other appropriate IV fluid.  
Thereafter, carfilzomib 
With: 
9.2 Intravenous Prehydration 
Subjects will receive IV prehydration prior 
to each carfilzomib infusion during Cycle 1.  
Prehydration will consist of 250 to 500 mL 
normal saline or other appropriate IV fluid.  
Thereafter, carfilzomib prehydration should 
only be administered if the subject’s 
condition and/or risk factors require it.  The 
Revised text for clarification 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 135 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
prehydration should only be 
administered if the subject’s 
condition and/or risk factors 
require hydration.  The total 
amount of prehydration will be 
reported and the reason for 
hydration after Cycle 1 will be 
reported. 
total volume of prehydration and the reason 
for prehydration after Cycle 1 will be 
recorded. 
Section: 9.2.1 Study Treatment 
Administration, Figure 3, footnote c 
Replace: 
C Dexamethasone on Day 22 in 
both treatment arms will be 
administered only during Cycles 1 
to 9 and should be given PO; 
dexamethasone will not be 
administered on Day 22 after 
Cycle 9. 
With: 
C Dexamethasone on Day 22 in both 
treatment arms will be administered only 
during Cycles 1 to 9 and should be given 
PO, whenever possible 
Revised text for clarification 
Section: 9.2.1.1 Carfilzomib, paragraph 2, 
sentence 2 
Replace: 
The lyophilized product is 
reconstituted with Sterile Water 
for Injection (SWI), United States 
Pharmacopeia (USP), to a final 
carfilzomib concentration of 
2.0 mg/mL prior to administration. 
With: 
The lyophilized product is reconstituted with 
Sterile Water for Injection (SWI), United 
States Pharmacopeia (USP), to a final 
carfilzomib concentration of 2.0 mg/mL. 
Revised text for clarifcation 
Section: 9.2.1.1 Carfilzomib, paragraph 2, 
sentences 3, 4 and 5 
 
Delete: 
The dose can be calculated using the 
subject’s actual body surface area (BSA) at 
Baseline; however, dosing adjustments for 
subsequent actual BSA determinations are 
allowed per institutional guidelines.  
Subjects with a BSA > 2.2 m2 will receive a 
dose based upon a 2.2 m2 BSA.  Dose 
adjustments must be made for weight 
Revised text for clarification 


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CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
gains/losses of ≥ 20% of baseline body 
weight. 
Section: 9.2.1.1 Carfilzomib, paragraph 3, 
sentences 4 and 5 
Replace: 
Carfilzomib should be 
administered via a dedicated IV 
line.  If an existing IV line or 
permanent infusion device (e.g., 
porta-cath) is used for carfilzomib 
administration, the line must be 
flushed with a minimum of 20 mL 
of 5% Dextrose Injection (D5W), 
prior to and following carfilzomib 
infusion. 
With: 
Carfilzomib should be administered via a 
dedicated IV line, whenever possible.  
Refer to the IPIM for detailed 
information regarding equipment and 
flush requirements. 
Added cross reference to IPIM to 
avoid text duplication 
Section: 9.2.1.2 Dexamethasone, sentence 
2 
Replace: 
Dexamethasone will be 
administered at least 30 minutes 
(but no more than 4 hours) prior to 
carfilzomib infusion on Days 1, 8, 
and 15 in both arms. 
With: 
Dexamethasone will be administered at least 
30 minutes (but no more than 4 hours) prior 
to carfilzomib infusion on Days 1, 8, and 15 
in both treatment arms. 
Revised text for clarification 
Section: 9.2.1.2 Dexamethasone, sentence 
3 
Replace: 
Dexamethasone on Day 22 should 
be taken PO. 
With: 
Dexamethasone on Day 22 should be taken 
PO, whenever possible. 
Revised text for clarification 
Section: 9.2.1.2 Dexamethasone, sentence 
4 
Replace: 
Note: Dexamethasone on Day 22 
in both treatment arms will only 
be administered during Cycles 1 to 
9; dexamethasone will not be 
administered on Day 22 after 
Cycle 9. 
With: 
Note: Dexamethasone on Day 22 in both 
treatment arms will only be administered 
during Cycles 1 to 9. 
Revised text for clarification  
Section: 9.3 Dose Modification Rules 
Replace: 
With: 
Clarified procedures for dose 


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Section   
Text in Protocol  
Amended Text  
Rationale for Change 
9.3 Dose Modification Guidelines 
In the event of a possible study 
treatment-related AE, the clinical 
investigator should assess to the 
best of his/her ability its 
relationship to carfilzomib and/or 
dexamethasone.  Dose reduction 
guidelines for carfilzomib include 
guidelines where the dose of 
carfilzomib is decreased based on 
the observed toxicity. 
• 
If a subject requires an 
interruption of carfilzomib of 
more than 4 weeks, the subject 
should be removed from study 
treatment.  Exceptions to this 
must be discussed with the study 
medical monitor. 
• 
If the carfilzomib dose is 
reduced, the reduced dose level 
will be continued for at least 1 
complete cycle.  If the reduced 
dose level is well tolerated for at 
least one complete cycle, the dose 
level prior to the reduction may 
be resumed at the investigator’s 
discretion. 
If carfilzomib is permanently 
stopped due to toxicity per below 
dose modification guidelines 
(Table 5 and Table 6), 
dexamethasone dosing should also 
be stopped and the subject 
9.3 Dose Modification Rules 
In the event of a possible study 
treatment-related AE, the clinical 
investigator should assess, to the best of 
his/her ability, its relationship to carfilzomib 
and/or dexamethasone.  Dose reduction 
rules for carfilzomib are presented in 
Tables 4 and 5 and are often event-
specific. 
• 
If a subject requires interruption of 
carfilzomib for more than 28 days, the 
subject should be removed from study 
treatment.  Exceptions must first be 
approved by the study medical monitor. 
• 
If a subject requires carfilzomib dose 
reduction, the reduced dose level will be 
continued for at least 1 complete cycle.  
After that, if the reduced dose level has 
been well tolerated, the previous dose level 
may be resumed at the investigator’s 
discretion. 
• 
If carfilzomib is temporarily held due 
to an AE, dexamethasone should be 
continued, unless the investigator 
determines that criteria for interrupting 
dexamethasone have also been met. 
• 
If carfilzomib is permanently 
discontinued due to toxicity, 
dexamethasone must also be discontinued 
and the subject will be followed for disease 
progression per the guidelines in Section 
10.10.1. 
interruption for a carfilzomib AE. 


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CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
followed for disease progression 
per protocol-specified disease 
response criteria prior to initiating 
new antimyeloma therapies.   
• 
If dexamethasone is 
permanently withdrawn due to 
toxicity, the subject may continue 
to receive carfilzomib at the 
clinical investigator’s discretion 
and must follow protocol required 
procedures and assessments. 
 
• 
If dexamethasone is permanently 
discontinued due to toxicity, the subject 
may continue to receive study treatment 
with carfilzomib at the investigator’s 
discretion. 
Section: 9.3.1 Carfilzomib: Rules for 
Dose Modification, heading 
Replace: 
9.3.1 Carfilzomib: Guidelines for 
Dose Modification  
With: 
9.3.1 Carfilzomib: Rules for Dose 
Modification 
Administrative change 
Section: 9.3.1 Carfilzomib: Rules for 
Dose Modification, paragraph 1  
Replace: 
Dose reduction levels of 
carfilzomib for toxicity 
management of individual subjects 
are provided in Table 4. 
With: 
Dose decrements for carfilzomib are 
provided in Table 3. 
Revised text for clarification 
Section: 9.3.1 Carfilzomib: Rules for 
Toxicities and Dose Modification, Table 
3, footnote 1 
 
Add: 
Added footnote to dose column.  
a Note: If dose reduction of carfilzomib is 
required on C1D1 (Arm A) or C1D1 or 
D2 (Arm B), the investigator should 
contact the medical monitor to discuss the 
situation, before any additional doses of 
carfilzomib are administered. 
Revised text for clarification 
Section: 9.3.1 Carfilzomib: Guidelines for 
Toxicities and Dose Modification, 
Replace: 
Treatment guidelines for specific 
With: 
The requirements for carfilzomib dose 
Revised text for clarification 


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CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
paragraph 2 
hematologic toxicities are outlined 
in Section 9.3.1.1 and 
nonhematologic toxicities in 
Section 9.3.1.2. 
modification for specific hematologic and 
nonhematologic toxicities are outlined in 
Sections 9.3.1.1 and 9.3.1.2, respectively. 
Section:  9.3.1.1 Hematologic Toxicity, 
paragraph 1 
Replace: 
Guidelines for dose modification 
in the event of thrombocytopenia 
and neutropenia are summarized 
in Table 5. 
With: 
Requirements for dose modification of 
carfilzomib in the events of 
thrombocytopenia, neutropenia, or 
neutropenic fever are summarized in 
Table 4. 
Revised text for clarification 
Section:  9.3.1.1 Hematologic Toxicity, 
Table 4, title 
Replace: 
Carfilzomib Dosing Guidelines for 
Treatment-emergent 
Hematologic Toxicity 
With: 
Carfilzomib Dose Modification Rules for 
Treatment-emergent Hematologic Toxicity 
Revised text for clarification 
Section:  9.3.1.1 Hematologic Toxicity, 
Table 4 
Replace: 
Original Table 5 below  
With: 
Revised Table 4 below 
Revised for clarity and for 
consistency with current carfilzomib 
safety guidance 


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Original Table 5: 
Hematologic Toxicity 
Recommended Actiona 
Thrombocytopenia 
When platelets 
fall to ≤ 30 × 109/L 
If platelets 10–30 × 109/L without evidence of 
bleeding 
Continue at same dose. 
If evidence of bleeding or platelets < 10 × 109/L 
Withhold dose until platelets return to ≥ 10 × 109/L and/or 
bleeding is controlled, then resume at same dose. 
For each subsequent drop to ≤ 30 × 109/L 
If platelets 10–30 × 109/L without evidence of 
bleeding 
Continue at same dose. 
If evidence of bleeding or platelets < 10 × 109/L 
Withhold dose until platelets return to ≥ 10 × 109/L and/or 
bleeding is controlled, then resume at 1 dose decrement. 
Neutropenia 
When ANC 
falls to ≤ 0.75 × 109/L 
If ANC 0.5–0.75 × 109/L 
Continue at same dose. 
If ANC < 0.5 × 109/L 
Withhold dose until ANC returns to ≥ 0.5 × 109/L, then 
resume at same dose. 
For each subsequent drop to ≤ 0.75 × 109/L 
If ANC 0.5–0.75 × 109/L 
Continue at same dose. 
If ANC < 0.5 × 109/L 
Withhold dose until ANC returns to ≥ 0.5 × 109/L, then 
resume at 1 dose decrement. 
Neutropenic fever 
1) If < 1000/mm3 and single temperature > 
38.3°C  
OR 
2) temperature > 38.0°C for more than 1 
hour 
Withhold dose until ANC returns to baseline grade, then 
resume at same dose. 
ANC = absolute neutrophil count; NA = not applicable. 
a The maximum allowed dose interruption is 4 weeks. 
 


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CONFIDENTIAL 
Revised Table 4: 
Hematologic Toxicity 
Required Action 
Thrombocytopenia 
• 
Platelets ≤10 × 109/L, OR  
• 
Platelets ≤30 × 109/L with evidence of 
bleeding/bruising  
1st episode 
• 
Withhold doses. 
• 
Resume at the same dose level when platelets 
≥ 10 × 109/L and bleeding is controlled. 
Subsequent episodes 
• 
Withhold doses. 
• 
Resume at 1 dose decrement when platelets 
≥ 10 × 109/L and bleeding is controlled. 
Neutropenia   
 
• 
 
• 
ANC < 0.5 × 109/L  
1st episode 
• 
Withhold doses. 
• 
Resume at the same dose level when ANC  ≥ 0.5 × 109/L 
Subsequent episodes 
• 
Withhold doses. 
• 
Resume at 1 dose decrement when ANC ≥ 0.5 × 109/L  
Febrile neutropenia   
• 
ANC < 0.5 x 109/L and oral temperature 
either: 
o 
> 38.5°C, OR 
o 
 > 38.0°C on 2 consecutive 
measurements over 2 hours 
  
1st and subsequent episodes 
• 
Withhold doses.  
• 
Resume at the same dose level when ANC returns to 
baseline grade and fever resolves. 
ANC = absolute neutrophil count; NA = not applicable. 


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CONFIDENTIAL 
9.3.1.2 Nonhematologic Toxicity, 
paragraph 1 
Replace: 
Guidelines for dose modification 
in the event of nonhematologic 
toxicities are summarized in 
Table  6. 
With: 
Requirements for dose modification of 
carfilzomib in the event of nonhematologic 
toxicities are summarized in Table 5. 
Revised text for clarification 
9.3.1.2 Nonhematologic Toxicity, 
Table 5, Title 
Replace: 
Carfilzomib Dosing Guidelines for 
Nonhematologic Toxicity 
With: 
Carfilzomib Dose Modifications for 
Nonhematologic Toxicity 
Revised text for clarification 
Section:  9.3.1.2 Nonhematologic 
Toxicity, Table 5 
Replace: 
Original Table 6 below  
With: 
Revised Table 5 below 
Revised text for clarification 
 


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CONFIDENTIAL 
Original Table 6: 
Nonhematologic Toxicity 
Recommended Actiona 
Renal Dysfunction 
Serum creatinine equal to or greater than 2 × 
Baseline, or CrCl < 15 mL/min (or CrCl 
decreases to ≤ 50% of baseline), or need for 
dialysis 
Withhold dose and continue monitoring renal function (serum creatinine or creatinine clearance).  
If attributable to carfilzomib, resume when renal function has recovered to within 25% of Baseline; start at 
1 dose level reduction. 
If not attributable to carfilzomib, dosing may be resumed at the discretion of the physician. 
If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.  For 
patients on dialysis receiving carfilzomib, the dose is to be administered after the dialysis procedure. 
≥ Grade 3 Elevation in LFTs (AST, ALT, or 
total bilirubin)b 
Withhold dose.  Resume at 1 dose decrement when toxicity has resolved to Baseline.c 
Grade 3 Infection 
• Withhold carfilzomib until infection resolves.  Resume carfilzomib at same dose. 
Congestive heart failure 
• Any subject with symptoms of congestive heart failure, whether or not drug related, must have the dose held 
until resolution or return to Baseline, after which treatment may continue at a reduced dose, or the subject 
may be permanently discontinued.   
• If no resolution after 4 weeks, the subject will be withdrawn from all study treatment. 
LVEF Reductions 
For resting LVEF < 40% or reduction of 
LVEF to < 55% if the drop is greater than 
20% from Baseline 
Withhold until LVEF returns to > 40% or, if held due to a drop to < 55%, to within 15% of Baseline.  Resume at 
1 dose decrement.c 
Micro-Angiopathy 


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CONFIDENTIAL 
Nonhematologic Toxicity 
Recommended Actiona 
Thrombotic thrombocytopenic 
purpura/hemolytic uremic syndrome 
(TTP/HUS) 
If suspected TTP/HUS, withhold carfilzomib.   
Manage symptoms per standard of care including plasma exchange as clinically indicated.   
If the diagnosis of TTP/HUS is excluded, carfilzomib administration may resume if clinically appropriate. 
Any Other Drug-Related Non-Hematologic 
Toxicity ≥ Grade 3 
For carfilzomib attribution, withhold dose.   
Resume at 1 dose decrement when toxicity has resolved to Grade 2 or less or to Baseline grade. 
If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. 
Additional dose modification guidance for adverse drug reactions are per the Carfilzomib IB. 
Pulmonary Hypertension 
Withhold until resolved or returned to baseline. 
Restart at the dose used prior to the event or reduce dose by 1 dose level (i.e., 27 mg/m2 to 20 mg/m2 for the 
twice weekly schedule or 70 mg/m2 to 56 mg/m2 for the once weekly schedule), at the discretion of the 
physician. 
If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. 
Posterior reversible encephalopathy syndrome 
(PRES;  with symptoms including headaches, 
altered mental status, seizures, visual loss, and 
hypertension) 
If suspected PRES, withhold carfilzomib.   
Consider evaluation with neuroradiological imaging for onset of visual or neurological symptoms suggestive of 
PRES.   
If the diagnosis of PRES is excluded, carfilzomib administration may resume if clinically appropriate. 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; CrCl = creatinine clearance; eCRF = electronic Case Report 
Form; IB = Investigator’s Brochure;  
LFTs = liver function tests; LVEF = left ventricular ejection fraction; mL = milliliter(s); ULN = upper limit of normal. 
Note: Carfilzomib dose schedule does not need to be adjusted for baseline renal dysfunction. 
a The maximum allowed dose interruption is 4 weeks. 
b If AST or ALT is ≥ 3 × ULN, the “evaluation of treatment-emergent liver abnormalities” eCRF should be completed. 
c Dose reduction should be attempted first to manage treatment-emergent toxicities.   


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CONFIDENTIAL 
Revised Table 5: 
Nonhematologic Toxicity 
Required Actiona 
Renal Dysfunction 
• 
Serum creatinine ≥ 2 × baseline, OR 
• 
CrCl < 15 mL/min, OR  
• 
rCl decreases to ≤ 50% of baseline, OR 
• 
Requirement for dialysis 
• Withhold doses while the cause of renal dysfunction is being assessed. 
• If attributable to carfilzomib, resume at 1 dose decrement when CrCl has recovered to within 25% of 
baseline 
• If not attributable to carfilzomib, resume the same dose or reduce by 1 dose decrement, at the investigator’s 
discretion, when CrCl has recovered to within 25% of baseline 
• For patients on dialysis receiving carfilzomib, the dose is to be administered after the dialysis procedure. 
Hepatic Dysfunction 
• 
≥ Grade 3 Elevations of AST, ALT, or 
total bilirubin 
• Withhold doses. 
• Resume at 1 dose decrement when the grade has returned to baseline.c 
Infection 
• 
≥ Grade 3 Infection 
• Withhold doses. 
•  Resume at the same dose level, when the infection is controlled. 
Cardiovascular Dysfunction 
• 
Congestive Heart Failure 
• Withhold doses for any subject with symptomatic heart failure, whether or not it is attributed to 
carfilzomib  
• Resume at 1 dose decrement, when symptoms have resolved or returned to baseline 
• 
LVEF < 40%, OR 
• 
LVEF < 55%, if decreased > 20% from 
Baseline 
  
• Withhold doses 
• Resume at 1 dose decrement, when LVEF returns to ≥ 40%, or to within 15% of baseline, if carfilzomib 
was held due to a drop to <55% 
• 
Pulmonary Hypertension 
• Withhold doses and assess the benefit: risk of resuming carfilzomib. 
• If the assessment favors benefit, carfilzomib may be resumed at the same dose level or at 1 dose 
decrement, at the investigator’s discretion. 
Thrombotic Microangiopathy 
• 
Thrombotic thrombocytopenic 
purpura/hemolytic uremic syndrome 
• Withhold doses when TTP/HUS is suspected. 


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Nonhematologic Toxicity 
Required Actiona 
(TTP/HUS) 
• If the diagnosis is excluded, resume at the same dose level. 
• If the diagnosis is confirmed, the decision to resume or not resume carfilzomib is at the investigator’s 
discretion.  The safeness of resuming carfilzomib following TTP/HUS is unknown. 
• Manage symptoms per standard of care including, plasma exchange as clinically indicatedb.   
Encephalopathy 
• 
Posterior reversible encephalopathy 
syndrome (PRES) 
• Withhold doses and assess the benefit:risk of resuming carfilzomib. 
• Consider evaluation with neuroradiological imaging for onset of visual or neurological symptoms suggestive 
of PRES.   
• If the diagnosis is excluded, resume at the same dose level. 
• If the diagnosis is confirmed, the decision to resume or not resume carfilzomib is at the investigator’s 
discretion.  The safeness of resuming carfilzomib following PRES is unknown. 
Other Nonhematologic Toxicity 
• 
≥ Grade 3 and attributed to 
carfilzomib 
• Withhold doses.   
• Resume at 1 dose decrement,, when toxicity has resolved to Grade ≤ 2 or to Baseline. 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; CrCl = creatinine clearance; eCRF = electronic Case Report 
Form; IB = Investigator’s Brochure;  
LFTs = liver function tests; LVEF = left ventricular ejection fraction; mL = milliliter(s); ULN = upper limit of normal. 
Note: Carfilzomib dose schedule does not need to be adjusted for baseline renal dysfunction. 
a The maximum allowed dose interruption is 4 weeks, except with approval by the medical monitor. 
b Subjects requiring plasma exchange must be withdrawn from study treatment.  Every effort should be made to assess disease status in accordance with 
IMWG criteria, before plasma exchange is initiated. 


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CONFIDENTIAL 
 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 9.3.2 Dexamethasone: 
Guidelines for Toxicities and Dose 
Modification, paragraph 1 
Replace: 
Dose reduction levels of 
dexamethasone for toxicity 
management of individual subjects 
are provided in Table 7. 
With: 
Dose decrements for dexamethasone are 
provided in Table 6.  
Revised text for clarification 
Section: 9.3.2 Dexamethasone: 
Guidelines for Toxicities and Dose 
Modification, paragraph 2 
Replace: 
Dexamethasone will be 
permanently discontinued after 
2-dose level reductions in the event 
of additional 
dexamethasone-related toxicities.  
At the investigator’s discretion, 
dexamethasone may be tapered, 
prior to complete discontinuation, 
according to institutional practice.  
Guidelines for 
dexamethasone-related toxicities 
are summarized in Table 8 
With: 
Dexamethasone will be permanently 
discontinued, if toxicity persists following 
2 dose level reductions.  At the 
investigator’s discretion, dexamethasone 
may be tapered, prior to complete 
discontinuation, according to institutional 
practice.  The requirements for dose 
modification due to dexamethasone-related 
toxicities are summarized in Table 7 
Revised text for clarification 
Section: 9.3.2 Dexamethasone: 
Guidelines for Toxicities and Dose 
Modification, Table 7, title  
Replace: 
Treatment Guidelines for 
Dexamethasone-related Toxicities 
With: 
Treatment Rules for Dexamethasone-related 
Toxicities 
Revised text to emphasize 
requirement 
Section:  9.3.2 Dexamethasone: 
Guidelines for Toxicities and Dose 
Modification,, Table 7 
Replace: 
Original Table 8 below  
With: 
Revised Table 7 below 
Revised text for clarification 


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Original Table 8: 
Dexamethasone-related Toxicities, All Days and Cycles 
Symptom 
Findings 
Recommended Action 
Cardiovascular 
Edema > Grade 3 (anasarca or limiting 
function and unresponsive to therapy) 
Diuretics as needed, and restart dexamethasone at 1 dose decrement; if edema persists despite above 
measures, decrease dose by another dose decrement. 
Discontinue dexamethasone permanently if symptoms persist despite second reduction. 
Gastrointestinal 
Toxicity 
Dyspepsia, gastric or duodenal ulcer, or 
gastritis Grade 1or 2 (requiring medical 
management) 
Continue dexamethasone at same dose and treat with therapeutic doses of histamine 2 (H2) blockers, 
or proton pump inhibitor. 
Consider adding sucralfate or other antiulcer treatment as clinically indicated. 
If symptoms persist despite above measures, decrease dexamethasone dose by 1 dose level. 
Dyspepsia, gastric or duodenal ulcer, or 
gastritis ≥ Grade 3 (requiring 
hospitalization or surgery) 
Withhold dexamethasone until symptoms return to Baseline.  
Restart dexamethasone at 1 dose decrement along with concurrent therapy with H2 blockers, 
sucralfate, or omeprazole. 
If symptoms persist despite above measures, discontinue dexamethasone permanently. 
Acute pancreatitis 
Discontinue dexamethasone permanently. 
General Disorders Limb edema > Grade 3 (> 30% limb 
discrepancy in volume; gross deviation 
from normal anatomic contour; limiting 
self-care activities of daily living) 
Withhold dexamethasone until symptoms return to Baseline. 
Diuretics as needed, and restart dexamethasone at 1 dose decrement; if edema persists despite above 
measures, decrease dose by another dose decrement. 
Discontinue dexamethasone permanently if symptoms persist despite second reduction. 
Psychiatric 
Disorders 
Confusion or mood alteration ≥ Grade 2 
(interfering with function ± interfering 
with activities of daily living) 
Withhold dexamethasone until symptoms return to Baseline. 
Restart dexamethasone at 1 dose decrement. 
If symptoms persist despite above measures, reduce by another dose decrement. 
Musculoskeletal 
Muscle weakness ≥ Grade 2 
(symptomatic and interfering with 
function ± interfering with activities of 
daily living) 
Decrease dexamethasone by 1 dose decrement. 
If weakness persists, decrease dose by another dose decrement. 
Discontinue dexamethasone permanently if symptoms persist. 


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CONFIDENTIAL 
Revised Table 7: 
Toxicity 
Required Action 
Edema 
≥ Grade 3: 
• 
Limb Edema 
• 
Truncal Edema 
• Withhold doses and diurese as needed. 
• Resume at 1 dose decrement when Grade ≤ 1 or baseline.  
Gastrointestinal Distress 
Grade 1 or 2: 
• 
Dyspepsia, OR 
• 
Gastritis, OR 
• 
Gastric or Duodenal Ulcer 
• Continue doses while attempting medical management. 
• If symptoms persist, reduce by 1 dose decrement 
≥ Grade 3: 
• 
Dyspepsia, OR 
• 
 Gastritis, OR 
• 
Gastric or  Duodenal Ulcer 
• Withhold doses.  
• Resume at 1 dose decrement, when symptoms return to baseline. 
• If symptoms recur despite appropriate medical management discontinue dexamethasone 
permanently. 
• 
Acute pancreatitis 
• Discontinue dexamethasone permanently. 
Psychiatric Disorders 
≥ Grade 2: 
• 
Confusion, OR  
• 
mood alteration  
• Withhold doses. 
• Resume at 1 dose decrement, when symptoms return to baseline. 
Other Toxicities 
• 
≥ Grade 3 and attributed to dexamethasone 
• Withhold doses.  
• Resume at 1 dose decrement, when toxicity has resolved to ≤ Grade 2. 


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CONFIDENTIAL 
 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 9.3.3 Conditions not 
Requiring Dose Reduction, 
paragraph 1 
Replace: 
The following conditions are exceptions to the 
above guidelines.  Carfilzomib and 
dexamethasone do not need to be held in the 
following cases: 
With: 
The following conditions are exceptions to the 
requirements presented above.  Carfilzomib 
and dexamethasone do not require dose 
modification in the following cases: 
Revised text for 
consistency within 
overall protocol 
Section: 9.3.3 Conditions not 
Requiring Dose Reduction, 
paragraph 1, bullet 1 
Replace: 
Grade 3 nausea, vomiting, or diarrhea (unless 
persisting more than 3 days with adequate 
treatment of antiemetics or antidiarrheal agents) 
With: 
Grade 3 nausea, vomiting, or diarrhea (unless 
persisting more than 3 days despite appropriate 
use of antiemetics or antidiarrheal agents) 
Revised text for 
clarification 
Section: 9.3.3 Conditions not 
Requiring Dose Reduction, 
paragraph 1, bullet 2 
Replace: 
• Grade 3 dexamethasone-related 
hyperglycemia 
With: 
• Grade 3 hyperglycemia 
Removed requirement 
for hyperglycemia to 
be 
dexamethasone-related 
Section: 9.4 Concomitant Medications 
and Therapies, heading 
Replace: 
Concomitant Medications and Concomitant 
Therapies 
With: 
Concomitant Medications and Therapies 
Administrative change 
Section: 9.4 Concomitant Medications 
and Therapies, paragraph 1, sentence 2 
Replace: 
For all randomized subjects, all administered 
concomitant medications and therapies, from 
signing of the informed consent until 30 days 
after the subject’s last dose of study treatment, 
must be recorded in the designated electronic 
Case Report Form (eCRF). 
With: 
For all randomized subjects, all administered 
concomitant medications and therapies, from 
signing of the informed consent until 30 days 
after the last dose of study treatment, must be 
recorded in the designated electronic Case 
Report Form (eCRF). 
Administrative change 
Section: 9.4 Concomitant Medications 
and Therapies, paragraph 2 
Replace: 
Concomitant medications required for the study 
or used prophylactically should be described as 
such in the designated CRF.  Concomitant 
medications prescribed for “prn (as needed) use” 
on an “as needed” basis should not be reported 
With: 
Concomitant medications required for the study 
or used prophylactically should be described as 
such in the designated eCRF.  Concomitant 
medications prescribed for “prn” or “as needed” 
use should not be reported, unless actually 
Administrative change 


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unless actually administered. 
administered. 
Section: 9.4 Concomitant Medications 
and Therapies, paragraph 3 
Replace: 
Blood or blood products are not considered 
concomitant medications and must be recorded 
on the appropriate eCRF. 
With: 
Blood and blood products are not considered 
concomitant medications and must be recorded 
on the appropriate eCRF. 
Administrative change 
Section:  9.4.1 Required Concomitant 
Medications 
Replace: 
Required prophylactic medications should be 
initiated at least 24 hours prior to the first 
administration of carfilzomib. 
With: 
Required prophylactic medications should be 
initiated at least 1 day prior to the first 
administration of carfilzomib. 
Revised text for 
clarification 
Section:  9.4.1.1 (old) Antiviral 
Prophylaxis 
 
Section moved to section 9.4.2.1 
Revised for 
consistency with the 
current label 
Section:  9.4.1.1 (newly renumbered) 
Gastrointestinal Prophylaxis 
Replace: 
Lansoprazole, 15 mg PO daily, or other oral 
proton-pump inhibitor according to institutional 
practice to prevent peptic ulcer disease is a 
required concomitant medication throughout the 
duration of study treatment with dexamethasone. 
With: 
Lansoprazole or other oral proton-pump 
inhibitor, dosed according to institutional 
practice, is required to prevent peptic ulcer 
disease throughout the duration of treatment 
with dexamethasone. 
Administrative change 
Section: 9.4.1.2 Pregnancy and 
Contraception, paragraph 1 
Replace: 
Contraception must continue during study drug 
dose interruption intervals until 30 days after the 
last study drug administration. 
With: 
Contraception must continue during study drug 
dose interruption intervals until 30 days 
(females) and 90 days (males) after the last 
study drug administration. If applicable, refer to 
the Country Specific Pregnancy and 
Contraceptive Supplement (refer to 
Appendix K). 
Updated text to align 
with current 
carfilzomib core safety 
language 
Section: 9.4.1.2 Pregnancy and 
Contraception, paragraph 2 
Replace: 
If the subject thinks she may be pregnant (e.g., if 
a menstrual period in a FCBP does not occur at 
With: 
If a subject thinks she may be pregnant (e.g., if a 
menstrual period in an FCBP does not occur at 
Revised text for 
consistency within 
overall protocol 


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the anticipated time), study drug treatment must 
be interrupted, and a serum pregnancy test must 
be performed locally.  Study drug administration 
may resume after documentation of a 
nonpregnant state. 
the anticipated time), study drug treatment must 
be interrupted, and a urine or serum pregnancy 
test must be performed locally.  Study drug 
administration may resume after documentation 
of a nonpregnant state. 
Section 9.4.2 Recommended 
Concomitant Medications, heading 
Replace:  
Optional and Allowed Concomitant Medications 
With: 
Recommended Concomitant Medications 
Revised text for 
clarification 
Section 9.4.2 Recommended 
Concomitant Medications 
Replace: 
Allopurinol (or other approved uric acid-
lowering agent) in subjects at high risk for tumor 
lysis syndrome (TLS) due to high tumor burden 
may be prescribed at the investigator’s 
discretion.  Subjects should be well hydrated to 
reduce the risk of TLS and decline in renal 
function; refer to the current Carfilzomib IB for 
safety guidance regarding TLS. 
Mycostatin or oral fluconazole to prevent oral 
thrush is optional and may be given at the 
investigator’s discretion. 
Subjects may receive antiemetics and 
antidiarrheal agents as necessary.  Myeloid 
growth factors may be used if neutropenia 
occurs in accordance with American Society of 
Clinical Oncology (ASCO) Guidelines 
(Smith 2006), but should not be given 
prophylactically.  Subjects may receive RBC 
transfusions, erythropoietic stimulating agents, 
or platelet transfusions if clinically indicated in 
accordance with institutional guidelines.  
Subjects may receive bisphosphonates. 
Palliative radiation for pain management is 
permitted with the written approval of the study 
With: 
9.4.2.1 Antiviral Prophylaxis 
Valacyclovir (or an equivalent antiviral agent) is 
recommended for prophylaxis against herpes 
zoster reactivation. 
9.4.2.2 Uric Acid-lowering Agents 
Allopurinol or other approved uric acid-lowering 
agent are recommended for subjects at high 
risk for tumor lysis syndrome (TLS) due to high 
tumor burden. Refer to the current Carfilzomib 
IB for safety guidance regarding TLS. 
9.4.2.3 Mycostatin or Oral Fluconazole 
Mycostatin or oral fluconazole may be given to 
prevent oral thrush throughout the duration of 
treatment with dexamethasone. 
9.4.2.4 Antiemetics and Antidiarrheal Agents 
Antiemetics and antidiarrheal agents are 
recommended for prophylaxis and/or 
management of treatment-related 
gastrointestinal symptoms. 
Headings added for 
ease of use within the 
protocol 


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medical monitor. 
Section: 9.4.3 Excluded Concomitant 
Medications and Therapies 
Replace: 
The clinical investigator should contact the study 
medical monitor if concomitant use of excluded 
medications or therapies is required, to 
determine the appropriateness of continued study 
treatment administration. 
Concurrent therapy with a marketed or 
investigational anticancer therapeutic or 
radiation to large marrow reserves for either a 
palliative or therapeutic intent is prohibited. 
Additionally, no alternative or investigational 
anticancer therapy (other than that received in 
the study) is allowed prior to documentation of 
PD per protocol-specified disease response 
criteria.  Any new anticancer therapies a subject 
received during the study (from randomization 
to study completion or early discontinuation) 
must be recorded in the designated eCRF. 
Corticosteroids for nonmalignant conditions 
(e.g., asthma, inflammatory bowel disease) 
equivalent to a dexamethasone dose 
> 4.0 mg/day or prednisone > 20 mg/day are not 
permitted.  Higher steroid doses given short term 
for exacerbations of nonmalignant conditions 
(e.g., asthma flare) are permitted with the 
approval of the study medical monitor. Subjects 
requiring the use of excluded concomitant 
medications or procedures will be withdrawn 
from study treatment. 
Plasmapheresis is not permitted at any time 
during the Screening period or while the subject 
With: 
If an investigator deems that use of an 
excluded concomitant medication or therapy 
is required, but does not believe that 
withdrawal from study treatment is indicated, 
he/she must contact the study medical 
monitor to determine if continued study 
treatment is acceptable. 
9.4.3.1 Anticancer Agents 
Therapy with a marketed or investigational 
anticancer agent that is not required per this 
protocol is prohibited, while subjects remain 
on study treatment, and should be avoided 
prior to documentation of disease 
progression.   
9.4.3.2 Radiation Therapy 
Radiation to large marrow reserves is 
prohibited, however, focal palliative radiation 
is allowed with permission from the study 
medical monitor. 
9.4.3.3 Myeloid Growth Factors 
Prophylactic use of myeloid growth factors is 
prohibited, but they may be used for 
management of neutropenia, in accordance 
with American Society of Clinical Oncology 
(ASCO) Guidelines (Smith 2006). 
9.4.3.4 Corticosteroids 
Corticosteroids should not be used to treat 
concurrent medical conditions, unless the dose 
remains less than the equivalent of 4 mg/day 
Reorganized section 
and added headings 
for ease of use within 
the protocol and to 
clarify concomitant 
medications and 
therapies that were 
excluded 


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is receiving study treatment.  If a subject who 
has started screening procedures requires 
plasmapheresis, or is anticipated to require 
plasmapheresis during or after the Screening 
period, this subject will be considered ineligible 
and will not be enrolled. 
For subjects requiring plasmapheresis while on 
study treatment every attempt should be made to 
document disease status by IMWG criteria first, 
and then discontinue study treatment and enter 
LTFU for monitoring survival and PFS. 
Subjects requiring plasmapheresis must have 2 
serum samples (for serum protein 
electrophoresis [SPEP] and immunofixation) and 
at least one 24-hour urine sample (urine protein 
electrophoresis [UPEP] and immunofixation) 
obtained prior to the procedure. 
of dexamethasone.  Short term use of higher 
doses may be permitted to treat acute 
exacerbations of concurrent medical 
conditions, but this must be discussed with the 
study medical monitor as soon as is possible. 
9.4.3.5 Plasmapheresis 
Plasmapheresis is not permitted at any time 
during the Screening period or while the subject 
is receiving study treatment.  If a subject who 
has started screening procedures requires 
plasmapheresis, or is anticipated to require 
plasmapheresis during or after the Screening 
period, this subject will be considered ineligible. 
For subjects requiring plasmapheresis while on 
study treatment, every attempt should be made 
to document disease status by IMWG criteria 
first.  Study treatment must be discontinued 
and the subject will enter LTFU. 
9.4.3.6 Novel Agents for Non-neoplastic 
Conditions 
The use of novel agents for non-neoplastic 
conditions is prohibited throughout the 
duration of treatment and for 30 days 
following the last dose of study treatment. 
Section: 10.1.1 Multiple Myeloma 
History and Prior Lines of Therapy 
Assessment, paragraph 1, sentence 1 
 
Delete: 
Subjects must have confirmed and verifiable 
diagnosis of multiple myeloma and documented 
relapse after at least 2 but no more than 
3 therapies for multiple myeloma. 
Deleted text to remove 
redundancies 
Section: 10.1.1 Multiple Myeloma 
History and Prior Lines of Therapy 
Replace: 
A new therapy is also considered to start when a 
With: 
A new therapy is also considered to start when a 
Revised text for 
clarification 


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Assessment, paragraph 1, bullet 1, 
sentence 2 
planned period of observation off-therapy is 
interrupted by a need for additional lines of 
therapy for the disease. 
planned period of observation off-therapy is 
interrupted by a need for additional lines of 
therapy. 
Section: 10.1.1 Multiple Myeloma 
History and Prior Lines of Therapy 
Assessment, paragraph 1, bullet 2 
Replace: 
• An increase in treatment administration, with 
the intention of recapturing response in a 
patient with evidence of disease progression 
on that line of therapy is considered a new 
therapy. 
With: 
• An increase in treatment administration, with 
the intention of recapturing response in a 
patient with evidence of disease progression 
on that line of therapy, is considered to be a 
new line of therapy. 
Revised text for 
clarification 
Section: 10.1.1 Multiple Myeloma 
History and Prior Lines of Therapy 
Assessment, paragraph 2, after bullet 2 
 
Add: 
If available, historical FISH data should be 
entered into the eCRF. The following results 
should be captured: 
o 
t(4;14) 
o 
t(6;14) 
o 
t(11;14) 
o 
t(14;16) 
o 
t(14;20) 
o 
Del 17p 
o 
Del 13 
o 
Chromosome 1 abnormalities 
Updated to clarify that 
cytogenetic 
abnormalities from 
prior testing should be 
reported as part of 
multiple myeloma 
history 
Section: 10.1.3 Complete Physical 
Examination 
Replace: 
A physical examination will be performed 
during Screening, prior to dosing on Day 1 of 
each cycle and at the EOT.  For Cycle 1 Day 1, 
the screening physical examination may be used 
if within 7 days prior to Cycle 1 Day 1.  Physical 
exam may be completed up to 3 days prior to 
Day 1 of each cycle.  Additional physical 
With: 
A physical examination will be performed 
during Screening, prior to dosing on Day 1 of 
each cycle, and at the EOT.  For Cycle 1 Day 1, 
the screening physical examination may be used 
if performed within 7 days prior to Cycle 1 
Day 1.  Physical exam may be completed up to 
3 days prior to Day 1 of each cycle. At a 
Clarified required 
components of 
complete physical 
examination 


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examinations may be performed at the discretion 
of the study investigator to assess potential AEs 
and for the medical management of the subject.  
Abnormal findings that should be recorded as an 
AE and will include but not limited to: 
• Examination of cardiovascular and 
respiratory systems  
• Abdominal examination 
• Peripheral neuropathy (PN) assessment 
(including the neurologic physical exam)  
• Height (at Screening only) 
• Weight 
Body surface area determination should occur on 
Day 1 of each cycle prior to dosing.  BSA is 
determined by a standard formula such as the 
Mosteller Formula (Mosteller 1987):  BSA (m²) 
= ([Height (cm) × Weight (kg)]/ 3600)½.  
Abnormal physical examination findings prior to 
Screening will be captured as medical history.  
Abnormal physical examination findings 
observed after the signing of informed consent 
will be recorded as AEs. 
minimum, the physical exam should include 
constitutional, abdominal, cardiovascular, 
and respiratory assessments. 
Clinically significant abnormal findings 
identified after the signing of informed 
consent must be reported as AEs and 
examined more frequently, as clinically 
indicated. Note: Clinically significant 
abnormal physical examination findings 
identified prior to the signing of informed 
consent should be reported as part of Medical 
History, not as AEs. 
BSA is to be determined by a standard formula, 
such as the Mosteller Formula (Mosteller 1987):  
BSA (m²) = ([Height (cm) × Weight (kg)]/ 
3600 )½.  BSA must be recalculated and used 
for subsequent dose determinations, if the 
subject experiences a weight change of ≥20%.  
Recalculations of BSA must be made using 
the same technique as used at baseline. 
Section: 10.1.4 Eastern Cooperative 
Oncology Group Performance Status 
Replace: 
Eastern Cooperative Oncology Group 
Performance Status will be assessed during 
physical examination at Screening prior to 
randomization to determine eligibility and at the 
EOT visit.  Eastern Cooperative Oncology 
Group Performance Status grades and 
descriptions are tabulated in Appendix E. 
With: 
Eastern Cooperative Oncology Group 
Performance Status will be assessed at Screening 
and at the EOT visit.  Eastern Cooperative 
Oncology Group Performance Status grades and 
descriptions are tabulated in Appendix E. 
Revised text for 
clarification 
Section: 10.1.5 International Staging 
Replace: 
With: 
Revised text for 


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System Stage Determination 
Beta-2 microglobulin and albumin will be 
assessed at the central laboratory during 
Screening to determine ISS Stage at study entry 
(refer to Appendix B and Appendix H).  The ISS 
Stage determined within the 21 days prior to 
randomization will be used to stratify the 
subject.  These results must be evaluated at the 
central laboratory and available at the time of 
randomization. 
Beta-2 microglobulin and albumin will be 
assessed at the central laboratory during 
Screening, to determine ISS Stage (refer to 
Appendix B and Appendix H).  These results 
must be available, prior to randomization. 
consistency within 
overall protocol 
Section: 10.1.6 24-Hour Urine 
 
Delete: 
10.1.6 24 Hour Urine 
Subjects will be instructed to collect 24-hour 
urine samples for assessment of UPEP at 
Screening, and as required during the study.  
This collection will occur over 2 days and will 
be assessed at the central laboratory.  For further 
instruction, refer to study laboratory manual. 
Relocated text for 
clarity 
Section: 10.2 Multiple Myeloma 
Disease Assessments, paragraph 2 
(old) 
 
Delete: 
Results for disease assessments SPEP, UPEP, 
SFLC, and immunofixation must be available at 
Screening and before randomization and will be 
repeated on Cycle 1 Day 1 (unless screening 
values are within 7 days of Cycle 1 Day 1).  
Post-Cycle 1 Day 1 UPEP and urine 
immunofixation will be measured: 
• Only if Cycle 1 Day 1 UPEP 
≥ 200 mg/24 hours 
• To confirm a disease response (for very good 
partial response [VGPR] or better) or 
progression (if applicable) 
Reorganized section 
for clarification 
Section: 10.2 Multiple Myeloma 
Replace: 
With: 
Reorganized section 


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Disease Assessments, paragraph 3 
Cycle 1 Day 1 (screening values may be used if 
obtained within 7 days prior to Cycle 1 Day 1), 
Cycle 2 Day 1 and each cycle thereafter, EOT 
and during LTFU (every 4 weeks, until PD 
and/or started a subsequent antimyeloma 
therapy): 
• SPEP, UPEP (24-hour assessment, no 
substitute method is acceptable), 
and immunofixation 
• SFLC 
• Quantitative immunoglobulins 
 
Cycle 1 Day 1 before treatment begins 
(screening values may be used if obtained within 
7 days prior to Cycle 1 Day 1), and every 
28 days (± 4 days) thereafter, at EOT and 
during LTFU if disease progression has not 
already been documented (every 28 days ± 
4 days, until PD and/or started a subsequent 
antimyeloma therapy): 
• SPEP, immunofixation 
• UPEP (24-hour assessment, no substitute 
method is acceptable), and immunofixation: 
post-Cycle 1 Day 1 measurements 
required only if Cycle 1 Day 1 UPEP 
≥ 200 mg/24 hours or to confirm a disease 
response (for very good partial response 
[VGPR] or better) or progression (if 
applicable) 
• SFLC: post-Cycle 1 Day 1 measurements 
required only for SFLC measurable 
disease or to confirm stringent complete 
response (sCR) 
for clarification 
Section: 10.2 Multiple Myeloma 
Disease Assessments, paragraph 4 
 
Add: 
Subjects will be instructed to collect 24-hour 
urine samples for assessment of UPEP at 
Screening and as required during the study.  
This collection will occur over 2 days and will 
be assessed at the central laboratory.  For 
further instructions, refer to the Central 
Laboratory Services Manual. 
Reorganized section 
for clarification 
Section: 10.2 Multiple Myeloma 
Disease Assessments, paragraph 5 
Replace: 
Disease assessments at baseline are collected 
With: 
Radiological disease assessments at baseline are 
Reorganized section 
for clarification 


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only after subject eligibility is confirmed by the 
study medical monitor and may be done after 
randomization (as long as it is done before the 
start of treatment and no more than 21 days 
before Cycle 1 Day 1 dosing) and include: 
• A plasmacytoma evaluation will be 
conducted at baseline only if a lesion is 
suspected clinically.  Historical assessment 
for extramedullary plasmacytoma evaluation 
done as part of standard of care may be used 
as baseline as long as it was performed 
within 30 days prior to Cycle 1 Day 1 dosing. 
Extramedullary Plasmacytoma Assessment 
• If an extramedullary plasmacytoma is 
detected, evaluation will be repeated during 
treatment only to confirm a response of PR or 
better, or to confirm PD. 
• Measurable lesions must have a longest 
diameter of at least 1 cm and the product of 
cross diameter is at least 1 cm2.  
Plasmacytomas of lesser size are considered 
unmeasurable.  Bidimensional lesion 
measurements must be performed and 
recorded in the designated eCRF.  The same 
technique may include: palpation, ultrasound, 
x-ray, computed tomography (CT) scan, 
magnetic resonance imaging (MRI), positron 
emission tomography (PET), or other 
standard-of-care method must be employed 
for each measurement 
• Skeletal survey will include lateral 
Skeletal Survey 
collected after subject eligibility is confirmed 
and may be done after randomization (as long as 
they are done before the start of treatment). 
Radiological disease assessments that were 
done per standard of care within 30 days 
before Cycle 1 Day 1 can be used as study 
baseline disease assessments.  They include: 
• A plasmacytoma evaluation will be 
conducted at baseline, only if a lesion is 
suspected clinically. 
Extramedullary Plasmacytoma Assessment 
• If an extramedullary plasmacytoma is 
detected, evaluation will be repeated during 
treatment, to confirm a response of PR or 
better or to assess for PD based on 
plasmacytoma. 
• Plasmacytomas are considered measurable 
if they have a longest diameter of at least 1 
cm and the product of cross diameter 
measurements is at least 1 cm2.  
Plasmacytomas of lesser size are considered 
unmeasurable.  Bidimensional measurements 
must be recorded in the designated eCRF.  
The same technique must be used to 
evaluate plasmacytomas throughout the 
duration of study participation and may 
include: palpation, ultrasound, x-ray, 
computed tomography (CT) scan, magnetic 
resonance imaging (MRI), positron emission 
tomography (PET), or any other technique 
that is considered to be standard of care. 
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radiograph of the skull, anteroposterior and 
lateral views of the spine, and anteroposterior 
views of the pelvis, ribs, femora, and humeri.  
The skeletal survey will be conducted at 
baseline and will be repeated if worsening 
clinical symptoms suggest PD, or as 
clinically indicated. A historical survey may 
be used if performed within 30 days prior to 
Cycle 1 Day 1. 
• Skeletal survey will include lateral 
radiograph of the skull, anteroposterior and 
lateral views of the spine, and anteroposterior 
views of the pelvis, ribs, femora, and humeri.  
The skeletal survey will be conducted at 
baseline and will be repeated if worsening 
clinical symptoms suggest PD, or as 
clinically indicated.  
• Other radiologic modalities for 
performing skeletal assessment (e.g., 
low-dose CT scan) are acceptable, in 
accordance with regional standards. 
Section: 10.3.1 Disease Response and 
Progression Assessments 
Replace: 
Determination of disease response must be based 
on the reported values from the central 
laboratory results not on local laboratory results.  
Local laboratory results may be used for 
hypercalcemia (corrected calcium using 
albumin) but a confirmatory sample should be 
collected and sent to the central laboratory for 
documentation.  As with all clinically significant 
or relevant local laboratory results, 
hypercalcemia values should be entered into the 
Case Report Form (CRF). 
Response will be determined by the investigator 
based on the disease assessments described 
above and the IMWG-URC (see definitions in 
Appendix G).  Myeloma response will be 
assessed at each cycle prior to the initiation of 
subsequent cycles. 
With: 
Determination of disease response must be based 
on the reported values from the central 
laboratory.  Local laboratory results may be used 
for hypercalcemia (corrected calcium based on 
albumin), but a confirmatory sample should be 
collected and sent to the central laboratory for 
documentation.  
Investigator-determined responses must be 
based on results from the central laboratory 
and must be consistent with the IMWG-URC 
(see definitions in Appendix G).   
Reworded text for 
clarification 
Section: 10.3.2 Tumor Response 
Assessment, bullets 1, 2, 3, 4, and 5 
Replace: 
• All laboratory-based PD (except bone 
With: 
• All laboratory-based PD (except bone 
Reworded text for 
clarification 


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marrow sample) and all response categories 
require 2 consecutive assessments made at 
any time before initiation of any new therapy.  
Confirmatory lab samples should be 
separated by at least 1 calendar day. 
• All response categories also require no 
evidence of progression including new bone 
lesions if radiographic studies were 
performed. 
• The preferred method for a confirmation of 
CR or sCR is a bone marrow biopsy.  
However, an aspirate slide is acceptable for 
confirmation of CR (a confirmatory bone 
marrow sample is not required). 
• Extramedullary plasmacytoma evaluation (if 
present at Screening).  It is not required to 
have 2 consecutive radiographic tests to 
confirm response or progression of 
extramedullary plasmacytoma. 
• In the case where a patient does not have 
measurable M-protein by UPEP at baseline 
(i.e., screening UPEP < 200 mg/24 hours), 
when SPEP is consistent with response (i.e., 
≥ PR), 2 consecutive UPEP must be 
performed to confirm response. 
marrow sample) and all response categories 
require 2 consecutive assessments made at 
any time before initiation of new therapy. 
• All response categories require that there be 
no evidence of disease progression, including 
confirmation of no new bone lesions, if 
radiographic studies were performed. 
• The preferred method of confirming CR or 
sCR is a bone marrow biopsy; however, a 
bone marrow aspirate is also acceptable for 
confirmation of CR. 
• Extramedullary plasmacytoma evaluation (if 
present at Screening).  Two consecutive 
radiographic tests are not required to 
confirm response or progression of 
extramedullary plasmacytoma. 
• In the case where a patient does not have 
measurable M-protein by UPEP at baseline 
(i.e., baseline UPEP < 200 mg/24 hours), 
when SPEP is consistent with response (i.e., 
≥ PR), 2 consecutive UPEP measurements 
must be performed to confirm response. 
Section: 10.3.3 Disease Progression, 
paragraph 1, sentence 2 
Replace: 
Signs and symptoms related to disease 
progression (e.g., pathologic fracture in a subject 
with progressive multiple myeloma) should be 
reported in the appropriate CRF as an AE or as 
an SAE (if the event in question meets the 
criteria for seriousness). 
With: 
Signs and symptoms related to disease 
progression (e.g., pathologic fracture in a subject 
with progressive multiple myeloma) should be 
reported in the appropriate eCRF as an AE or as 
an SAE (if the event in question meets the 
criteria for seriousness). 
Revised text for 
consistency within 
overall protocol 


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Section:10.3.3 Disease Progression, 
paragraph 2 
Replace: 
Decisions to discontinue subjects due to PD 
(including PD due to development of 
hypercalcemia attributed solely to 
recurrence/progression of multiple myeloma) 
must be based on central laboratory evaluation, 
and must also be verified by the medical 
monitor. Confirmation of PD will require 2 
consecutive central laboratory evaluations that 
indicate PD.  There is no specified time 
requirement between the 2 central laboratory 
evaluations.  Local laboratory evaluation will not 
be accepted and change of treatment decisions 
may only be made based on results of central 
laboratory evaluation.  Progressive disease by 
non-laboratory based assessment (i.e., 
plasmacytoma or skeletal lesion) does not 
require confirmatory report.  The assessments 
outlined in Appendix B are required for PD. 
With: 
Study treatment should not be discontinued 
on the basis of disease progression, until PD 
has been appropriately confirmed per 
IMWG-URC.  Disease progression during 
LTFU must also be confirmed by these same 
criteria.  Confirmation of PD will require 2 
consecutive central laboratory evaluations that 
indicate PD, except in cases where PD is based 
on extramedullary lesions or hypercalcemia 
that is attributed solely to PD.  These 
assessments should be separated in time by at 
least 1 calendar day, but no more than 28 ± 4 
calendar days.  Local laboratory results may 
not be used to determine or confirm disease 
progression, except when PD is based on 
hypercalcemia.  The assessments outlined in 
Appendix B are required for PD determination. 
Clarified requirements 
discontinuation of 
subjects for PD 
Section: 10.4 Laboratory Tests, 
paragraphs 1 and 2 
Replace: 
Laboratory tests for efficacy and safety during 
scheduled and unscheduled study visits will be 
performed at a central laboratory and results 
recorded in the study database.  Additional 
laboratory samples may be collected and 
analyzed by local laboratories if immediate 
results are necessary for management of 
treatment-emergent adverse events (TEAEs) or 
dosing determination.  Investigator evaluation of 
disease response should be based solely on the 
central laboratory results, not on local 
laboratory. 
With: 
Laboratory tests for efficacy and safety during 
scheduled and unscheduled study visits, 
including screening will be performed at a 
central laboratory.  Additional safety laboratory 
samples must also be collected and analyzed by 
local laboratories if the results are necessary to 
determine the appropriateness of dose 
administration. In rare circumstances, when 
the central laboratory is unable to provide 
results for tests that are needed to determine 
eligibility, the study medical monitor may 
grant permission for local laboratory results 
to be applied to the screening requirements.  
Clarified because at 
post Cycle 4 there are 
no Day 8 lab samples 
required 


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Clinical laboratory samples may be obtained 
anytime within the 24 hours prior to the 
carfilzomib administration and must be reviewed 
prior to the start of carfilzomib infusion on 
Days 1, 8, and 15 of all cycles. 
Local labs may also be required for 
management of treatment-emergent adverse 
events (TEAEs).  Laboratory tests for disease 
assessment are described in Section 10.2. 
Safety samples must be obtained within the 1 
day prior to carfilzomib administration and the 
results must be reviewed prior to the start of the 
carfilzomib infusions on Days 1, 8, and 15 of 
Cycles 1 to 4. Beyond Cycle 4, these labs are 
only required on Days 1 and 15 of each cycle. 
Section: 10.4.1 Hematology, 
paragraph 1 
Replace: 
Hematology (central laboratory, Table 9) will be 
performed during Screening, on Days 1, 8, and 
15 for Cycles 1 to 4, and EOT.  Beyond Cycle 4 
labs will be performed on Days 1 and 15 of each 
cycle.  For Cycle 1 Day 1, full hematology from 
Screening can be used if within 3 days.  For 
subsequent visits, hematology may be completed 
up to 24 hours prior to scheduled dose. 
With: 
Hematology assessments (Table 8) will be 
performed during Screening, on Days 1, 8, and 
15 for Cycles 1 to 4, and EOT.  Beyond Cycle 4 
labs will be performed on Days 1 and 15 of each 
cycle.  For Cycle 1 Day 1, hematology 
assessments from Screening can be used, if they 
were obtained within 3 days prior to 
carfilzomib administration.  For subsequent 
visits, hematology assessments may be 
completed up to 1 day prior to the scheduled 
dose. 
Revised text for 
consistency within 
overall protocol 
Section: 10.4.1 Hematology, Table 8 
Replace: 
WBCs with complete manual or automated 
differential to include: a 
Total neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
With: 
WBC count with complete differential to 
include: a 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Revised text for 
consistency within 
overall protocol 


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RBCs 
 
RBC count 
Section: 10.4.1 Hematology, Table 8, 
footnote a 
Replace: 
a Absolute or percentage will be acceptable. 
With: 
a Absolute counts or percentage will be 
acceptable. 
Revised text for 
consistency within 
overall protocol 
Section: 10.4.2 Serum Chemistry, 
paragraph 1 
Replace: 
Full serum chemistry panel (central laboratory, 
Table 10) will be performed during Screening, 
on Days 1, 8, and 15 for Cycles 1 to 4, and EOT.  
Beyond Cycle 4, labs will be performed on 
Days 1 and 15 of each cycle.  For Cycle 1 Day 1, 
full chemistry from Screening can be used if 
within 3 days.  For subsequent visits, chemistries 
may be completed up to 24 hours prior to 
scheduled dose. 
With: 
A serum chemistry panel (Table 9) will be 
performed during Screening, on Days 1, 8, and 
15 for Cycles 1 to 4, and EOT.  Beyond Cycle 4, 
labs will be performed on Days 1 and 15 of each 
cycle.  For Cycle 1 Day 1, serum chemistry 
assessments from Screening can be used, if 
performed within 3 days prior to carfilzomib 
administration.  For subsequent visits, serum 
chemistries may be completed up to 1 day prior 
to the scheduled carfilzomib dose. 
Revised text for 
consistency within 
overall protocol 
Section: 10.4.2 Serum Chemistry, 
Table 9, Note at bottom of Table 
 
Delete: 
Note:  If AST or ALT is > 3 × ULN, the 
“evaluation of treatment-emergent liver 
abnormalities” eCRF should be completed. 
Removed reference to 
this eCRF, which is no 
longer being utilized 
Section: 10.5 Electrocardiogram, 
sentence 2 
Replace: 
Electrocardiogram will be required in all 
subjects at Screening and EOT. 
With: 
Electrocardiograms will be required from all 
subjects at Screening and EOT.   
Administrative change 
Section: 10.6 Echocardiogram, 
paragraphs 1 and 2 
Replace: 
A 2-D transthoracic echocardiogram (ECHO) to 
assess LVEF for eligibility purposes will be 
conducted on all potential subjects during 
Screening and will also serve as the baseline 
ECHO.  If transthoracic ECHO is not available, 
multigated acquisition (MUGA) will be 
With: 
A 2-D transthoracic echocardiogram (ECHO) is 
required to assess LVEF during Screening and 
will also serve as the baseline ECHO.  If 
transthoracic ECHO is not available, multigated 
acquisition (MUGA) will be acceptable for 
Administrative change 


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acceptable for screening LVEF evaluation. 
Additionally, any subject with a clinically 
significant cardiac-related AE should be 
evaluated by a cardiologist and have a follow-up 
ECHO if medically indicated. 
LVEF evaluation. 
Any subject with a clinically significant cardiac 
AE should be evaluated by a cardiologist and 
must have a follow-up ECHO, if medically 
indicated. 
Section: 10.7 Patient Reported 
Outcomes, paragraph 2, sentences 1 
and 2 
Replace: 
All questionnaires should be collected on Day 1 
of Cycle 1, then every other cycle during 
treatment. Questionnaires listed below should be 
completed by the subject prior to drug 
administration during treatment cycles: 
With: 
All questionnaires should be collected on Day 1 
of Cycle 1, then every second cycle (Cycle 1, 3, 
5, etc) during treatment. The questionnaires 
listed below should be completed by the subject 
prior to drug administration during treatment 
cycles: 
Revised text for 
consistency within 
overall protocol 
Section: 10.8 Healthcare Resource 
Utilization 
Replace: 
Healthcare resource utilization data related to 
AEs will be collected for all subjects during the 
study on the eCRF.  These data may include 
inpatient care, outpatient care, surgery, and use 
of other medications and therapeutic procedures 
related to AEs. 
With: 
Healthcare resource utilization data related to 
AEs will be collected for each subject.  These 
data may include inpatient care, outpatient care, 
surgery, and use of other medications and 
therapeutic procedures related to AEs.  Details 
on hospitalizations (not related to AEs) will 
also be collected.  
Added text for 
collection of 
hospitalizations not 
related to AEs to align 
to with previous 
section  
Section: 10.9 Correlative Studies 
Replace: 
Samples for correlative studies will be collected 
only after Screening laboratories confirm study 
eligibility for the subject.  Intensive PK and PDn 
will be conducted as a substudy at selected sites.  
The target number of subjects who participate in 
the intensive PK/PDn substudy is approximately 
15 per arm.  Sparse PK samples will only be 
collected at all other sites from subjects who 
consent to the additional testing. 
With: 
Samples for correlative studies will be collected 
only after confirmation of study eligibility.  
Intensive PK and PDn will be conducted as a 
substudy at selected sites.  Sparse PK samples 
will be collected at all other sites, from subjects 
who consent to the additional testing. 
Revised text for 
consistency within 
overall protocol 


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Section: 10.9.1 Intensive 
Pharmacokinetics/Pharmacodynamics 
Substudy, paragraph 1 
Replace: 
Approximately 15 subjects in each arm will 
participate in the intensive PK/PDn substudy at 
select sites.  On both arms, whole blood and 
PBMCs will be collected from all subjects on 
Days 1, 15, 16, 17, and 22 of Cycle 1 at the 
following timepoints summarized in Table 11.  
Directions for collection, processing, and 
shipping of PDn blood samples are provided in 
the laboratory manual.  The actual time of when 
the PDn sample was collected will be recorded. 
With: 
Approximately 15 evaluable subjects in each 
arm will participate in the intensive PK/PDn 
substudy at select sites.  On both arms, whole 
blood and PBMCs will be collected from all 
subjects on Days 1, 15, 16, 17, and 22 of Cycle 1 
at the timepoints (summarized in Table 10).  
Directions for collection, processing, and 
shipping of PDn blood samples are provided in 
the Central Laboratory Services Manual.  The 
actual time of when the PDn sample was 
collected will be recorded. 
Revised text for 
consistency within 
overall protocol 
Section: 10.9.1 Intensive 
Pharmacokinetics/Pharmacodynamics 
Substudy, Table 10 
Replace: 
Timepoints in days. 
With: 
Timepoints in hours. 
Revised text for 
consistency within 
overall protocol 
Section: 10.9.1 Intensive 
Pharmacokinetics/Pharmacodynamics 
Substudy, paragraph 2, sentence 1 
Replace: 
For both arms, PK plasma samples will be 
collected from all subjects for determination of 
plasma concentrations of carfilzomib on 
treatment Day 15 of Cycle 1 at the following 
time points: 
With: 
For both treatment arms, PK samples will be 
collected from all subjects for determination of 
plasma concentrations of carfilzomib on 
treatment Day 15 of Cycle 1 at the following 
time points: 
Revised text for 
consistency within 
overall protocol 
Section: 10.9.1 Intensive 
Pharmacokinetics/Pharmacodynamics 
Substudy, paragraph 3 
Replace: 
The actual time of PK sample collection will be 
recorded.  Samples will be collected within 
± 5 minute time window around the nominal 
time points (except for the time point 
immediately prior to the end of infusion in 
which the PK collection needs to occur prior to 
end of infusion).  Collecting PK samples at times 
other than nominal time points will not qualify 
for protocol deviation.  These samples will be 
With: 
The actual time of PK sample collection will be 
recorded.  Samples will be collected within 
± 5 minute time windows around the nominal 
time points (except for the time point 
immediately prior to the end of infusion, for 
which the PK collection needs to occur prior to 
the end of infusion).  Directions for collection, 
processing, and shipping of PK samples are 
provided in the Central Laboratory Services 
Revised text for 
clarification 


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assessed at a central laboratory.  Directions for 
collection, processing, and shipping of PK blood 
samples are provided in the laboratory manual. 
Manual. 
Section: 10.9.2 Sparse 
Pharmacokinetic Sampling, 
paragraph 1 
Replace: 
Sparse PK samples will only be collected at the 
sites from subjects who do not participate in the 
intensive PK/PDn substudy and who consent to 
the additional testing.  The actual time of the PK 
sample collection will be recorded.  These 
samples will be assessed at a central laboratory.  
Directions for collection, processing, and 
shipping of PK blood samples are provided in 
the lab manual. 
With: 
Sparse PK samples will be collected from 
subjects who do not participate in the intensive 
PK/PDn substudy and who consent to the 
additional testing.  The actual time of the PK 
sample collection will be recorded.  These 
samples will be assessed at a central laboratory.  
Directions for collection, processing, and 
shipping of PK samples are provided in the 
Central Laboratory Services Manual. 
Administrative change 
Section: 10.10.1 Long-term Follow-up 
Before Disease Progression, paragraph 
1, sentences 1 and 2 
Replace: 
For subjects who discontinued treatment before 
disease progression occurred, disease assessment 
measurements will be performed (using the 
central laboratory results) every 4 weeks (every 
28 days ± 4 days) until the subject has PD or 
until withdrawal of consent (Appendix B).  
Effort should be made to obtain confirmatory PD 
results (refer to Appendix G) prior to the 
initiation of new antimyeloma therapy. 
With: 
For subjects who discontinue treatment before 
disease progression occurs, disease assessments 
will be performed (using the central laboratory 
results) every 28 days ± 4 days until the subject 
has PD or until withdrawal of consent 
(Appendix B).  Confirmatory PD results (refer to 
Appendix G) must be obtained prior to the 
initiation of new antimyeloma therapy.   
Aligned with previous 
section as there will be 
no anticancer therapy 
until PD. 
Section: 10.10.2 Long-term Follow-up 
After Disease Progression (For 
Survival) 
Replace: 
After completion of the EOT visit, subjects who 
have discontinued due to disease progression 
will be followed for survival status queried by 
telephone contact or other method approximately 
every 3 months, or as needed until study closure. 
With: 
After completion of the EOT visit, subjects who 
have discontinued due to disease progression 
will be followed for survival status, queried by 
telephone contact or other method, 
approximately every 12 weeks ± 28 days, or as 
needed until study closure. 
Revised text for 
consistency within 
overall protocol 
Section: 11.1 Withdrawal of Subjects 
Replace: 
With: 
Administrative change 


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from Study Treatment, paragraph 1, 
bullet 5 
• Non-compliance 
• Non-compliance with study requirements 
Section: 11.1 Withdrawal of Subjects 
from Study Treatment, paragraph 1, 
bullet 7 
Replace: 
• Study terminated by Onyx 
With: 
Study termination by Sponsor 
Administrative change 
Section: 11.1 Withdrawal of Subjects 
from Study Treatment, paragraph 1, 
bullet 8 
Replace: 
• Physician decision 
With: 
• Investigator decision 
Administrative change 
Section: 11.1 Withdrawal of Subjects 
from Study Treatment, paragraph 3 
Replace: 
If the reason for study treatment discontinuation 
is the occurrence of an AE, the subject will be 
followed by the investigator until such event(s) 
resolve, stabilize, and, according to the 
investigator’s judgment, there is no need of 
further follow-up. 
With: 
If the reason for study treatment discontinuation 
is the occurrence of an AE, the subject will be 
followed by the investigator until such event(s) 
resolves, stabilizes, or, according to the 
investigator’s judgment, no longer requires 
follow-up. 
Revised text for 
clarification 
Section: 11.1 Withdrawal of Subjects 
from Study Treatment, paragraph 4 
Replace: 
Study treatment discontinuation due to 
progression should be recorded as “disease 
progression.” If the disease progression meets 
any of the serious criteria, as outlined in Section 
12.3 then it should also be recorded as a SAE in 
the AE eCRF. 
With: 
Study treatment discontinuation due to PD 
should be recorded as “disease progression.”  
Removed text to avoid 
duplication 
Section: 11.2 Withdrawal of Subjects 
from Study, paragraph 1, bullet 3 
Replace: 
• Onyx decision 
With: 
• Sponsor decision 
Administrative change 
Section: 11.3 Study Termination, 
paragraph 1, sentences 1 and 2 
Replace: 
Onyx has the right to terminate this study or to 
terminate a study site from participating in the 
study at any time. Reasons for study or site 
termination may include 
With: 
Sponsor has the right to terminate this study or 
to terminate a study site from participating in the 
study at any time. Reasons for study or site 
termination may include, but are not limited to: 
Administrative change 


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Section 12 Adverse Events and 
Serious Adverse Events 
Replace: 
An AE is any untoward medical occurrence in a 
study subject administered an IP regardless of 
the causal relationship with treatment. 
An AE, therefore, can be any unfavorable and 
unintended sign (including laboratory finding), 
symptom, or disease temporally associated with 
participation in an investigational study, whether 
or not considered drug-related.  In addition to 
new events, any increase in the severity or 
frequency of a pre-existing condition that occurs 
after the subject signs the ICF for participation is 
considered an AE.  This includes any side effect, 
injury, toxicity, or sensitivity reaction.  All 
reported AEs will be coded using the current 
version of Medical Dictionary for Regulatory 
Activities (MedDRA). 
With: 
An AE is any untoward medical occurrence in a 
subject administered a study drug and which is 
not necessarily caused by the study drug. An 
AE can therefore be any unfavorable and 
unintended sign (e.g. an abnormal laboratory 
finding), symptom, or disease temporally 
associated with the use of a medicinal product, 
combination product, or medical device, 
whether or not considered related to the 
product.   In addition to new events, any 
worsening of a pre-existing condition that 
occurs after the subject signs the ICF for 
participation is considered an AE.  Worsening 
indicates that the pre-existing medical 
condition or underlying disease has increased 
in severity, frequency, and/or duration more 
than would be expected, and/or has an 
association with a significantly worse outcome 
than expected. This includes any side effect, 
injury, toxicity, or sensitivity reaction.  All 
reported AEs will be coded using the current 
version of Medical Dictionary for Regulatory 
Activities (MedDRA). 
Revised text for 
clarification 
Section: 12.1.2 Severity, paragraph 1 
Replace: 
Whenever possible, the National Cancer 
Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) Version 4.03 
should be used to describe the event and for 
assessing the severity of AEs (NCI 2010). 
With: 
Whenever possible, the National Cancer 
Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) Version 4.03 
should be used to describe the event and to 
assess the severity of AEs (NCI 2010). 
Administrative change 
Section: 12.1.2 Severity, paragraph 3, 
sentence 2 
 
Add: 
Where applicable, clinical sequelae (not the 
Added text to clarify 
recording of 


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laboratory abnormality) are to be recorded as 
the AE. 
laboratory 
abnormalities 
Section: 12.1.3 Duration, sentence 1 
Replace: 
The start and stop date for all AEs will be 
recorded.  The start date is the first date that the 
subject was aware of the AE and the end date is 
the date that the event totally resolved or 
returned to baseline. 
With: 
The start and stop dates for all AEs will be 
recorded.  The start date is the first date that the 
subject was aware of the AE and the end date is 
the date that the event has changed in grade, 
totally resolved, or returned to baseline. 
Clarified definition of 
AE duration for events 
that change in grade 
Section: 12.1.3 Duration, sentence 2 
 
Add: 
Any changes in grade should be recorded as a 
separate event. 
Clarified definition of 
AE duration for events 
that change in grade 
Section: 12.1.4 Causality, paragraph 1 Replace: 
A relationship between carfilzomib and an 
adverse event is considered causal if there is at 
least a reasonable possibility the adverse event 
was caused by carfilzomib administration, i.e., 
the relationship cannot be ruled out. 
With: 
A relationship between study drug and an 
adverse event is considered causal if there is at 
least a reasonable possibility the adverse event 
was caused by carfilzomib administration, i.e., 
the relationship cannot be ruled out. 
Administrative change 
Section: 12.1.4 Causality, paragraph 4  
Delete: 
In the event of a possible drug-related AE, the 
investigator should to the best of his/her ability 
assess its relationship to each of the study drugs: 
carfilzomib and/or dexamethasone. 
Removed text that was 
duplicated 
Section: 12.2.1 General, paragraph 3, 
sentence 3 
Replace: 
For subjects who complete the EOT visit less 
than 30 days following the last dose of study 
drug, a follow-up of ongoing AEs should be 
attempted by telephone and documented in the 
subject’s source file. 
With: 
For subjects who complete the EOT visit less 
than 30 days following the last dose of study 
drug, a follow-up of ongoing AEs should be 
documented in the subject’s source file. 
Revised to clarify that 
follow up did not 
necessarily need to be 
done by telephone 
Section:  12.2.2 Disease Progression 
 
Delete: 
Removed text to avoid 


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12.2.2 Disease Progression 
Disease progression will be documented in an 
eCRF intended to capture PD information and 
will be analyzed as a study endpoint.  Signs and 
symptoms related to disease progression 
(e.g., pathologic fracture in a patient with 
progressive multiple myeloma) should be 
reported in the appropriate case report form as 
an AE or as a SAE (if the event in question 
meets the criteria for seriousness).  Verbatim 
terms such as “disease progression,” 
“progressive disease,” etc. should not be 
reported as AEs or SAEs unless the investigator 
considers the progression to be atypical, 
accelerated, or caused by the study drug.  
Similarly deaths occurring as a result of disease 
progression should be reported on the eCRF 
intended to capture death information and should 
not be reported as SAEs. 
duplication 
Section: 12.3 Serious Adverse Event 
Definition, bullet 2 
Replace: 
• Life-threatening experience defined as any 
adverse experience that places the subject, in 
the view of Onyx or investigator, at 
immediate risk of death at the time of 
occurrence (i.e., it does not include a reaction 
that, had it occurred in a more severe form, 
might have caused death). 
With: 
• Life threatening experience defined as any 
adverse experience that places the subject, in 
the view of the Sponsor or investigator, at 
immediate risk of death at the time of 
occurrence (i.e., it does not include a 
reaction that, had it occurred in a more 
severe form, might have caused death). 
Administrative change 
Section: 12.4 Serious Adverse Event 
Reporting and Documentation 
Requirements, paragraph 1 
Replace: 
Onyx Drug Safety must be notified of the 
occurrence of any SAE within 24 hours of the 
investigator, designee, or site personnel’s 
knowledge of the event.  The SAE will be 
With: 
Amgen Global Patient Safety must be notified 
of the occurrence of any SAE within 24 hours of 
the investigator, designee, or site personnel’s 
knowledge of the event.  The SAE will be 
Administrative change 


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reported by completing and submitting the SAE 
report form through the EDC system.  In the 
event that the EDC system is not available, paper 
SAE report forms may be used to report the SAE 
to Onyx Drug Safety.  Please refer to the SAE 
Reporting Guidelines in the study reference 
manual. 
reported by completing and submitting the SAE 
report form through the EDC system.  In the 
event that the EDC system is not available, paper 
SAE report forms may be used to report the SAE 
to Amgen Global Patient Safety.  Please refer 
to the SAE Reporting Guidelines in the study 
reference manual.   
Section: 12.4 Serious Adverse Event 
Reporting and Documentation 
Requirements, paragraph 3, sentence 2 
Replace: 
Onyx may request for additional source 
documentation pertaining to the SAE from the 
investigational site. 
With: 
The sponsor may request for additional source 
documentation pertaining to the SAE from the 
investigational site. 
Administrative change 
Section: 12.4 Serious Adverse Event 
Reporting and Documentation 
Requirements, paragraph 4 
Replace: 
Onyx is responsible for notifying the appropriate 
global health authorities of SAEs, 
when required, and in accordance with 
applicable laws and regulations. 
With: 
The Sponsor is responsible for notifying the 
appropriate global health authorities of SAEs, 
when required, in accordance with applicable 
laws and regulations. 
Administrative change 
Section: 12.4 Serious Adverse Event 
Reporting and Documentation 
Requirements, paragraph 5 
Replace: 
Properly anonymized and de-identified 
documents (e.g. hospital discharge summaries, 
autopsy reports, and/or death certificates), as 
available will be provided to Onyx Drug Safety. 
With: 
Properly anonymized and de-identified 
documents (e.g. hospital discharge summaries, 
autopsy reports, and/or death certificates), as 
available will be provided to Amgen Global 
Patient Safety. 
Administrative change 
Section: 12.5 Pregnancy and Lactation 
Exposure Reporting, paragraph 1 
Replace: 
Pregnancy occurring in a female subject or in a 
male subject’s partner while enrolled in this 
clinical study through 30 days after the last dose 
of any study drug was received, although not 
considered an SAE, must be reported on a 
Pregnancy Monitoring Form to Onyx Drug 
Safety and the contract research organization 
(CRO) within 24 hours of the investigator, 
With: 
Pregnancy, although not considered an SAE, 
must be reported to Amgen Global Patient 
Safety within 24 hours of the investigator’s 
awareness, if the pregnancy has occurred 
within 30 days of study treatment (for female 
participants) or within 90 days of study 
treatment (for female partners of male 
participants).  The pregnancy will be 
Updated the window 
for breastfeeding 
following the last dose 
of drug administration. 


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designee, or site personnel learning of the 
pregnancy. 
reported on a Pregnancy Notification 
Worksheet. Amgen Global Patient Safety will 
follow-up with the investigator regarding 
additional information that may be requested. 
Section: 12.5 Pregnancy and Lactation 
Exposure Reporting, paragraph 2, 
sentence 1 
Replace: 
If the subject becomes pregnant while taking an 
Onyx drug, the study treatment will be 
immediately discontinued. 
With: 
If a subject becomes pregnant while taking an 
Amgen drug, the study treatment will be 
immediately discontinued. 
Administrative change 
Section: 12.5 Pregnancy and Lactation 
Exposure Reporting, paragraphs 4, 5, 
and 6 
Replace: 
If the outcome of the pregnancy meets a criterion 
for immediate classification as an SAE (e.g., 
spontaneous abortion, stillbirth, neonatal death, 
fetal or neonatal congenital anomaly), the 
investigator will report the SAE via the EDC 
system. 
Newborns should be followed for a minimum of 
12 weeks. 
The investigator is responsible for notifying the 
Institutional Review Board (IRB) or Independent 
Ethics Committees (IEC) in accordance with 
local regulations, of all SAEs.  Onyx may 
request for additional source documentation 
pertaining to the SAE from the investigational 
site.  If a subject is permanently withdrawn from 
the study due to a SAE, this information must be 
included in the initial or follow-up SAE report in 
the eCRF. 
With: 
If the outcome of the pregnancy meets a 
criterion for immediate classification as an SAE 
(e.g., spontaneous abortion, stillbirth, neonatal 
death, fetal or neonatal congenital anomaly), the 
investigator will report the event as an SAE. 
With authorization of the subject or female 
partner, newborns should be followed-up at 6 
and 12 months of age. 
If a female subject breastfeeds during treatment 
with carfilzomib or up to 30 days following the 
last dose of study drug administration, the 
investigator will notify Amgen Global Patient 
Safety within 24 hours of learning of her 
breastfeeding.  The investigator will discuss the 
risks and concerns of breastfeeding while taking 
an IP.  The subject will be required to either 
discontinue breastfeeding or study treatment. 
The investigator will complete a Lactation 
Notification Worksheet. Amgen Global 
Patient Safety will follow-up with the 
investigator regarding additional information 
that may be requested. 
Updated text to align 
with current 
carfilzomib core safety 
language 


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Page 174 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 12.5 Pregnancy and Lactation 
Exposure Reporting, paragraph 7 
 
Delete: 
The investigator will complete a Pregnancy 
Monitoring Form and report the information 
regarding the pregnancy, outcome, and status of 
the newborn, as appropriate. 
Updated text to align 
with current 
carfilzomib core safety 
language 
Section: 12.6 Death Reporting 
Replace: 
All deaths that occur from signing of informed 
consent until 30 days after the last dose of study 
drug are to be reported as SAEs (other than due 
to PD - refer to Section 12.4).  Deaths occurring 
after the EOT visit do not need to be reported as 
SAEs.  Additional details of the event (such as 
the primary and contributory causes of death) 
should be reported on the death eCRF. 
With: 
All deaths that occur from signing of informed 
consent until 30 days after the last dose of study 
drug are to be reported as SAEs (unless due to 
PD - refer to Section 12.4).  Deaths occurring 
after the EOT visit do not need to be reported as 
SAEs.  Additional details of the event (such as 
the primary and contributory causes of death) 
should be reported on the end of study eCRF. 
Administrative change 
Section: 13 Statistical Considerations, 
sentence 2 
Replace: 
Further details of the analyses will be provided 
separately in the Statistical Analysis Plan (SAP). 
With: 
Further details will be provided separately in the 
Statistical Analysis Plan (SAP). 
Administrative change 
Section: 13.1.2 Secondary Endpoints, 
bullet 4 
 
Add: 
• Sparse PK 
Revised text for 
consistency within 
overall protocol 
Section: 13.3.2.1 Primary Efficacy 
Endpoint, paragraph 1, bullet 2 
Replace: 
• Refractory to proteasome inhibitor ([PI] 
bortezomib) treatment (Yes versus No) 
With: 
• Refractory to bortezomib treatment (Yes 
versus No) 
Revised text for 
consistency within 
overall protocol 
Section: 13.3.2.1 Primary Efficacy 
Endpoint, paragraph 3, sentence 3 
Replace: 
Investigator-assessed responses will be analyzed 
as a supportive analysis of ORR. 
With: 
Investigator-assessed responses will be analyzed 
as a supportive analysis of ORR, as will 
IRC-assessed responses, if an IRC is 
convened. 
Added text regarding 
potential use for an 
IRC 
Section: 13.3.2.2.1 Progression-Free 
Replace: 
With: 
Added text regarding 


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Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Survival, paragraph 2 
The primary analysis of PFS will be based on 
ORCA-assessed outcomes.  The PFS outcomes 
assessed by the investigator will serve as a 
supportive analysis of PFS. 
The primary analysis of PFS will be based on 
ORCA-assessed outcomes.  The PFS outcomes 
assessed by the investigator serve as a supportive 
analysis of PFS, as will IRC-assessed 
outcomes, if an IRC is convened. 
potential use for an 
IRC 
Section: 13.3.3.2 Safety Laboratory 
Values, paragraph 1 
Replace: 
For hematology, chemistry, and other laboratory 
values, the baseline values and changes from 
baseline to the minimum, maximum, and last 
observed values will be summarized 
descriptively by visit. 
With: 
For hematology, chemistry, and other laboratory 
values, the baseline values, changes from 
baseline by visit,  the minimum, maximum, and 
last observed values will be summarized 
descriptively. 
Administrative change 
Section: 13.3.3.2 Safety Laboratory 
Values, paragraph 4 
Replace: 
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 select laboratory 
parameters by assessing the maximum increase 
and/or decrease (as clinically relevant) observed 
during the course of study treatment relative to 
the baseline toxicity grade. 
With: 
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 by assessing the maximum increase 
and/or decrease observed during the course of 
study treatment relative to the baseline toxicity 
grade. 
Administrative change 
Section: 13.3.3.2 Safety Laboratory 
Values, paragraph 5 
Replace: 
The subject incidence of Grade 3 and 4 
hematological toxicities (including neutropenia, 
thrombocytopenia, and anemia) will be provided 
by treatment group.  Similar analyses will be 
done for selected chemistry tests. 
With: 
The subject incidence of Grade 3 and 4 
hematological laboratory abnormalities 
(including neutropenia, thrombocytopenia, and 
anemia) will be provided by treatment group. 
Revised text for 
consistency within 
overall protocol 
Section: 13.3.3.2 Safety Laboratory 
Values, paragraph 6 
Replace: 
The subject incidence of Grade 3 and 4 
nonhematological toxicities (including liver 
function test [LFT], CrCl) will be provided by 
treatment group.  Similar analyses will be done 
With: 
The subject incidence of Grade 3 and 4 
nonhematological laboratory abnormalities 
(including liver function test [LFT], CrCl) will 
be provided by treatment group.  Similar 
Revised text for 
consistency within 
overall protocol 


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Carfilzomib 
Page 176 of 185 
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CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
for selected chemistry tests. 
analyses will be done for selected chemistry 
tests. 
13.3.3.3 Vital Signs 
Replace: 
Vital sign results (systolic and diastolic blood 
pressure, pulse, and temperature) will be 
summarized descriptively for baseline values 
and changes from baseline to the minimum, 
maximum, and last observed values. 
With: 
Vital sign results (systolic and diastolic blood 
pressure, pulse, respiratory rate, and 
temperature) will be summarized descriptively 
for baseline values and changes from baseline to 
the minimum, maximum, and last observed 
values. 
Revised text for 
consistency within 
overall protocol 
13.3.4 Sparse Pharmacokinetic 
Analyses, paragraph 1, sentence 3 
Replace: 
Concentrations of carfilzomib will be measured 
in plasma with a validated assay method. 
With: 
Concentrations of carfilzomib will be measured 
in plasma using a validated assay method. 
Administrative change 
13.3.4 Sparse Pharmacokinetic 
Analyses, paragraph 2, sentence 1 
Replace: 
The population pharmacokinetic analysis will be 
a cumulative analysis that will include 
population pharmacokinetic data obtained from 
previous Phase 2 studies that used intensive 
sampling. 
With: 
The population pharmacokinetic analysis will be 
a cumulative analysis that will include 
population pharmacokinetic data obtained from 
previous Phase 2 and Phase 3 studies that used 
intensive or sparse PK sampling. 
Revised text to 
provided updated 
information and 
consistency 
Section: 13.6 Independent Review 
Committee 
Replace: 
No Independent Review Committee (IRC) will 
be used for this study. 
With: 
An IRC may be convened for this study, if 
required to support the ORCA-determined 
results. 
Updated text to 
potentially include an 
IRC if required 
Section: 13.7 Data Monitoring 
Committee, paragraph 1 
Replace: 
An independent Data Monitoring Committee 
(DMC) will be convened for this study and will 
act in an advisory capacity to the sponsor with 
respect to safeguarding the interests of study 
subjects through periodic safety data reviews, 
assessing interim safety and efficacy data, and 
monitoring the overall conduct of the study. 
With: 
An independent Data Monitoring Committee 
(DMC) will be convened for this study and will 
act in an advisory capacity to the sponsor with 
respect to safeguarding the interests of study 
subjects through periodic safety data reviews, 
assessments of interim safety and efficacy data, 
and monitoring of the overall conduct of the 
Administrative change 


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Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 177 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
study. 
Section: 13.7 Data Monitoring 
Committee, paragraph 2 
Replace: 
An Independent Statistical Reporting Group 
(ISRG) will function independently of the Onyx 
study team in support of the DMC.  The ISRG 
will conduct unblinded analyses, generate the 
open and closed reports to be reviewed at the 
DMC meetings, and serve as the liaison between 
Onyx and the DMC. 
With: 
An Independent Statistical Reporting Group 
(ISRG) will function independently of the 
Sponsor study team in support of the DMC.  
The ISRG will conduct unblinded analyses, 
generate the open and closed reports to be 
reviewed at the DMC meetings, and serve as the 
liaison between the Sponsor and the DMC. 
Administrative change 
Section: 14.1 Informed Consent, 
paragraph 2, sentence 1 
Replace: 
Onyx or its designated representative will 
provide the investigator with a sample ICF. 
With: 
The Sponsor or its designated representative 
will provide the investigator with a sample ICF. 
Administrative change 
Section: 14.1 Informed Consent, 
paragraph 3, sentence 3 
Replace: 
The original signed consent must be maintained 
by the investigator and available for inspection 
by Onyx its designated representative, or 
regulatory authority at any time. 
With: 
The original signed consent must be maintained 
by the investigator and available for inspection 
by the Sponsor, its designated representative, or 
regulatory authority at any time. 
Administrative change 
Section: 14.2 Compliance with Laws 
and Regulations, paragraph 2, 
sentence 2 
Replace: 
Before the investigational drug is shipped to the 
investigator, the investigator or designee will 
provide Onyx with a copy of the IRB/IEC 
approval letter stating that the study protocol and 
any subsequent amendments and the ICF have 
been reviewed and approved. 
With: 
Before the investigational drug is shipped to the 
investigator, the investigator or designee will 
provide the Sponsor with a copy of the IRB/IEC 
approval letter stating that the study protocol and 
any subsequent amendments and the ICF have 
been reviewed and approved. 
Administrative change 
Section: 14.2 Compliance with Laws 
and Regulations, paragraph 3, 
sentence 2 
Replace: 
Copies of the investigator’s annual report to the 
IRB/IEC and copies of the IRB/IEC continuance 
of approval must be submitted to Onyx or 
designee. 
With: 
Copies of the investigator’s annual report to the 
IRB/IEC and copies of the IRB/IEC continuance 
of approval must be submitted to the Sponsor or 
designee. 
Administrative change 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 178 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 14.2 Compliance with Laws 
and Regulations, paragraph 5, 
sentence 1 
Replace: 
Onyx will provide study sites with any 
Investigational New Drug (IND) safety reports, 
changes to the IB, and any safety updates. 
With: 
The Sponsor will provide study sites with any 
Investigational New Drug (IND) safety reports, 
changes to the IB, and any safety updates. 
Administrative change 
Section: 14.3 Subject Confidentiality, 
paragraph 2, sentence 1 
Replace: 
The investigator/institution will permit direct 
access to source data and documents by Onyx, 
its designee, the US FDA, and other applicable 
regulatory authorities. 
With: 
The investigator/institution will permit direct 
access to source data and documents by the 
Sponsor, its designee, the US FDA, and other 
applicable regulatory authorities. 
Administrative change 
Section: 15.1 Protocol Amendments, 
sentence 1 
Replace: 
Onyx will implement in writing any substantive 
changes to this protocol as a protocol 
amendment. 
With: 
The Sponsor will implement in writing any 
substantive changes to this protocol as a protocol 
amendment. 
Administrative change 
Section: 15.1 Protocol Amendments, 
sentence 4 
Replace: 
The investigator or designee must send a copy of 
the approval letter from the IRB/IEC, along with 
the revised ICF, to Onyx or designee. 
With: 
The investigator or designee must send a copy of 
the approval letter from the IRB/IEC, along with 
the revised ICF, to the Sponsor or designee. 
Administrative change 
Section: 15.2 Study Termination 
Replace: 
Onyx reserves the right to terminate the study at 
any time.  The investigator or designee should 
notify the IRB/IEC in writing of the study’s 
completion or early termination and send a copy 
of the notification to Onyx or designee. 
With: 
The Sponsor reserves the right to terminate the 
study at any time.  The investigator or designee 
should notify the IRB/IEC in writing of the 
study’s completion or early termination and send 
a copy of the notification to the Sponsor or 
designee. 
Administrative change 
Section: 15.3.1 Source Documents, 
sentence 3 
Replace: 
These documents are designed to record all 
observations and other pertinent data for each 
subject enrolled in this clinical study. 
With: 
These documents are designed to record all 
observations and other pertinent data for each 
subject randomized in this clinical study. 
Clarified that source 
document recorded 
information for 
subjects who are 
randomized. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 179 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
Section: 15.4.1 Electronic Case Report 
Forms, paragraph 1, sentence 4 
Replace: 
Onyx will supply the eCRF, which must be 
completed in English. 
With: 
The Sponsor will supply the eCRF, which must 
be completed in English. 
Administrative change 
Section: 15.5 Publication Policy 
 
Add: 
Publication policy statement 
Added publication 
policy for consistency 
with Amgen template 
Section: References 
 
Add: 
Amgen/Onyx. Carfilzomib Investigator’s 
Brochure, version 16. 1. Onyx Therapeutics, 
Inc. (a wholly owned subsidiary of Onyx 
Pharmaceuticals, Inc., an Amgen Inc. 
subsidiary); 16 Jan 2016. 
Administrative change 
Section: Appendix A Schedule of 
Assessments, footnote g, sentence 1 
Replace: 
Questionnaires to be collected on Day 1 of 
Cycle 1, then every other cycle during treatment 
and every 12 weeks (every 84 days ± 4 days) 
until progression, or withdrawal of consent  
during LTFU. 
With: 
Questionnaires to be collected on Day 1 of 
Cycle 1, then every second cycle (Cycle 1, 3, 5, 
etc) during treatment and every 12 weeks (every 
84 days ± 4 days) until progression, or 
withdrawal of consent during LTFU. 
Revised text for 
consistency within 
overall protocol 
Section: Appendix B Schedule of 
Disease Assessments, footnote a  
Replace: 
C1D1 (Screening values may be used if obtained 
within 7 days prior to C1D1).  C2D1 and each 
cycle thereafter, EOT and during LTFU every 
4 weeks, (every 28 days ± 4 days) until PD 
and/or start of a subsequent antimyeloma 
therapy.  Refer to Section 10.2. 
With: 
C1D1 before treatment begins (Screening 
values may be used if obtained within 7 days 
prior to C1D1) and every 28 days (± 4 days) 
thereafter, at EOT and during LTFU if disease 
progression has not already been 
documented, (every 28 days ± 4 days) until PD 
and/or start of a subsequent antimyeloma 
therapy.  Refer to Section 10.2. 
Revised text for 
consistency within 
overall protocol 
Section: Appendix B Schedule of 
Disease Assessments, footnote d, 
sentence 2 
Replace: 
All subjects will be followed for survival and 
disease status (if discontinuation is prior to 
With: 
All subjects will be followed for survival and 
disease status (if discontinuation is prior to 
Revised text for 
consistency within 
overall protocol 


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Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 180 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
progression) by telephone contact or other 
method every 3 months (± 1 week) for until 
study closure. 
progression) by telephone contact or other 
method every 12 weeks ± 28 days for until study 
closure. 
Section: Appendix B Schedule of 
Disease Assessments, footnote g, 
sentence 1 
Replace: 
Bone marrow samples:  Bone marrow biopsy or 
aspirate slides will be obtained to confirm sCR 
or CR, or as clinically indicated. 
With: 
Bone marrow samples:  Bone marrow biopsy or 
bone marrow aspirate will be obtained to 
confirm sCR or CR, or as clinically indicated. 
Revised text for 
consistency within 
overall protocol 
Section: Appendix D Schedule of 
Study Assessments for the 
Pharmacokinetic Sparse Sampling and 
Intensive Pharmacokinetic & 
Pharmacokinetic Pharmacodynamic 
Sub-Study 
 
Add: 
a 
24 hours ± 2 hours after the end of the 
Day 15 infusion 
b 
48 hours ± 2 hours after the end of the 
Day 15 infusion 
c 
168 hours ± 2 hours after the end of the 
Day 15 infusion 
d 
24 hours ± 2 hours after the end of the 
Day 16 infusion 
e 
144 hours ± 2 hours after the end of the 
Day 16 infusion 
Added text to clarify 
timing of PD sampling 
Section: Appendix G Summary of 
International Myeloma Working 
Group Uniform Response Criteria 
(IMWG-URC), sCR, bullet 3 
Replace: 
Absence of clonal cells in bone marrowc by 
immunohistochemistry or immunofluorescencec 
With: 
Absence of clonal cells in bone marrow by 
immunohistochemistry or immunofluorescencec 
Administrative change 
Section: Appendix G Summary of 
International Myeloma Working 
Group Uniform Response Criteria 
(IMWG-URC), CR 
Replace: 
CRb 
Add: 
CRb, h 
Added footnote h to 
clarify that for patients 
with sFLC measurable 
disease only, normal 
sFLC ratio is also 
required for CR in 
addition to the CR 
criteria listed in the 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 181 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
table. 
Section: Appendix G Summary of 
International Myeloma Working 
Group Uniform Response Criteria 
(IMWG-URC), CR, bullet 3 
Replace: 
• < 5% plasma cells in bone marrowc 
With: 
• < 5% plasma cells in bone marrow 
Footnote c is not 
applicable to this 
criterion. 
Section: Appendix G Summary of 
International Myeloma Working 
Group Uniform Response Criteria 
(IMWG-URC), Stable disease 
Replace: 
• Not meeting criteria for CR, VGPR, PR, or 
PD 
With: 
Not meeting criteria for sCR, CR, VGPR, PR, 
MR, or PD 
Added sCR and MR 
for completeness. 
Section: Appendix G Summary of 
International Myeloma Working 
Group Uniform Response Criteria 
(IMWG-URC), footnote  
Replace: 
Note: Patients with measurable disease in both 
serum (SPEP) and urine (UPEP) at study entry 
are required to meet response criteria in both 
UPEP and SPEP in order to qualify for a MR or 
better.  Conversely, it should be noted criteria 
for PD only needs to be met, and confirmed, in 1 
parameter.  For patients without measurable 
protein on UPEP at baseline, UPEP will need to 
be repeated to confirm a response. 
With: 
Note: For patients without measurable protein on 
UPEP at baseline, UPEP will need to be repeated 
to confirm a response of VGPR or better. 
Removed the 
sentences ‘Patients 
with measurable 
disease in both serum 
(SPEP) and urine 
(UPEP) at study entry 
are required to meet 
response criteria in 
both UPEP and SPEP 
in order to qualify for 
a MR or better.  
Conversely, it should 
be noted criteria for 
PD only needs to be 
met, and confirmed, in 
1 parameter. ‘ since 
they are redundant to 
footnote a. 
Added ‘of VGPR or 
better’ to clarify UPEP 
will need to be 
repeated to confirm 
VGPR or better (not 


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Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 183 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
containing) hormonal contraception 
associated with inhibition of ovulation 
o 
Oral 
o 
Intravaginal 
o 
Transdermal 
• 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation  
o 
Oral 
o 
Injectable 
o 
Implantable 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormonal-releasing system 
(IUS)  
• 
Bilateral tubal occlusion 
• 
Combined (estrogen and progestogen) 
hormonal methods:  pills, vaginal ring, or 
skin patch. 
• 
Single hormonal methods (progestogen to 
stop the release of the egg from the ovary): 
pills, shots/injections, implants (placed 
under the skin by a healthcare provider) 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormonal-releasing system 
(IUS) surgery to tie both fallopian tubes 
(bilateral tubal ligation/occlusion)  
 
Section: Appendix K Country Specific 
Pregnancy And Contraceptive 
Supplement, Male Subjects, 
paragraph 1 
Replace: 
Male subjects whose partner is a WOCBP 
potential must use an acceptable method of 
effective birth control during treatment and for 
an additional 30 days after the last dose of 
protocol-required therapies. 
• 
Acceptable methods of birth control for 
male subjects include: 
• The female partner uses a: 
o 
Hormonal birth control method  
‒ 
Oral 
‒ 
Injectable 
‒ 
Transdermal 
‒ 
Implantable 
‒ 
Intravaginal 
o 
Intrauterine device (IUD) 
With: 
If the male subjects sole female partner has 
received medical confirmation that she is 
postmenopausal or she has had a permanent 
sterilization method (hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy) or 
the male subject has had a vasectomy with 
medical confirmation of surgical success, or 
his sole female partner has had a bilateral 
tubal ligation/occlusion, additional 
contraceptive methods are not required 
during this study.  Otherwise, if the male 
subject’s female partner could become 
pregnant, the male must:  
• Practice true sexual abstinence. (Refraining 
from heterosexual intercourse during 
treatment and for an additional 90 days 
Updated the window 
for breastfeeding 
following the last dose 
of drug administration. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 184 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
o 
Intrauterine hormonal-releasing system 
(IUS) 
o 
The female partner has had a bilateral 
tubal occlusion 
• The male subject has had a vasectomy and 
has received a medical assessment of the 
surgical success. 
• Two barrier methods:  One by each partner 
and at least one of the barrier methods must 
include spermicide 
o 
Male must use a condom  
o 
Female partner may use a diaphragm, 
cervical cap, or contraceptive sponge.  
(Note: The female condom cannot be 
used with a male condom). 
• Sexual abstinence:  Refraining from 
heterosexual intercourse during the entire 
period of risk associated with the study 
treatment.  The reliability of sexual abstinence 
needs to be evaluated in relation to the 
duration of the clinical trial and the preferred 
and usual lifestyle of the subject. 
Unacceptable birth control methods for female 
and male subjects during treatment with 
protocol-required therapies include:  
• Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) 
• Withdrawal (coitus interruptus) 
• Spermicides only 
• Lactational amenorrhoea method (LAM) 
Female condom and male condom should not be 
following the last dose of study drug 
administration. The reliability of sexual 
abstinence needs to be evaluated in relation to 
the duration of the clinical trial and be the 
preferred and usual lifestyle of the subject.) 
Or 
• Use a condom with spermicide during 
treatment and for an additional 90 days 
following the last dose of study drug 
administration.  (Note a condom without 
spermicide is acceptable in countries where 
spermicide is not commercially available.)  
The female partner should also consider using 
an acceptable method of effective 
contraception such as: 
• Intrauterine device (IUD) 
• Intrauterine hormonal-releasing system (IUS) 
• Hormonal birth control method: pill, 
shots/injections, implants (placed under the 
skin by a healthcare provider), skin 
patches, or a vaginal ring 
• Female barrier method: diaphragm, cervical 
cap, or contraceptive sponge (a female 
condom is not an option because there is a 
risk of tearing when both partners use a 
condom) 
• 
Male subjects must not donate sperm 
during treatment and for an additional 90 days 
following the last dose of study drug 
administration. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. 20140355 
Carfilzomib 
Page 185 of 185 
Amendment 3: 22 April 2016 
 
CONFIDENTIAL 
Section   
Text in Protocol  
Amended Text  
Rationale for Change 
used together 
Males with pregnant partners must practice 
true sexual abstinence or wear a condom 
during vaginal sex to prevent exposure to the 
embryo/fetus through semen. 
Section: Appendix L Summary of 
Changes 
 
Add: 
Updated Appendix L to include current 
summary of changes. 
Administrative change 
 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ014 
Carfilzomib for Injection 
Page 110 of 126 
CONFIDENTIAL 
APPENDIX L 
SUMMARY OF CHANGES 
Study CFZ014 was amended to include the following:   
 Adverse events of pulmonary hypertension and TTP/HUS were added to the dose 
modification guidelines to be consistent with the guidance provided in the updated 
Investigator Brochure version 15, dated 26February 2015. 
 Updated PK timepoints for intensive and sparse PK sampling as carfilzomib will be 
administered as an IV infusion over 30 minutes in the once-weekly arm and over 
10 minutes in the twice-weekly arm.  There is a mid-infusion PK timepoint (15 min 
after the start of infusion) that is only applicable for the carfilzomib once weekly arm, 
where carfilzomib is administered over 30 min.  The protocol has been amended to 
state that this PK timepoint, 15 min after the start of infusion, is only required for the 
carfilzomib once weekly arm. 
 Updated clinical information for carfilzomib to be consistent with IB Version 15.0. 
 Updated text in the safety section of the protocol to accurately reflect Drug Safety 
requirements and how and to whom information is provided. 
 Updated Medical Monitor information. 
In addition, administrative updates have been made to enhance document clarity.  
Changes made to this protocol are listed in the table below.   
 


 
Onyx Therapeutics, Inc.
Clinical Study Protocol No. CFZ014
Carfilzomib for Injection
Page 109 of 115
CONFIDENTIAL
APPENDIX L
SUMMARY OF CHANGES
Amendment 1.0:  
Study CFZ014 was amended to include the following: 

Clarified that consent is required from subjects if additional blood samples will be 
collected for PK (sparse sampling) and for the intensive PK and PDn substudy.

Clarified that dexamethasone should be administrated orally on Day 22 in 
Cycles 1−9.  

Clarified that dexamethasone will not be administered on Day 22 after Cycle 9.

Clarified that events occurring prior to consent should be captured as medical history 
information.

Clarified the timing of safety labs after Cycle 4.

Clarified the timing of patient reported outcome questionnaires.
In addition, administrative updates have been made to enhance document clarity.  Changes 
made to this protocol are listed in the table below.  
Amendment 1.1:
Two additional administrative updates were made to correct errors found in 
Protocol CFZ 014 Amendment 1.0:

The header on pages 100-109, Appendix F, of protocol CFZ014 read 
“Protocol 2011−003, Amendment 3” instead of reading as “Clinical Study Protocol 
No. CFZ014”.

Two hyperlinks in the footnote of Appendix A read “Error! Reference source not 
found” instead of linking to Sections 10.4.1 (Hematology) and 10.4.2 (Serum 
Chemistry), respectively.

SAP_001.pdf: 
Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 1
STATISTICAL ANALYSIS PLAN
A Randomized, Open-label, Phase 3 Study in Subjects with Relapsed and 
Refractory Multiple Myeloma Receiving Carfilzomib in Combination with 
Dexamethasone, Comparing Once-weekly versus Twice-weekly Carfilzomib 
Dosing
Protocol Number:
20140355
Version:
1.0
Date:
09 Jun 2017
Author:
Table of Contents
Table of Abbreviations.....................................................................................................5
1.
Introduction.............................................................................................................7
2.
Objectives...............................................................................................................7
2.1
Primary Objective........................................................................................7
2.2
Secondary Objectives .................................................................................7
2.3
Exploratory Objectives ................................................................................7
3.
Study Overview ......................................................................................................8
3.1
Study Design...............................................................................................8
3.2
Sample Size................................................................................................9
4.
Study Endpoints and Covariates...........................................................................10
4.1
Study Endpoints........................................................................................10
4.2
Planned Covariates...................................................................................11
5.
Hypotheses and/or Estimations ............................................................................11
6.
Definitions.............................................................................................................11
7.
Analysis Subsets ..................................................................................................20
7.1
Primary Analysis Set .................................................................................20
7.2
Safety Analysis Set ...................................................................................20
7.3
Per Protocol Set........................................................................................20
7.4
Health-related Quality of Life Analyses Set ...............................................21
7.5
Pharmacokinetic/Pharmacodynamic Analyses Set....................................21
7.6
Interim Analyses Set .................................................................................21
7.7
Subgroup Analyses...................................................................................22
PPD
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IRUSXUSRVHVRISRVWLQJRQFOLQLFDOWULDOVJRY


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 2
8.
Interim Analysis and Early Stopping Guidelines....................................................22
9.
Data Screening and Acceptance...........................................................................23
9.1
General Principles.....................................................................................23
9.2
Data Handling and Electronic Transfer of Data .........................................24
9.3
Handling of Missing and Incomplete Data .................................................24
9.4
Detection of Bias.......................................................................................24
9.5
Outliers .....................................................................................................24
9.6
Distributional Characteristics.....................................................................24
9.7
Validation of Statistical Analyses...............................................................24
10.
Statistical Methods of Analysis..............................................................................25
10.1
General Principles.....................................................................................25
10.2
Subject Accountability ...............................................................................26
10.3
Important Protocol Deviations ...................................................................26
10.4
Demographic and Baseline Characteristics...............................................26
10.5
Efficacy Analyses......................................................................................27
10.5.1
Analyses of Primary Efficacy Endpoint ......................................27
10.5.2
Analyses of Secondary Efficacy Endpoints................................28
10.5.3
Exploratory Efficacy Analysis.....................................................30
10.6
Safety Analyses ........................................................................................31
10.6.1
Adverse Events .........................................................................31
10.6.2
Laboratory Test Results ............................................................32
10.6.3
Vital Signs .................................................................................32
10.6.4
Electrocardiogram (ECG) ..........................................................33
10.6.5
Exposure to Investigational Product ..........................................33
10.6.6
Exposure to Concomitant Medication ........................................33
10.7
Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Analysis ....................................................................................................33
10.7.1
Exposure-Response (E-R) Analysis ..........................................35
11.
Changes From Protocol-specified Analyses..........................................................36
12.
Literature Citations / References...........................................................................37
13.
Appendices...........................................................................................................39
List of Tables
Table 1. Censoring Rules for Primary PFS Analysis......................................................17
Table 2.  Planned Carfilzomib Dose per Week ..............................................................18
Table 3. Stopping Boundaries for Progression-free Survival..........................................23
Table 4. Stopping Boundaries for ORR and OS.............................................................26
Table 5.  Endpoint Summary Table ...............................................................................29


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 3
List of Figures
Figure 1
Study 20140355 Schema .........................................................................9


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 4
List of Appendices
Appendix A.  Handling of Dates, Incomplete Dates and Missing Dates for 
Adverse Events and Concomitant Medications1.....................................40
Appendix B.  Reference Values/Toxicity Grades2 .........................................................41
Appendix C.  Patient-reported Outcome Forms/Instruments3........................................43


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 5
Table of Abbreviations
Term or Abbreviation
Description
AE(s)
Adverse Event(s)
ANC
Absolute Neutrophil Count
AUC
Area Under Curve
BSA
Body Surface Area
CBR
Clinical Benefit Rate
CDM
Clinical Data Management
CI
Confidence Interval
Cmax
Maximum plasma concentration
CR
Complete Response
CrCl
Creatinine Clearance
CSR
Clinical study report
CT-L
chymotrypsin-like
CV
coefficient of variation
BSA
Body Surface Area
CRF
Case Report Form
DMC
Data Monitoring Committee
DCB
Duration of Clinical Benefit
DOR
Duration of Response
EBMT
European Group for Blood and Marrow Transplant
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ELISA
Enzyme-linked Immunosorbent Assay
EORTC
European Organization for Research and Treatment of Cancer
EuroQOL
European Quality of Life
EQ-5D-5L
European Quality of Life-5 Dimensions
EOI
Event of Interest
EOT
End of Treatment
E-R
Exposure-Response
FDA
Food and Drug Administration
FISH
Fluorescence in situ hybridization
GSO-DM
Global Study Operations-Data Management
HR
Hazard Ratio
IBG
Independent Biostatistics Group


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 6
IMiD
Immunomodulatory Agent
IMWG-URC
International Myeloma Working Group-Uniform Response Criteria
IPD
Important Protocol Deviation
IRC
Independent Review Committee
ISS
International Staging System
IV
Intravenous(ly)
KM
Kaplan-Meier 
LC–MS/MS
Liquid chromatography–mass spectrometry/ mass spectrometry
LFT
Liver Function Test
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Regulatory Activities
MR
Minimal Response
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for 
Adverse Events
ORR 
Overall Response Rate
OS
Overall Survival
PASS
Power Analysis and Sample Size Software
PD
Progressive Disease
PDn
Pharmacodynamics
PFS 
Progression-free Survival
PI
Proteasome Inhibitor
PK
Pharmacokinetics
PKDM
Pharmacokinetics and Drug Metabolism
PO
Orally
PR
Partial Response
QLQ-C30
Quality of Life Core Module
QLQ MY20
Quality of Life Multiple Myeloma Module 20
QTc
corrected QT-interval
RDI
Relative Dose Intensity
SAE(s)
Serious Adverse Event(s)
SAP
Statistical Analysis Plan
sCR
Stringent Complete Response
SD
Stable Disease
SSAP
Supplemental Statistical Analysis Plan
VGPR
Very Good Partial Response
WHODRUG
World Health Organization Drug dictionary


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 7
1.
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for carfilzomib study 20140355,
dated 08 Feb 2017.  The scope of this plan includes the interim analysis and the final 
analysis that are planned and will be executed by the Biostatistics department unless 
otherwise specified. PK analyses will be provided by the Department of Clinical 
Pharmacology, Modeling & Simulation (CPMS).
2.
Objectives
2.1
Primary Objective
The primary objective of this study is to compare the progression-free survival (PFS) of 
once weekly carfilzomib dosing in combination with dexamethasone to the PFS of twice 
weekly carfilzomib dosing in combination with dexamethasone in subjects with relapsed 
and refractory multiple myeloma who have received prior treatment with a proteasome 
inhibitor and an IMiD (immunomodulatory agent).
2.2
Secondary Objectives 
The secondary objectives of the study are to compare the following between treatment 
groups: 

Overall response rate (ORR)

Overall survival (OS)

Safety and tolerability

Pharmacokinetics (PK) of carfilzomib using sparse sampling 
2.3
Exploratory Objectives
The exploratory objectives are to evaluate the following between treatment groups:

Intensive pharmacokinetics (PK) and pharmacodynamics (PDn) of carfilzomib in 
a subset of subjects (substudy)

All subscales of the European Organization for Research and Treatment of 
Cancer (EORTC) Quality of Life Core Module (QLQ-C30), and the EORTC 
Quality of Life Multiple Myeloma Module 20 (QLQ-MY20)

European Quality of Life-5 Dimensions (EQ-5D-5L); a standardized measure of 
health status developed by the European Quality of Life (EuroQol) Group 

Patient reported convenience and satisfaction with the carfilzomib dosing 
schedule


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 8

Healthcare resource utilization
3.
Study Overview
3.1
Study Design
This is an open label, multicenter, randomized Phase 3 study comparing once weekly 
carfilzomib dosing in combination with dexamethasone to twice weekly carfilzomib 
dosing in combination with dexamethasone in subjects with relapsed and refractory 
multiple myeloma, 2 or 3 prior therapies, and previously treated with a proteasome 
inhibitor and an IMiD.  The primary endpoint is PFS. The study design is illustrated in 
Figure 1.  
Eligible subjects will be randomized in a 1:1 ratio to receive a regimen consisting of 
either once-weekly or twice weekly carfilzomib in combination with dexamethasone.  
The randomization will be stratified by:
• International Staging System (ISS) Stage at study entry (Stage 1 versus Stage 2 or 3)
per International Myeloma Working Group (Greipp 2005).
• Refractory to bortezomib treatment (Yes versus No)
• Age (< 65 versus ≥ 65 years)  
Study treatment will be administered in 28 day cycles.  Subjects will receive the study 
treatment determined by randomization until disease progression, unacceptable toxicity, 
withdrawal of consent, or death (whichever occurs first).  No crossover between the 2 
treatment groups will be allowed.  
Following termination of study treatment, all subjects will be followed for disease status 
(if progressive disease [PD] has not been reached), subsequent antimyeloma treatment, 
and survival.  
All subjects will be followed for safety for at least 30 additional days after the last study 
treatment administration.  All treatment-related adverse events (AEs) and serious 
adverse events (SAEs) will be followed until resolution or stabilization.  


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
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Figure 1
Study 20140355 Schema
ECOG = Eastern Cooperative Oncology Group; IMiD = immunomodulatory agents; IV = 
intravenous(ly); ORR = overall response rate; OS = overall survival; PD = disease progression; 
PFS = progression-free survival; PI = proteasome inhibitor; PO = orally.
Subjects will be assessed for response using central laboratory results every 28 days (± 
4 days until confirmed PD. Long-term follow-up (LTFU) for disease status (only in cases 
where subjects discontinued treatment prior to PD) and for survival (after reaching PD) 
will continue after treatment discontinuation or until the subject has withdrawn consent 
for further participation, is lost to follow-up, has died, or the sponsor makes a decision to 
close the study.  For subjects who discontinued treatment before disease progression 
occurred (such as for an adverse event, noncompliance, etc.), disease response 
assessments will be performed using central laboratory results every 28 ± 4 days until 
disease progression.  Follow up for survival will continue approximately every 12 weeks 
± 28 days, or as needed, for all surviving subjects until study closure.  For any subject 
who is lost to follow-up, the study site will attempt to ascertain survival information via 
public database search.  
3.2
Sample Size
 
 
CCI


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 10
 
 
 
 
 
 
 
  
a total of 350 PFS events will be 
needed for the final PFS analysis, in order to have 83% power to detect a significant 
difference in PFS between the two treatment groups at 1-sided significance level of 
0.025 with 1 interim analysis performed at approximately 75% information time (i.e., 75% 
of 350 PFS events) using the Lan-DeMets spending function with an O’Brien-Fleming 
approach,
 
There is no target number of events for OS analysis. The analysis of OS will be 
conducted at the time of the PFS analysis (interim or final), only if both PFS and ORR 
analyses are positive.  
4.
Study Endpoints and Covariates
4.1
Study Endpoints
Primary Endpoint
The primary endpoint is PFS, which is defined as the time in months from 
randomization to the earlier of disease progression or death due to any cause.
Secondary Endpoints
The secondary endpoints of the study are as follows:
!
ORR, defined as the proportion of subjects who achieved a confirmed PR, VGPR, 
CR, or sCR, according to the IMWG URC
!
OS, defined as the time in months from randomization to death due to any cause
!
Safety and tolerability 
!
Sparse PK
CCI
CCI
CCI


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 11
4.2
Planned Covariates
The primary analysis of PFS, ORR and OS will be stratified by the stratification factors at 
randomization: ISS stage at study entry (Stage 1 versus Stage 2 or 3), refractory to 
bortezomib treatment (yes versus no) , and age (< 65 versus ≥ 65 years). 
5.
Hypotheses and/or Estimations
The inferential comparison of PFS between treatment groups will be made using a log-
rank test stratified by randomization stratification variables. The 1-sided p-value from the 
stratified log-rank test will be compared against the value specified by the alpha 
spending function specified in Section 8 at the given analysis (interim or final) to test the 
null hypothesis that weekly arm doesn’t have superior PFS than twice weekly arm. The 
inferential comparison of ORR between treatment groups will be made using a Cochran-
Mantel-Haenszel test stratified by randomization stratification variables. The inferential 
comparison of OS between treatment groups will be made using a log-rank test stratified 
by randomization stratification variables. 
6.
Definitions
Anti-myeloma therapies during long term follow-up
Anti-myeloma therapies during long term follow-up will be those therapies entered in the 
anti-myeloma therapy case report form (CRF) administered during the long term follow-
up period of the study.
Baseline
For analyzing progression-free survival time (PFS) and overall survival time (OS), 
baseline will be defined as the day of randomization.
For the analysis of other endpoints, baseline will be defined as the value measured on 
day1 of the first cycle of protocol-specified therapy. The protocol specifies that all study 
procedures on day 1 should be completed before the initiation of protocol-specified 
therapy, which will be the assumption in the analysis, unless the time of the assessment 
is recorded. If a day 1 value is not available, the latest value before the day of the start of 
protocol-specified therapy will be used. If a subject doesn’t receive any protocol-
specified therapy, then the latest value prior to or on randomization date will be used.
Best overall response 


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 12
Best overall response will be assessed by computational assessment, Independent 
Review Committee (IRC) and investigator. The primary analysis of ORR will be based on
best overall response assessed by computational assessment.
Best overall response by computational assessment
Best overall response will be derived using a computer based algorithm for multiple 
myeloma disease assessments based on The International Myeloma Working Group 
Uniform Response Criteria (Durie et al. 2006, with corrections, Rajkumar et al. 2011) 
(IMWG-URC), the protocol, and The European Group for Blood and Marrow Transplant
(EBMT) criteria (Bladé et al. 1998) for the assessment of minimal response only. The 
detailed algorithm is documented in a separated document ‘SPECIFICATIONS FOR 
ONYX RESPONSE COMPUTATIONAL ASSESSMENT (ORCA) BASED ON IMWG 
UNIFORM RESPONSE CRITERIA’.
Best overall response by IRC assessment
Best overall response by IRC will be collected on CRF.
Best overall response by investigator assessment
Best overall response by investigator assessment is the best confirmed response by the 
analysis trigger date based on the responses by visit collected on myeloma response 
assessment eCRF. The response assessments done after initiation of new anti-myeloma 
therapy will be excluded from the analysis.
A confirmed response of minimal response (MR) or better requires at least two 
consecutive assessments with the same response or better. Stable disease (SD)
requires a duration of at least 6 weeks. Progressive disease (PD) requires two 
consecutive PD assessments based on the same analyte except when PD is due to any 
of the following criteria:

Definite development of new bone lesions or definite increase in the size of 
existing bone lesions

Definite  increase or new appearance of soft tissue plasmacytomas

Definite increase of % plasma cells in Bone Marrow.
Best overall response will be decided in the following order of confirmed responses:
stringent complete response (sCR), complete response (CR), very good partial response 
(VGPR), partial response (PR), MR, SD, PD starting from the best to the worst.


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 13
Clinical Benefit Rate (CBR)
CBR is the proportion of subjects whose best overall response is MR, PR, VGPR, CR, or 
sCR.
Cumulative Dose of Study Treatment
Carfilzomib: Cumulative dose will be calculated in mg and mg/m2. The cumulative dose 
in mg will be calculated as the summation of total quantity administered (mg) over all 
infusions. The cumulative dose in mg/m2 will be calculated as the following over 
infusions.
BSA is to be determined by a standard formula, such as the Mosteller Formula
(Mosteller 1987): body surface area (BSA) (m²) = ([Height (cm) × Weight (kg)]/
3600 )½. The one collected on cycle 1 day 1 will be used in the calculation till when BSA 
changes ≥20% from cycle 1 day 1. Every time BSA changes ≥20% from current BSA 
used in the calculation, the new BSA will be used for subsequent infusions. If BSA is 
>2.2, then 2.2 will be used in the calculation.
Dexamethasone: The cumulative dose in mg will be calculated as the summation of 
total quantity administered (mg) over the study. 
Death Date 
For subjects who die during the study, the death date will be recorded on the end of 
study CRF in the end of study date field. Incomplete death dates where only the day of 
death date is missing will be imputed using the following rules:
Day 1 of the month will be used if year and month indicate that death happened in 
different month from last known alive date;
One day after last known alive date will be used if death happened in the same month as 
last known alive date. 
The imputed death date will be used in calculation of duration of response, progression-
free survival and overall survival. 
Duration of Clinical Benefit (DCB)


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 14
DCB will be calculated only for subjects who achieve a best overall response of MR or 
better, i.e., sCR, CR, VGPR, PR, or MR. The duration will be calculated in months from 
the earliest date a response of MR or better is first achieved and subsequently confirmed
to the earliest date of confirmed PD or death due to any cause:
DCB=(PD/death date-MR/better response start date +1)/30.4
Subjects will be censored using the same censoring rules for PFS as listed in table 1 if 
applicable.
Duration of Response (DOR)
DOR will be calculated only for subjects who achieve a best overall response of PR or 
better, i.e., sCR, CR, VGPR, or PR. The duration will be calculated in months from the 
earliest date a response of PR or better is first achieved and subsequently confirmed to
the earliest date of confirmed PD or death due to any cause:
DOR=(PD/death date-response start date +1)/30.4
Subjects will be censored using the same censoring rules for PFS as listed in table 1 if 
applicable.
Duration of Study Treatment
Duration of treatment with carfilzomib and dexamethasone will be defined as the time 
from the first start date of each drug to the last stop date of the drug. Duration of the 
whole study treatment will be from the earliest start date among the two drugs to the 
latest stop date among the two drugs.
End of Study Treatment Date 
The end of study treatment date is the date the decision was made to end investigational 
product reported on the end of investigational product administration CRF.
End of Study
For an individual subject: a subject ends the study in the event of death, , consent 
withdrawal, or lost to follow-up. The end of study date will be captured on the end of 
study CRF.
For the study as a whole: the end of study as a whole is defined as the time when the 
last subject is assessed or receives intervention for the purposes of final collection of 
data for the final analysis of PFS, which will be triggered when 350 PFS events (PD or 
death) are reported or by end of year 2018, whichever is earlier. Subjects who have not 


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
Page 15
completed all expected treatment at the time of the end of study as a whole will continue 
to follow protocol specified treatment and procedures until completion.
Enrollment Date 
The date of enrollment is the date the subject gets randomized.
Fluorescent in Situ Hybridization (FISH) Risk Group
The subjects with genetic abnormalities t(4;14), t(14;16), and deletion 17p, as indicated 
on FISH/Conventional Cytogenetics CRF are categorized in the high risk group. The 
other subjects are in the standard risk group.
International Staging System (ISS) Stage at Baseline
ISS stage at baseline will be calculated using serum beta-2 microglobulin and serum 
albumin values collected at baseline, based on the criteria published by the International
Myeloma Working Group (Greipp 2005):
Stage I: Serum beta-2 microglobulin < 3.5 mg/L and serum albumin ≥3.5 g/dL
Stage II:Serum beta-2 microglobulin < 3.5 mg/L and serum albumin < 3.5 g/dL or Serum 
beta-2 microglobulin 3.5–<5.5 mg/L irrespective of the serum albumin
Stage III: Serum beta-2 microglobulin ≥5.5 mg/L
Last Dose Date of Study Treatment
It is the latest date of drug taken among carfilzomib and dexamethasone.
 
CCI


Product:  Carfilzomib
Statistical Analysis Plan:  20140355
Date: 09 Jun 2017
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Overall Response Rate (ORR)
ORR is the proportion of subjects whose best overall response is PR, VGPR, CR, or 
sCR.
Overall Survival (OS)
OS time in months will be calculated from date of randomization until death due to any 
cause:
OS=(death date-randomization date +1)/30.4
Subjects still alive will be censored at the date last known to be alive. If the date last 
known to be alive is after the date that triggers the analysis, the subject will be censored 
at the analysis trigger date.
Progression-Free Survival (PFS) 
PFS time will be calculated from thedate of randomization until PD or death due to any 
cause, whichever occurs first:
PFS=(PD/death date-randomization date +1)/30.4
The duration of PFS will be right censored for subjects who meet 1 of the following 
conditions: 1) no baseline disease assessments; 2) starting a new anti-myeloma therapy 
before documentation of progressive disease or death; 3) progressive disease or death 
immediately after more than 1 consecutively missed disease assessment visit or; 4) alive 
without documentation of disease progression before the analysis trigger date. The 
C
C
I


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censoring rules for PFS primary analysis are described in Table 1. These rules are
based on the May 2007 FDA Guidance for Industry, ‘Clinical Trial Endpoints for the
Approval of Cancer Drugs and Biologics’ (www.fda.gov/cder/guidance/7478fnl.htm).
Table 1. Censoring Rules for Primary PFS Analysis
Situation
Date of Progression or Censoring
Outcome
No baseline disease 
assessments
Date of randomization
Censored
New anti-myeloma treatment 
started before documentation of 
PD or death
Date of last disease assessment 
prior to start of a new anti-myeloma
treatment
Censored
Death or PD immediately after 
more than 1 consecutively 
missed disease assessment
visit*
Date of last disease assessment visit
before the first missed visit
Censored
Alive and without PD 
documentation
Date of last disease assessment
Censored
Death or PD between planned 
disease assessments
Date of death or first disease 
assessment showing PD, whichever 
occurs first
Progressed
Death before first disease 
assessment
Date of death
Progressed
* If death or PD is more than 64 days after previous disease assessment, or randomization date if 
there is no previous disease assessment..
Randomization Date 
Randomization Date is defined as the date the subject was allocated to a treatment 
group. Per protocol, study treatment will ideally commence on the day of randomization, 
but at least within 5 calendar days of randomization.
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. 
Carfilzomib: Actual dose intensity is defined as the actual amount of drug in mg/m2
delivered to a subject per week of treatment. 
 
 
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Table 2.  Planned Carfilzomib Dose per Week
Arm
Cycle
Week
Protocol Specified Dose for 
Treatment Week  (mg/m2 )
Once-weekly 
carfilzomib with 
dexamethasone
1
1st
20
2 or later
1st
70
All cycles
2nd ,3rd
70
All cycles
4th
0
Twice-weekly 
carfilzomib with 
dexamethasone
1
1st
40
2 or later
1st
54
All cycles
2nd ,3rd
54
All cycles
4th
0
Dexamethasone: Actual dose intensity is the actual amount of drug in mg delivered to a 
subject per week of treatment. 
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Refractory to prior multiple myeloma therapy
Subject is refractory to a drug received in prior regimens if the data collected on prior 
multiple myeloma therapy CRF indicates that any of the following criteria is met:
a.
Best Response to any regimen containing the drug is stable disease or 
progressive disease
b.
Reason the drug was stopped is progression in any regimen 
c.
Date of relapse/progression is after start date and within 60 days after stop date 
of the drug in any regimen
Study Day 1 
Study day 1 is the earliest date when carfilzomib or dexamethasone is given for subjects 
who receive at least one dose of study drug, randomization date for subjects who are 
randomized but not treated.
Time to Response
Time to response will be calculated only for subjects who achieve a best overall 
response of PR or better, i.e., sCR, CR, VGPR, or PR. It will be calculated in months 
from randomization date to the earliest date a response of PR or better is first achieved 
and subsequently confirmed:
Time to Response=(response start date-randomization date +1)/30.4
Treatment-emergent Adverse Event 
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AEs starting on or after first dose of investigational product as determined by the flag 
indicating if the adverse event started prior to the first dose on the Events CRF and up to 
and including 30 days after the end of study treatment. 
7.
Analysis Subsets
7.1
Primary Analysis Set
The primary analysis of efficacy will be performed on all randomized subjects analyzed 
according to their randomized treatment assignment, regardless of the treatment 
received.
7.2
Safety Analysis Set
The primary analysis of safety will be performed on the Safety Analysis Set which will 
include all subjects who received at least one dose of study treatment analyzed 
according to the treatment they received.
7.3
Per Protocol Set
The Per Protocol Set will include all randomized subjects who did not have any 
important protocol deviations which could have an impact on the efficacy evaluation of 
the subject. 
Subjects with the following protocol deviations will be excluded from the per protocol set
for OS analysis:
•
Inclusion criteria of relapsed multiple myeloma
•
Inclusion criteria of refractory multiple myeloma
•
Inclusion criteria of 2 or 3 prior therapies for multiple myeloma
•
Inclusion criteria of prior exposure to an IMiD
•
Inclusion criteria of prior exposure to a Proteasome Inhibitor (PI)
•
Inclusion criteria of documented response of at least partial response (PR) to at least 
1 prior line of therapy.
•
Inclusion criteria of measurable disease 
•
Exclusion criteria of second malignancy within the past 5 years
•
Exclusion criteria of cytotoxic chemotherapy or other antineoplastic within 28 days 
prior to randomization
•
Exclusion criteria of immunotherapy such as an IMiD or PI within 21 days prior to 
randomization


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•
Exclusion criteria of glucocorticoid therapy exceeding a cumulative dose of 160mg 
within 21 days prior to randomization
•
Subject received concurrent therapy with a marketed or investigational anticancer 
therapeutic or radiation to large marrow reserves for either a therapeutic or palliative 
intent while receiving study treatment
•
Subject received wrong treatment other than treatment assigned to
In addition to the deviations listed above, subjects who had the following deviations will 
also be excluded from per-protocol set for PFS and ORR analysis:
•
Subject permanently discontinued treatment due to progressive disease (PD) based
on local labs not central labs 
•
Subject ended treatment before confirmed PD but no further disease assessments 
were carried out
•
Baseline laboratory disease assessment was not done in such a way subject is not 
measurable as defined per protocol
•
Subject received plasmapheresis while receiving study treatment
Subjects will be analyzed according to their randomized treatment assignment.
7.4
Health-related Quality of Life Analyses Set 
All randomized subjects will be included in Health-related Quality of Life Analyses Set.
7.5
Pharmacokinetic/Pharmacodynamic Analyses Set
All subjects who participated in the intensive PK/PDn substudy or the sparse PK 
sampling will be included in the Pharmacokinetic/Pharmacodynamic Analyses Set. 
These subjects will be evaluated for pharmacokinetics and pharmacodynamics unless 
significant protocol deviations affect the data analysis or if key dosing, dosing 
interruption, or sampling information is missing.
7.6
Interim Analyses Set
The interim analyses set will include all randomized subjects. The independent safety 
reviews, which are scheduled to occur approximately every 6 months, will include all 
randomized subjects for efficacy analyses and all treated subjects at the time of the 
database snapshot for a given review.


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7.7
Subgroup Analyses
Exploratory subgroup analyses for the primary endpoint and key secondary endpoints
(ORR and OS) will be performed for each level of the three randomization stratification 
factors: International Staging System (ISS) Stage at study entry (Stage 1 vs. Stage 2 or 
3), Refractory to bortezomib treatment (Yes vs. No) and Age (< 65 vs. ≥ 65 years, <75 
vs. ≥ 75). Additional subgroup analyses will be based on the following factors: 

Sex (male vs. female) 

Race (White vs. Asian vs. Other)

Ethnicity (Hispanic or Latino vs. Not Hispanic or Latino)

Geographic region (Europe vs. North America vs. Asian Pacific)

Baseline ECOG (0 vs. 1)

Baseline creatinine clearance (30 - < 50 ml/min vs. 50 - < 80 ml/min vs. ≥80 
ml/min)

FISH risk group (high risk vs. standard risk vs. unknown)

β2 microglobulin level (< 3.5 mg/L vs. ≥ 3.5 mg/L)

ISS stage at baseline (Stage I vs. Stage II and III)

ISS stage at diagnosis (Stage I vs. Stage II and III vs. Unknown)

Corrected calcium at baseline (≤11.5 mg/dL vs. >11.5 mg/dL)

Lines of prior treatment (2 vs. 3)

Prior transplant (Yes vs. No)

Prior lenalidomide (Yes vs. No)

Refractory to lenalidomide (Yes vs. No)
These subgroups, except for stratification variables, will be re-examined and 
appropriately re-categorized before unblinding. Subgroup analysis containing a 
subgroup of less than 5% of the whole population will not be conducted.
8.
Interim Analysis and Early Stopping Guidelines
One interim analysis will be conducted for PFS when approximately 263 (75% of total 
350) PFS events are observed. The objective of the interim analysis is to monitor for 
differences between treatment arms for evidence of a substantial benefit in the 
carfilzomib once-weekly with dexamethasone arm.
To ensure proper control of type I error rate, the interim and final analysis of PFS will be 
analyzed under a group sequential design framework with the stopping boundaries 
constructed using the Lan-DeMets spending function with an O’Brien-Fleming approach. 
The stopping boundaries in an example scenario are calculated using East 6.4 and 
presented in Table 3. Actual boundaries will be calculated on the basis of observed PFS 
events up to the data cut-off date for the interim analysis. .  


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An external independent Data Monitoring Committee (DMC) will review the interim PFS 
analysis results and recommend whether the study should stop early for efficacy. If the 
DMC recommends to stop the study for efficacy, the sponsor will consider stopping the 
trial and conclude that the carfilzomib once-weekly with dexamethasone arm prolongs 
PFS compared to the carfilzomib twice-weekly with dexamethasone arm. In addition, the 
DMC will assess safety approximately every 6 months. An Independent Biostatistics 
Group (IBG) will perform the analyses and provide the interim reports to the DMC. The 
IBG and DMC will have access to subjects’ individual treatment assignments.To 
minimize the potential introduction of bias to the conduct of the study, members of the 
DMC and IBG will not have any direct contact with study center personnel or subjects. 
The DMC will communicate major safety concerns and recommendations regarding 
study modification or termination based on the safety and efficacy parameters to Amgen 
in accordance with the DMC charter.
Records of all meetings will be maintained by the DMC for the duration of the study. 
Records of all meetings will be stored in the Amgen official document management 
system at the conclusion of the study. Further details are provided in the DMC charter.
9.
Data Screening and Acceptance
9.1
General Principles
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. The 
database will be subject to edit checks outlined in the data management plan by Amgen 
Clinical Data Management (CDM) department. 
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9.2
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. Laboratory data will be collected by COVANCE Central Laboratory Services
and transferred to Amgen GSO-DM weekly in cumulative files. Quality of life data will be 
collected by ERT and transferred to Amgen GSO-DM monthly in cumulative files.
9.3
Handling of Missing and Incomplete Data
The descriptive statistics will identify the extent of missing data. Rules for handling 
missing data related to endpoints are described in the endpoint definitions (Section 6) or 
in the description of analyses (Section 10). The handling of incomplete and partial dates 
for adverse events and concomitant medications are described in Appendix B. Handling 
of missing or incomplete data for Exposure-Response (E-R) analysis will be described in 
the documents to support population PK/PDn dataset generation and E-R analysis.
9.4
Detection of Bias
Methods to detect bias are described in the analyses of particular endpoints (Section 
10).
9.5
Outliers
Any suspected outliers will be investigated by the study team and will be included in the 
database unless determined to be an error or there is supporting evidence or 
explanation to justify the exclusion. Any outliers excluded from the analysis will be 
discussed in the Clinical Study Report (CSR), including the reasons for exclusion and 
the impact of their exclusion on the study. PK concentration data will be evaluated for 
outliers by visual inspection, and decisions to re-assay individual samples will be made 
in accordance with standard PKDM practice.
9.6
Distributional Characteristics
The statistical assumptions for analysis methods will be assessed. If the assumptions for 
the distributional characteristics are not met, these will be described and further 
analyses may be carried out using data transformations or alternative analysis methods. 
The use of transformations or alternative analysis methods will be justified in the final 
study report.
9.7
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 9.3 or 
later. For the PK/PDn analysis, refer to section 10.7 for software used.
10.
Statistical Methods of Analysis
10.1
General Principles
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, KM proportions at select time points, KM 
quartiles (when estimable), the number of subjects with events, the number of subjects 
censored, and censoring reasons. Duration of follow up for time to event endpoints will 
be estimated using the reverse Kaplan Meier method (Schemper and Smith 1996). Point 
estimates for efficacy endpoints will be accompanied by 2-sided 95% confidence 
intervals including estimates of KM quartiles (Klein and Moeschberger, 1997), KM 
proportions (Kalbfleisch and Prentice, 1980), and binomial proportions (Clopper CJ and 
Pearson, 1934). To examine non-proportionality between the treatment groups for time 
to event endpoints, the log cumulative hazard curves will be plotted.  The scaled 
Schoenfeld residuals by time plot will be examined for evidence of a non-zero 
correlation, which indicates non-proportionality. Interaction between treatment and the 
log event time will be also tested at 10% level in a Cox model stratified by randomization 
stratification variables to test for non-proportionality
The hypotheses for the primary efficacy endpoint, PFS, and secondary efficacy 
endpoints (ORR and OS) will be tested using a fixed sequence hierarchical testing
procedure to control the family-wise Type I Error rate below 1 sided 0.025 level.  The 
family of hypotheses is ordered as follows: 1) PFS, 2) ORR, and 3) OS.  Starting with the 
hypothesis of PFS, if any hypothesis in the sequence is rejected, then the subsequent 
hypothesis will be tested; if any hypothesis is accepted, then the subsequent hypotheses 
will not be tested. Furthermore, potential multiplicity from testing at two possible times of 
PFS IA and final analysis for ORR and OS will be adjusted using the Lan-DeMets 
spending function with an O’Brien-Fleming approach and a Pocock approach 
respectively (Hung et al 2007). 
 
 
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10.2
Subject Accountability
The number and percent of subjects who were screened, randomized, received study 
treatment, entered long-term follow-up before disease progression and long-term follow-
up for survival will be summarized by treatment group. The number and percent of 
subjects who discontinued study treatment, long-term follow-up before disease 
progression, and study will be tabulated, along with the reason for discontinuation. The 
number and percent of subjects randomized will be tabulated by the stratification factors. 
The number and percent of subjects randomized will be tabulated by study site. Key 
study dates for the first subject randomized, last subject randomized, and data cut-off 
date for analysis will be presented.
10.3
Important Protocol Deviations
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock. These definitions of IPD categories, sub-category codes, and 
descriptions will be used during the course of the study. Eligibility deviations are defined 
in the protocol.
10.4
Demographic and Baseline Characteristics
Demographic (ie, age, age group [<65, 65-74, 75-84, ≥85], sex, race, and ethnicity) and 
baseline disease characteristics will be summarized by treatment group and overall 
using descriptive statistics for the Primary Analysis Set. The baseline characteristics to 
be summarized include:
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
Geographic region (Europe, North America, Asian Pacific)

Reproductive status

Baseline ECOG 

Baseline laboratories including: hemoglobin, ANC, platelet count, and creatinine 
clearance

Baseline LVEF (%)

Time from initial multiple myeloma diagnosis to randomization (months)

Measurable disease category

M-protein heavy and light chain subtype

FISH risk group

Serum free light chain Kappa/Lambda ratio

Presence of any plasmacytoma

Presence of any bone lesion

Corrected calcium at baseline

β2 microglobulin level 

ISS stage at diagnosis

ISS stage at baseline

Lines of prior treatment 

Prior transplant 

Prior bortezomib

Prior lenalidomide

Prior thalidomide

Refractory to bortezomib

Refractory to lenalidomide 
10.5
Efficacy Analyses 
10.5.1
Analyses of Primary Efficacy Endpoint
1-sided stratified log-rank test, stratified by the randomization factors, will be used to 
compare PFS between treatment groups as primary inference. In addition, a hazard ratio 
with a 95% confidence interval will be estimated from a stratified Cox regression model. 
The KM summaries described in Section 10.1 will be performed by treatment group. The 
primary analysis will be performed on the Primary Analysis Set based on computational 
assessments. Sensitivity analyses will be performed using investigator assessments, 
Independent Review Committee (IRC) assessments, different censoring rules regarding 
use of new anti-myeloma therapy and different analysis population. The details are 
documented in table 5. The discordance between the results regarding progression 
status and timing from the internal computational assessment, investigator and IRC will 
be summarized. Subgroup analyses will be performed to explore the consistency of the 
treatment effect for subgroups described in Section 7.7. Piecewise Cox models for 3-
month time intervals may be explored given evidence of non-proportional hazards 


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(Collett, 2003).  This model will allow estimation of an overall weighted hazard ratio 
(weights equal to fraction of total events in each interval (Lu & Pajak, 2000)) as well as 
within interval treatment hazard ratio.  Additional analysis may be performed to explore 
potential sources for non-proportionality by considering baseline prognostic factors and 
other potential confounding factors.
10.5.2
Analyses of Secondary Efficacy Endpoints
The ORR will be analyzed at the time of the PFS analysis (interim or final), only if the 
PFS analysis crosses the stopping boundary.  The ORR will be calculated by treatment 
group and the associated 95% CI will be estimated using the Clopper Pearson method. 
The inferential comparison of ORR between treatment groups will be performed using 
Cochran-Mantel-Haenszel test stratified by the randomization stratification factors. 1-
sided p-value from the test will be compared against the alpha value specified in Table 4
to determine the significance. Odds ratio (and its 95% CI) will be estimated using 
Mantel-Haenszel method . The primary analysis of ORR will be based on computational 
assessments for the Primary Analysis Set. Sensitivity analyses will be performed based 
on investigator assessments, Independent Review Committee (IRC) assessments,
unstratified method, and for Per Protocol Set. The discordance between the results from 
the internal computational assessment, investigator and IRC will be summarized. 
Subgroup analyses will be performed to explore the consistency of the treatment effect 
for subgroups described in Section 7.7.
The analysis of OS will be conducted at the time of the PFS analysis (interim or final), 
only if both PFS and ORR analyses are positive.  The same method as for analysis of 
PFS will be used for analysis of OS.The primary analysis of OS will be performed on the 
Primary Analysis Set. Sensitivity analyses will be performed based on unstratified 
analyses, and for Per Protocol Set. Subgroup analyses will be performed to explore the 
consistency of the treatment effect for subgroups described in Section 7.7. Piecewise 
Cox models for 6-month time intervals may be explored given evidence of non-
proportional hazards.  


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Table 5.  Endpoint Summary Table
Endpoint
Primary Summary and 
Analysis Method 
Sensitivity Analysis
Primary Endpoint
Progression-Free Survival
Based on internal 
computational assessments:

KM summaries

1-sided p-value from 
stratified log-rank test

Hazard ratio and 95% CI 
from stratified Cox 
regression

Investigator assessments: same 
as primary summary and 
analysis method based on 
investigator assessments.

IRC assessments: Same as 
primary summary and analysis 
method based on IRC 
assessments.

Unstratified analyses: 1-sided p-
value from unstratified log-rank 
test, hazard ratio and 95% CI 
from unstratified Cox 
regression.

Initiation of new anti-myeloma
therapy treated as PFS Event: 
The data censoring rules are 
the same as those for the 
primary analysis of PFS except 
that the use of new anti-
myeloma therapy will be treated 
as an event rather than a 
mechanism for censoring. The 
same analysis method as for 
primary analysis will be used.

Initiation of new anti-myeloma
therapy treated as neither a 
PFS event nor a censoring 
event: The data censoring rules 
are the same as those for the 
primary analysis of PFS except 
that the initiation of new anti-
cancer therapy will be excluded 
as a mechanism for censoring.
The same analysis method as 
for primary analysis will be 
used.

Per-Protocol subset: same as 
primary summary and analysis 
method for Per-Protocol subset.

Lost to follow-up or withdrawal 
of consent treated as event: 
The data censoring rules are 
the same as those for the 
primary analysis of PFS except 
that subjects who were lost to 
follow-up or withdrew consent 
without PD/ death are treated 


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10.5.3
Exploratory Efficacy Analysis
The KM summaries described in Section 10.1 will be performed by treatment group for 
duration of response and clinical benefit. 
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.
QLQ-C30, QLQ-MY20 and EQ-5D-5L questionnaires will be administered prior to study 
treatment on Day 1 of Cycle 1, then every second cycle (Cycle 1, 3, 5, etc) during 
treatment and every 12 weeks (every 84 days ± 4 days) until progression, or withdrawal 
of consent during LTFU. Patient convenience and satisfaction questionnaire will be 
collected at Cycle 2 and EOT only.  All QLQ-C30 and QLQ-MY20 subscale scores will 
as having an event at the next 
scheduled assessment time in 
both treatment arms. The same 
analysis method as for primary 
analysis will be used.
Secondary Endpoints
Overall Response Rate
Based on internal 
computational assessments:

Point estimate of ORR 
and 95% CI by treatment 
group using the Clopper 
Pearson method

1-sided p-value from 
Cochran-Mantel -
Haenszel test stratified 
byrandomization 
stratification factors

Odds ratio associated 
with 95% CI using 
Mantel-Haenszel method

Investigator assessments: 
Same as primary summary and 
analysis method based on 
investigator assessments.

IRC assessments: Same as 
primary summary and analysis 
method based on IRC
assessments.

Unstratified analyses: 1-sided p-
value is from Fisher exact test 
and odds ratio (95%CI)
estimate is not adjusted for 
randomization stratification 
factors.

Per-Protocol subset: Same as 
primary summary and analysis 
method for Per-Protocol subset.
Overall Survival

KM summaries

1-sided p-value from 
stratified log-rank test

Hazard ratio and 95% CI 
from stratified Cox 
regression

Unstratified analyses: 1-sided p-
value from unstratified log-rank 
test, hazard ratio and 95% CI 
from unstratified Cox
regression.

Per-Protocol subset: same as 
primary summary and analysis 
method for Per-Protocol subset.


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be summarized descriptively by visit and by treatment group using the number of 
subjects with non-missing data (n), mean, standard deviation, median, minimum and 
maximum. Change from baseline will be summarized using the same statistics. EQ-5D-
5L data will be summarized by presenting the frequency and proportion of each level for 
each dimension by visit and by treatment group.  EQ VAS data arm will be summarized 
using the same method for QLQ-C30 and QLQ-MY20 subscale scores. Patient 
convenience and satisfaction questionnaire has only two questions about whether the 
patients feel the carfilzomib dosing schedule convenient and how statisfied/dissatisfied 
they are with the dosing schedule. The frequency and proportion of each category will be 
summarized for the two questions by treatment group at cycle 2 and EOT. The 
comparison analyses of health-related quality of life between treatment groups will be 
implemented in addition to the descriptive analyses described above. For instance, 
Global Health Status/QoL scale, an important subscale of QLQ-C30, will be compared 
between treatment groups across visits using a restricted maximum likelihood-based 
mixed model for repeated measures (MMRM) under the assumption of missing at 
random (MAR) (Mallinckrodt et al, 2008).
10.6
Safety Analyses
10.6.1
Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) version 19.1 or later will be 
used to code all adverse events (AE) to a system organ class and a preferred term. AEs 
of interest (EOI) categories will be based on search strategies defined by the EOI 
steering committee. All adverse event tables will be summarized by treatment group.
The subject incidence of AEs will be summarized for all treatment-emergent AEs, ≥
grade 3 TEAEs, serious AEs, AEs leading to modification (i.e., dose reduction or dose 
interruption) of investigational product, AEs leading to withdrawal of investigational 
product, and fatal AEs.
Subject incidence of all treatment-emergent AEs, ≥grade 3 TEAEs ,serious AEs, AEs 
leading to modification (i.e., dose reduction or dose interruption) of investigational 
product, AEs leading to withdrawal of investigational product, and fatal AEs will be 
tabulated by system organ class and preferred term in descending order of frequency; 
similar summaries will be repeated for EOIs. Time to onset and duration of select EOIs 
may also be summarized.
Summaries of treatment-emergent AEs and serious AEs will be presented by preferred 
term in descending order.


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A summary of treatment-emergent AEs will be tabulated by system organ class, 
preferred term, and causal relationship to study drug.
A summary of treatment-emergent AEs will be tabulated by system organ class, 
preferred term, and worst grade based on NCI-CTCAE Version 4.03.
Subgroup analyses (if there is a medical rationale) will be presented by system organ 
class and preferred term or EOI in descending order of frequency. 
10.6.2
Laboratory Test Results
For hematology, chemistry, and other laboratory values, the baseline values and, 
changes from baseline by visit,  the minimum, maximum, and last observed values will 
be summarized descriptively.  
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.  
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 defined in Appendix C by assessing the maximum increase 
and/or decrease observed during the course of study treatment relative to the baseline 
toxicity grade.
The subject incidence of Grade 3 and 4 hematological laboratory abnormalities 
(including neutropenia, thrombocytopenia, and anemia) will be provided by treatment 
group.    
The subject incidence of Grade 3 and 4 nonhematological toxicities (including liver 
function test [LFT], CrCl) will be provided by treatment group.  
10.6.3
Vital Signs
Vital sign results (systolic and diastolic blood pressure, pulse, respiratory rate, and 
temperature) will be summarized descriptively for baseline values, changes from 
baseline by visit, the minimum, maximum, and last observed values.  
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 


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excluded.  Vital sign results taken > 30 days after the last administration of protocol 
therapy will be excluded from all vital sign summaries.  
Shifts in scores for ECOG performance status scores between baseline and end of 
treatment visit will be tabulated by treatment group.
10.6.4
Electrocardiogram (ECG)
Twelve lead electrocardiograms (ECGs) including corrected QT-interval (QTc; 
representing the corrected duration of ventricular electrical activity) will be performed 
locally.  Electrocardiograms will be required from all subjects at Screening and EOT.  
ECG results (PR, QRS, QT, QTc, heart rate, and result) will be summarized descriptively 
by treatment group.
10.6.5
Exposure to Investigational Product
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group for subjects in the Safety Analysis Set.  The number of cycles of
protocol-specified therapy administered will be summarized with an additional 
breakdown of the number of cycles started. In addition, the duration of therapy, the 
cumulative dose, and the average dose per administration and relative dose intenstiy will 
be summarized for each drug. The number and percent of subjects with dose 
modifications (eg, dose reductions, dose interruptions) and reason for modification will 
be summarized for both treatment groups. 
10.6.6
Exposure to Concomitant Medication
The number and proportion of subjects receiving concomitant medications from study 
day 1 through safety follow-up will be summarized by preferred term as coded by the 
World Health Organization Drug (WHODRUG) dictionary by treatment group in the 
Safety Analysis Set. In addition, the number and proportion of subjects receiving anti-
myeloma therapies during long term follow-up will be summarized by WHODRUG 
preferred term for each treatment group in the Full Analysis Set.
10.7
Pharmacokinetic or Pharmacokinetic/Pharmacodynamic Analysis 
Analysis plan for sparse PK data
Blood samples will be collected on Day 1 of Cycle 2 at specified times, processed and 
stored until analysis.
Plasma samples will be analyzed by LC–MS/MS analysis to measure the plasma 
concentration of carfilzomib.   Sparse PK data collected from this study will be used to 


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update a population PK model previously developed (TR-1162-171) and will be 
described in a separate report. 
The analysis population will contain all subjects who have at least one PK sample 
collected according to the protocol and laboratory manual. Actual collection times will be 
recorded and used in the analysis. The population modeling program, NONMEM 
(version 7.2 or higher).will be used to fit a nonlinear mixed effects model to estimate PK 
parameters including clearance and volume of distribution, the inter- and intra-subject 
variability and the population variability in the parameter estimates. The PK 
concentrations obtained from subjects who participate in the sparse PK sampling along 
with results from the intensive PK/PDn sub-study and other carfilzomib studies will be 
used in the development of a structural model. The best model will be evaluated by 
goodness-of-fit statistics and reduction in the objective function and posterior predictive 
checks. Subject characteristics such as age, gender, body weight, BSA, and race will be 
included in the model to identify potential covariates affecting PK of carfilzomib.
Analysis plan for PK and PDn sub-study
Intensive pharmacokinetic (PK) and pharmacodynamic (PDn) samples will be obtained
as a sub-study (approximately n = 15 in each arm) from subjects who consent to the 
additional testing at selected sites. Pharmacokinetic samples will be collected on Day 15
of Cycle 1 and PDn samples will be collected on Days 1, 5, 6, and 7 of Cycle 1 and day 
2 of Cycle 2.
For both arms, PK plasma samples will be collected from all subjects for determination 
of plasma concentrations of carfilzomib on treatment Day 15 of Cycle 1 at the following 
time points:
•
Predose (within 5 minutes before the start of infusion)
•
15 minutes (± 5 minutes) after the start of infusion for Arm A only (once-weekly 
carfilzomib)
•
Immediately prior to (within 2 minutes before) the end of infusion
•
15 minutes (± 5 minutes) after the end of infusion
•
60 minutes (± 5 minutes) after the end of infusion
•
2 hours (± 5 minutes) after the end of infusion
PK
The analysis population will contain all subjects who have at least one PK sample 
collected according to the protocol and laboratory manual. Actual collection times will be 


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recorded and used in the analysis. Individual and mean plasma concentration versus 
time data will be tabulated and plotted by dose level. The PK parameter will be 
estimated based on noncompartmental methods. The PK parameter estimates for 
carfilzomib will be summarized, including total plasma exposure (AUC, Cmax, time to 
maximum plasma concentration [tmax], total plasma clearance, and t1/2 [as appropriate 
for data collected]). Estimates for these parameters will be tabulated and summarized
(i.e., n, Mean, Standard deviation, CV%, Median, Min, and Max, GeoMean and 
GeoCV%).  These estimates will be summarized descriptively by each arm (Once-
weekly vs Twice-weekly).  Plasma PK parameters of carfilzomib will be computed in 
WinNonlin® Enterprise v.5.2 or higher.
PDn
PD analyses will be performed using a whole-blood 20S proteasome specific activity 
inhibition assay.  The percent inhibition of 20S proteasome activity relative to baseline 
will be determined by a fluorogenic and/or luminescent substrate assay for the 
chymotrypsin-like (CT-L) (Beta5 subunit of the constitutive proteasome and LMP7 
subunit of the immunoproteasome), the trypsin-like (T-L), and caspase-like (C-L) 
activities of the proteasome. Individual and the mean percent inhibition of 20S 
proteasome activity relative to baseline will be determined and will be tabulated and 
plotted versus nominal sampling time by each arm (Once-weekly vs Twice- weekly).  
10.7.1
Exposure-Response (E-R) Analysis 
PK data collected from individuals who consent to the sparse PK sampling or PK/PDn 
sub-study will be used to explore the E-R relationship for efficacy and safety endpoints.  
The data from this study will be used to update a previously developed E-R model 
(Amgen Pharmacometrics Report: 121604) and will be described in a separate report. 
In brief, each exposure metric will be calculated using the individual subject’s 
parameters from the population PK model (see Section 10.7 Analysis plan for sparse PK 
data) and dosing history. The exposure metrics will be computed from the estimated 
Cmax and AUC and combined with the response/adverse event data to examine the E-R 
relationships for efficacy and safety endpoints.  A pooled analysis of data from this study 
and other carfilzomib clinical studies will be conducted. In addition, an E-R analysis 
based on this study alone may also be conducted.
Categorical responses will be tabulated by count and proportion by study. In the 
analysis, a quantitative assessment of the effect of each of the exposure metrics will be


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performed either using logistic regression for binary endpoints or log-rank test by 
exposure quartile for time-to-event endpoints. Endpoints exhibiting a statistically 
significant relationship to carfilzomib exposure will be further evaluated with multiple 
logistic or Cox proportional hazards models (for time-to-event endpoints) to assess the 
effects of covariates in conjunction with carfilzomib exposure on efficacy and safety 
responses.  Additional multiple logistic regression analysis will not be performed on the 
endpoints that showed inverse relationship.
Efficacy endpoints
The efficacy endpoints will include Progression-free survival (PFS),  ORR and CBR.  
Safety endpoints
Safety endpoints will include the subject incidence of any grade adverse events leading 
to study drug discontinuation, any Grade 3 or higher adverse events , serious adverse 
events, TEAEs with a fatal outcome, and cardiac, hepatic, and renal adverse events.   
Additional endpoints of interests may be included in the analysis. 
Covariates of interest
Endpoints exhibiting a statistically significant relationship to carfilzomib exposure will be 
further evaluated with multiple logistic models. The key covariates tested in the multiple 
logistic regression analysis may include the following:
bortezomib refractory in any prior regimen (yes/no), number of prior regimens, Eastern 
Cooperative Oncology Group (ECOG) performance status, sex, age, race, baseline 
CrCL, baseline hemoglobin (g/L), baseline serum beta-2 microglobulin (mg/L), and 
baseline platelet count (<150, ≥150 [109/L]). Additional covariates of interests may be 
included in the analysis.
11.
Changes From Protocol-specified Analyses
In the protocol, it specifies that logistic regression model will be used for ORR analysis. 
However, since Cochran-Mantel -Haenszel test is more widely used in analysis of binary 
endpoints to support regulatory filings, Cochran-Mantel-Haenszel test is specified to be 
used for ORR analysis in the SAP. The CMH test statistic and the score test statistic of 
the conditional logistic regression are approximately identical (Day N.E.& Byar D.P., 
1979), so this analysis method change will not affect the conclusion of ORR analysis. 


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12.
Literature Citations / References
Bladé J, Samson D, Reece D, et al. European Group for Blood and Marrow Transplant.
Myeloma Subcommittee of the EBMT. Criteria for evaluating disease response and
progression in subjects with multiple myeloma treated by high-dose therapy and
haemopoietic stem cell transplantation. Br J Haematol. 1998 Sep; 102(5):1115–23.
Clopper CJ and Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of the binomial, Biometrika. 1934; 26(4):404-413.
Collett D. Modelling Survival Data in Medical Research. 2nd edition. London, UK: 
Chapman & Hall/CRC; 2003.
Day N.E., Byar D.P. (September 1979), Testing hypotheses in case-control studies-
equivalence of Mantel–Haenszel statistics and logit score tests, Biometrics: 623–630
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.
Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple 
myeloma. J Clin Oncol. 2005;23(15):3412–20.
Hryniuk W, Goodyear, M. The calculation of received dose intensity. Journal of Clinical
Oncology 8:1935–1937, 1990 
Hung, H.M.,Wang, S. J. and O’Neil, R. (2007). Statistical considerations for testing
multiple endpoints in group sequential or adaptive clinical trials. Journal of 
Biopharmaceutical Statistics 17, 1201–1210.
Kalbfleisch, J. D. and Prentice, R. L. The Statistical Analysis of Failure Time Data, New 
York: John Wiley & Sons; 1980
Klein, J. P. and Moeschberger, M. L. (1997), Survival Analysis: Techniques for Censored 
and Truncated Data, New York: Springer-Verlag.Longo D, Duffey P, DeVita V, Wesley 
M, Hubbard S, Young R. The calculation of actual or received dose intensity: A 
comparison of published methods. Journal of Clinical Oncology 9:2042–2051, 1991
Lu, J., and Pajak, T. F. (2000), Statistical Power for a Long-Term Survival Trial with a 
Time-Dependent  Treatment Effect, Controlled Clinical Trials, 21, 561–573.
Mallinckrodt CH, Lane PW, Schnell D, Peng Y, and Mancuso, JP. Recommendations for 
the primary analysis of continuous endpoints in longitudinal clinical trials. Drug 
Information Journal, Vol. 42, pp.303-319, 2008
Mosteller RD. Simplified calculation of body surface area. N Engl J Med 
1987;317(17):1098 (letter).
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


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Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time.
Controlled Clinical Trials 17:343–346, 1996
US Food & Drug Administration: Guidance for Industry. Clinical Trial Endpoints for the
Approval of Cancer Drugs and Biologics. www.fda.gov/cder/guidance/7478fnl.htm


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13.
Appendices 


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CCI


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Appendix B.  Reference Values/Toxicity Grades2
Laboratory Values
Safety laboratory values below a distinct limit (eg. detection limit, documented as 
“< [limit]”) will be substituted by half of the limit and values above a distinct limit 
(documented as “> [limit]”) will be substituted by the limit itself for all analyses.
A Grade (based on CTC AE version 4.0 [v4.03: June 14, 2010]) will be assigned to each 
laboratory result as detailed in Table 2. Depending on the toxicity definition, the same 
result may be assigned to two grading for deviations towards higher or lower values. 
Values not meeting any of the criteria will be assigned a grade 0.
Table 2.  Grading of Select Laboratory Parameters
Laboratory Abnormality
[Unit]
Grade 1
Grade 2
Grade 3
Grade 4
Decreased Lymphocytes 
[G/L]
0.8 -  < LLN
0.5 - < 0.8
0.2 - < 0.5
< 0.2
Decreased Neutrophils  
[G/L]
1.5 - < LLN
1.0 - < 1.5
0.5 - < 1.0
< 0.5
Decreased Platelets [G/L]
75 - < LLN
50 - < 75
25 - < 50
< 25
Decreased WBC [G/L]
3.0 - < LLN
2.0 - < 3.0
1.0 - < 2.0
< 1.0
Decreased Hemoglobin 
[g/L]
100 - < LLN
80 - < 100
< 80
not 
defined
Decreased Albumin [g/L]
30 - < LLN
20 - < 30
< 20
not 
defined
Increased AST
> ULN – 3*ULN
> 3*ULN – 5*ULN
> 5*ULN –
20*ULN
> 20*ULN
Increased ALT 
> ULN – 3*ULN
> 3*ULN – 5*ULN
> 5*ULN –
20*ULN
> 20*ULN
Increased Total Bilirubin
> ULN –
1.5*ULN
>1.5*ULN – 3*ULN
> 3*ULN –
10*ULN
> 10*ULN
Increased Creatinine
>1 - 1.5 * BL or  
>ULN -
1.5 *ULN
>1.5 - 3.0 * BL or 
>1.5 -
3.0 * ULN
>3.0 * BL or 
>3.0 - 6.0 *
ULN
>6.0 * 
ULN
Decreased Corrected 
Calcium [mmol/L]
2.0 - < LLN
1.75 - < 2.0
1.5 - < 1.75
< 1.5
Increased Corrected 
Calcium [mmol/L]
>ULN - 2.9
>2.9 – 3.1
>3.1 – 3.4
>3.4
Decreased Potassium 
[mmol/L]*
3.0 - < LLN
3.0 - < LLN; 
symptomatic; 
intervention
indicated
2.5 - < 3.0
< 2.5


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Laboratory Abnormality
[Unit]
Grade 1
Grade 2
Grade 3
Grade 4
Increased Potassium 
[mmol/L]
5.5 - >ULN
>5.5 – 6.0
>6.0 – 7.0
>7.0
Decreased
Sodium[mmol/L]
130-<LLN
not defined
120-<130
<120
Increased
Sodium[mmol/L]
>ULN-150
>150-155
>155-160
>160
Decreased Phosphorus
[mmol/L]
0.8 - <LLN 
0.6 - <0.8
0.3 - <0.6
<0.3
Increased Magnesium
[mmol/L]
>ULN – 1.23
not defined
>1.23 – 3.30
>3.30
Decreased Magnesium 
[mmol/L]
0.5 - <LLN
0.4 - <0.5
0.3 - <0.4
<0.3
Increased Uric Acid 
[mmol/L]^
>ULN – 0.59 
without 
physiologic
consequences
not defined
>ULN – 0.59
with 
physiologic 
consequences
>0.59
BL: baseline value, LLN: Lower limit of normal, ULN: Upper limit of normal
Clinical criteria from CTCAE 4.0 grading were not considered in order to assign grades unless 
specified otherwise
*: Details will be recorded on Potassium CTC Details CRF for central lab values and Chemistry (Local 
Lab) CRF for local lab values.
^: Details will be recorded on Uric Acid CTC Details CRF for central lab values and Chemistry (Local 
Lab) CRF for local lab values.


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Appendix C.  Patient-reported Outcome Forms/Instruments3
The following sections describe the scoring algorithms used for both the QLQ-C30 and
QLQ-MY20 questionnaires. Scoring procedures are similar for both questionnaires and
can be found in the EORTC QLQ-C30 Scoring Manual, ver. 3 (Fayers et al. 2001) and
Cocks et al (2007). All scale scores range from 0 to 100.
QLQ-C30 Scoring
For all scales, calculate the raw score (RS) of a scale using the mean of the item scores 
in the scale as follows:
RS = (S1 + S2 + …+Sn) / n
where Si: i=1, …, n, are the item scores and n is the number of items with valid scores,
assuming the number of items with valid scores meets the minimum requirement as
specified in Table 3 or this scale score will be assumed missing.
Use a linear transformation to standardize the raw score in order that scores will range
from 0-100:
Global Health Status/QOL = {(RS-1)/range} * 100
Functional Scales = {1- (RS-1)/range} * 100
Symptom Scales = {(RS-1)/range} * 100
where range for each scale is defined in Table 3.
For the Global Health Status/QOL scale and functional scales in QLQ-C30 a higher 
score represents a better health state and for the symptom scores in QLQ-C30 a lower 
score represents a better health state.
QLQ-MY20 Scoring
For all scales, calculate the raw score (RS) of a scale using the mean of the item scores 
in the scale as follows:
RS = (S1 + S2 + …+Sn) / n
where Si: i=1, …, n, are the item scores and n is the number of items with valid scores,
assuming the number of items with valid scores meets the minimum requirement as


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specified in Table 3 or this scale score will be assumed missing.
Use a linear transformation to standardize the raw score in order that scores will range
from 0-100:
Disease Symptom Scale (DS) = {(RS – 1) / range} * 100
Side Effects of Treatment Scale (SE) = {(RS – 1) / range} * 100
Future Perspective Scale (FP) = {1 - (RS – 1) / range} * 100
Body Image (BI) = {1 - (RS – 1) / range} * 100
where range for each scale is defined in Table 3.
Table 3: QLQ-C30 and QLQ-MY20 Scales and Scoring Details
Number 
of Items
Item 
Range a
Item 
Numbers
Minimum Not 
Missing
QLQ-C30
Global Health 
status/QOL
2
6
29,30
1
Functional Scales
 Physical Functioning
5
3
1-5
3
 Role Functioning
2
3
6,7
1
 Emotional Functioning
4
3
21-24
2
 Cognitive Functioning
2
3
20,25
1
 Social Functioning
2
3
26,27
1
Symptom Scales / Items
 Fatigue
3
3
10,12,18
2
 Nausea/vomiting
2
3
14,15
1
 Pain
2
3
9,19
1
 Dyspnoea
1
3
8
N/A
 Insomnia
1
3
11
N/A
 Appetite Loss
1
3
13
N/A
 Constipation
1
3
16
N/A
 Diarrhoea
1
3
17
N/A
 Financial Difficulties
1
3
28
N/A
QLQ-MY20
Symptom Scales 
     Disease Symptoms
6
3
31-36
3
     Side Effects of 
Treatment
10
3
37-46
5
Functional Scales/Items
   Future Perspective
3
3
48-50
1
   Body Image
1
3
47
N/A


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a Range is the difference between the maximum possible value of the Raw Score and the minimum possible
value.
For the Disease Symptoms and the Side Effects of Treatment scales a high score
represents a high level of symptomatology / problems (symptom scale). For Body Image 
and Future Perspective scales a high score represents a high level of functioning
(functional scale), i.e. a better future perspective or body image.