Clinical trial NCT02335983
Conditions: Multiple Myeloma
Sponsor: Amgen
Start date: 2015-04-30; Completion date: 2019-10-28
Enrollment: 107 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to assess the safety, tolerability and activity of a once-weekly regimen of carfilzomib in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma.

Detailed description:

Arms: arm 1: Participants with relapsed or refractory multiple myeloma (RRMM) received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death.

Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 56 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8. arm 2: Participants with RRMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death.

Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8. arm 3: Participants with RRMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death.

Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8. arm 4: Participants with newly diagnosed multiple myeloma (NDMM) received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death.

Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1 day 1, 56 mg/m² on cycle 1 days 8 and 15, and then 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8. arm 5: Participants with NDMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death.

Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8. arm 6: Participants with NDMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death.

Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 56 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8.
Interventions: intervention 1: Carfilzomib intervention 2: Lenalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Administered once weekly by 30-minute intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle. intervention 2: Administered orally once daily on days 1-21 of each 28-day cycle. intervention 3: Administered by mouth or IV at 40 mg on days 1, 8, and 15 of each 28-day cycle and on day 22 of cycles 1 to 8.

Protocol documents:
Prot_000.pdf: 
Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 1 of 108 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
Phase 1b Study of Carfilzomib Administered Once Weekly in 
Combination With Lenalidomide and Dexamethasone in 
Subjects With Multiple Myeloma 
Protocol Number: 
CFZ013 
Name of Investigational 
Product: 
Kyprolis® (Carfilzomib for Injection [carfilzomib]) 
IND Number: 
IND 71,057 
EudraCT Number: 
Sponsor: 
Onyx Therapeutics, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Study Medical Monitor: 
, MD, PhD 
One Amgen Center Drive 
MS 38-2-A 
Thousand Oaks, CA 91320 
Principal Investigator: 
, MD, PhD  
John Theurer Cancer Center at 
Hackensack University Medical Center 
92 Second Street 
Hackensack, NJ 07601 
Date of Protocol: 
26 August 2014 
Amendment 1: 
02 March 2016 
Amendment 2: 
14 October 2016 
Amendment 3: 
13 December 2016 
Confidentiality 
Statement: 
This material is the property of Onyx Therapeutics, Inc., a wholly owned 
subsidiary of Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary.  The 
material is highly confidential and is to be used only in connection with 
matters authorized by a senior representative of Onyx Therapeutics, Inc., and 
no part of it is to be disclosed to a third party without the express prior 
written permission of Onyx Therapeutics, Inc. 
Compliance Statement: 
This study will be conducted in accordance with Protocol CFZ013, the 
relevant Onyx Therapeutics, Inc., an Amgen Inc. subsidiary, policies and 
procedures, the International Conference on Harmonisation (ICH), Guideline 
for Good Clinical Practice (GCP), and the applicable country and regional 
(local) regulatory requirements. 
NCT Number: NCT02335983
This NCT number has been applied to the document for 
purposes of posting on Clinicaltrials.gov


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 2 of 108 
CONFIDENTIAL 
PROTOCOL ACCEPTANCE PAGE 
Issue/Date:  CFZ013 Amendment 3/13 December 2016 
I have read this protocol for Study CFZ013 entitled: 
Phase 1b Study of Carfilzomib Administered Once Weekly in Combination With 
Lenalidomide and Dexamethasone in Subjects With Multiple Myeloma 
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 Therapeutics, Inc. or its 
designee (please retain a copy for your files). 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 3 of 108 
CONFIDENTIAL 
1 
Name of 
sponsor/company: 
SYNOPSIS 
Onyx Therapeutics, Inc. 
Name of product: 
Carfilzomib for Injection 
Title of study and 
protocol number 
and phase: 
CFZ013:  Phase 1b study of carfilzomib administered once weekly in combination with 
lenalidomide and dexamethasone for the treatment of multiple myeloma 
Study objective(s): 
Primary Objective  
• 
To evaluate the safety and tolerability of a once-weekly carfilzomib, 
lenalidomide, and dexamethasone (KRd) regimen in relapsed and refractory 
multiple myeloma (RRMM) and newly diagnosed multiple myeloma (NDMM) 
subjects 
Secondary Objectives 
• 
To evaluate the pharmacokinetics (PK) of carfilzomib when administered  
once weekly in a KRd regimen in RRMM and NDMM subjects 
• 
To evaluate the clinical activity (efficacy) of a once-weekly KRd regimen in 
RRMM and NDMM subjects 
Exploratory Objectives 
• 
To explore the genomic and transcriptional biomarkers that might predict 
response and resistance to a once-weekly KRd regimen  
• 
To characterize the pharmacodynamics (PDn) of proteasome inhibition with a 
once-weekly KRd regimen in RRMM and NDMM subjects 
• 
To assess minimal residual disease (MRD) status with a once-weekly KRd 
regimen in RRMM and NDMM subjects 
• 
To assess subject convenience and satisfaction with a once-weekly KRd 
regimen using subject questionnaire in RRMM and NDMM subjects  


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 4 of 108 
CONFIDENTIAL 
Study design: 
This is an open-label, multicenter, Phase 1b, dose-finding study of carfilzomib 
administered once weekly in combination with lenalidomide and dexamethasone (KRd).  
Once-weekly carfilzomib in a KRd regimen will be evaluated in RRMM and NDMM 
subjects.   
There will be 2 parts in the study: Dose Evaluation and Dose Expansion.   
Prior to protocol amendment 2
Two dose levels of once-weekly carfilzomib in a KRd regimen (Cohort 1 and Cohort 2) 
will be evaluated during the Dose-evaluation Component in RRMM subjects; a third 
optional KRd regimen (with a reduced dose level of lenalidomide) may also be evaluated 
(Cohort 3).  Approximately 8 dose-limiting toxicity (DLT) evaluable RRMM subjects 
will be enrolled into each opened Dose-evaluation cohort.   
: 
The second part is the Dose-expansion Component during which approximately  
60 subjects (30 RRMM and 30 NDMM subjects) will receive the KRd regimen selected 
in the Dose-evaluation Component. 
Per protocol amendment 2
NDMM subjects will be enrolled into an additional Dose-evaluation Cohort 4.  
Approximately 8 DLT-evaluable subjects will be treated with carfilzomib given once 
weekly with 2-step-up dosing in a KRd regimen.  The Cohort Safety Review Committee 
(CSRC) may then elect to open enrollment to a Dose-expansion Component for an 
additional 30 NDMM subjects.  
: 
Subjects may continue to receive study treatment for up to 18 cycles.  Newly diagnosed 
multiple myeloma subjects may interrupt therapy after cycle 4 for autologous stem cell 
transplant (ASCT).   
All subjects will be evaluated for safety at an End of Treatment (EOT) visit, 28 ± 7 days 
after the last study treatment, and with an EOT echocardiogram (ECHO), done within 
28 ± 7 days after the last study treatment.  
Following the EOT, subjects who have not had disease progression or allogeneic stem 
cell transplant will enter Active Follow-up.   
Number of 
investigational 
sites: 
Approximately 30 sites 
Planned number 
of subjects: 
Approximately 114 subjects in total.  
Prior to protocol amendment 2, 56 RRMM and 20 NDMM subjects were enrolled in the 
study.  Twenty-two RRMM subjects were enrolled into the RRMM Dose-evaluation 
Component; 34 RRMM subjects were enrolled into the RRMM Dose-expansion 
Component of the study.  Enrollment of RRMM subjects is completed. 
Per protocol amendment 2
NDMM subjects enrolled prior to protocol amendment 2 who are DLT-evaluable at 
Cohort 4 dosing will be considered Cohort 4 subjects. 
, approximately 38 NDMM subjects will be enrolled in the 
study: approximately 8 subjects will be enrolled into the NDMM Dose-evaluation 
Component, and approximately 30 subjects will be enrolled in the second NDMM 
Dose-expansion Component of the study. 
Sample size 
justification: 
Sample sizes are determined to provide preliminary information on safety, clinical 
activity, PDn, and PK.  With respect to safety, 38 subjects with relapsed disease in the 
dose cohort selected to move into the expansion component and 38 NDMM subjects will 
allow an approximately 86% probability to detect an occurrence of an adverse event 
(AE) with 5% incidence rate.   
Study population: 
Subjects with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy 
and subjects with newly diagnosed, transplant-eligible or transplant-ineligible multiple 
myeloma.    


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 5 of 108 
CONFIDENTIAL 
Treatment 
regimen(s): 
Carfilzomib combination therapy will be given for up to 18 cycles.  The combination 
regimens evaluated in the Dose-evaluation Component include: 
Dose-evaluation Component 
Cohort 1 (RRMM):  
KRd = carfilzomib 20/56 mg/m2/ lenalidomide 25 mg/ dexamethasone 40 mg 
Carfilzomib dosing: 20 mg/m2 Day 1 of Cycle 1; 56 mg/m2 Days 8 and 15 of Cycle 1; 
Days 1, 8, and 15 of Cycle 2 and beyond 
Cohort 2 (RRMM):  
KRd = carfilzomib 20/70 mg/m2/ lenalidomide 25 mg/ dexamethasone 40 mg 
Carfilzomib dosing: 20 mg/m2 Day 1 of Cycle 1; 70 mg/m2 Days 8 and 15 of Cycle 1; 
Days 1, 8, and 15 of Cycle 2 and beyond 
Optional Cohort 3 (RRMM):  
KRd = carfilzomib 20/70 mg/m2/ lenalidomide 10 mg/  
dexamethasone 40 mg  
Carfilzomib dosing: 20 mg/m2 Day 1 of Cycle 1; 70 mg/m2  Days 8 and 15 of Cycle 1; 
Days 1, 8, and 15 of Cycle 2 and beyond 
Cohort 4 (NDMM):  
2-step-up KRd = carfilzomib 20/56/56/70 mg/m2/ lenalidomide 25 mg/ 
dexamethasone 40 mg.  
Carfilzomib dosing: 20 mg/m2 Day 1 of Cycle 1; 56 mg/m2 on Days 8 and 15 of Cycle 1; 
70 mg/m2 on Days 1, 8, and 15 of Cycle 2 and beyond 
 
KRd will be given in 28-day cycles: 
• 
Carfilzomib will be administered once weekly intravenously (IV) on Days 1, 8, 
and 15 
• 
Lenalidomide will be administered once daily by mouth on Days 1–21. 
• 
Dexamethasone will be administered once daily by mouth or IV on  
Days 1, 8, and 15.  Dexamethasone will also be given on Day 22 of  
Cycles 1–8.   
 
If a regimen evaluated during the Dose-evaluation Component is safe and tolerable, 
approximately 30 additional subjects may be enrolled for treatment in a Dose-expansion 
arm.  
Dose-expansion Component 
Inclusion criteria: 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Age ≥ 18 years 
2. Able to provide written informed consent in accordance with federal, local, and 
institutional guidelines 
3. Newly diagnosed or relapsed multiple myeloma 
a. 
For subjects with relapsed multiple myeloma: 
i. 
1 to 3 prior lines of therapy for multiple myeloma (induction therapy 
followed by stem cell transplant and consolidation/maintenance therapy 
will be considered as one line of therapy), and  
ii. Documented response of at least partial response (PR) to 1 line of prior 
therapy.  Investigator assessment is acceptable as PR documentation. 
b. For subjects with newly diagnosed, transplant-eligible or transplant-ineligible 
multiple myeloma:   
i. 
Symptomatic multiple myeloma (per International Myeloma Working 
Group [IMWG] diagnostic criteria) and  
ii. No prior treatment for multiple myeloma 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 6 of 108 
CONFIDENTIAL 
Inclusion criteria 
(cont’d): 
4. Measurable disease with at least 1 of the following assessed within 21 days prior to 
Cycle 1 Day 1: 
a. 
Serum M-protein ≥ 0.5 g/dL, 
b. Urine M-protein ≥ 200 mg/24 hour,  
c. 
In subjects without detectable serum or urine M-protein, serum free light 
chain (SFLC) > 100 mg/L (involved light chain) and an abnormal serum 
kappa lambda ratio 
d. For immunoglobulin (Ig) A subjects whose disease can only be reliably 
measured by serum quantitative immunoglobulin (qIgA), a qIgA level of 
≥ 750 mg/dL (0.75 g/dL) 
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2 
6. Left ventricular ejection fraction (LVEF) ≥ 40% 
8. Absolute neutrophil count (ANC) ≥ 1000/mm3 within 21 days prior to Cycle 1 Day 1 
with (1) no nonpegylated growth factor support for ≥ 7 days and (2) no pegylated 
growth factor support for ≥ 14 days 
9. Hemoglobin ≥ 8.0 g/dL within 21 days prior to Cycle 1 Day 1.  Use of erythropoietic 
stimulating factors and red blood cell (RBC) transfusions per institutional guidelines 
is allowed 
10. Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the bone 
marrow is > 50%) within 21 days prior to Cycle 1 Day 1 with no platelet 
transfusions for ≥ 7 days 
11. Calculated or measured creatinine clearance (CrCl) of ≥ 50 mL/min within 21 days 
prior to Cycle 1 Day 1.  Calculation must be based on standard formula such as the 
Cockcroft and Gault. 
12. Females of childbearing potential (FCBP) must have a negative serum pregnancy 
test within the 10 to 14 days prior to study drug administration and a negative urine 
or serum pregnancy test within the 24 hours prior to the first study drug 
administration 
13. FCBP and male subjects who are sexually active with a FCBP must agree to use 
2 highly effective methods of contraception during the study.  FCBP subjects are 
required to continue use of 2 highly effective methods of contraception for 30 days 
following discontinuation of study drugs.  Vasectomized male subjects who have 
received medical confirmation of surgical success are not required to use additional 
methods of contraception.  Otherwise, male subjects with a FCBP partner must agree 
to use 2 highly effective methods of contraception during study and for 90 days 
following discontinuation of study drugs 
14. Male subjects must agree to not donate sperm while taking study drugs and 90 days 
after the last dose of study drugs 
15. Normal hepatic function within 21 days prior to Cycle 1 Day 1: 
a. Bilirubin ≤ the upper limit of normal (ULN) 
b. Aspartate aminotransferase (AST) and alanine aminotransferase  
(ALT) ≤ the ULN 
 
Exclusion criteria: 
 
 
 
 
 
 
 
1. Waldenström macroglobulinemia 
2. For newly diagnosed multiple myeloma:  multiple myeloma of IgM subtype 
3. For relapsed disease: 
a. 
If treated with a lenalidomide and dexamethasone-containing combination, 
progression during the first 3 months after initiating treatment 
b. Any progression during treatment if the lenalidomide and 
dexamethasone-containing regimen was the most recent line of therapy 
c. 
Any prior treatment with carfilzomib 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 7 of 108 
CONFIDENTIAL 
 
Exclusion criteria 
(cont’d): 
4. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes)  
5. Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential) 
6. Myelodysplastic syndrome 
7. Second malignancy within the past 5 years except: 
a. 
Adequately treated basal cell or squamous cell skin cancer, or 
b. Carcinoma in situ of the cervix, or  
c. 
Prostate cancer < Gleason score 6 with undetectable prostate-specific antigen 
(PSA) over 12 months, or 
d. Ductal breast carcinoma in situ with full surgical resection (ie, negative 
margins), or 
e. 
Treated medullary or papillary thyroid cancer, or 
f. 
Similar condition with an expectation of > 95% five-year disease-free survival 
8. Amyloidosis 
9. Cytotoxic chemotherapy within 28 days prior to Cycle 1 Day 1 
10. Immunotherapy within 21 days prior to Cycle 1 Day 1 
11. Glucocorticoid therapy within 14 days prior to Cycle 1 Day 1 that exceeds a 
cumulative dose of 160 mg of dexamethasone 
12. Radiation therapy: 
a. 
Focal therapy within 7 days prior to Cycle 1 Day 1 
b. Extended field therapy within 21 days prior to Cycle 1 Day 1 
13. Prior treatment with carfilzomib or oprozomib 
14. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize 
carfilzomib) 
15. Contraindication to lenalidomide or dexamethasone 
16. Contraindication to any of the required concomitant drugs or supportive treatments, 
including hypersensitivity to antiviral drugs or intolerance to hydration due to 
preexisting pulmonary or cardiac impairment 
17. Active congestive heart failure (New York Heart Association [NYHA] Class III to 
IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional 
intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or 
myocardial infarction within 6 months prior to Cycle 1 Day 1 
18. Active infection within 14 days prior to Cycle 1 Day 1 requiring systemic antibiotics 
19. Pleural effusions requiring thoracentesis within 14 days prior to Cycle 1 Day 1 
20. Ascites requiring paracentesis within 14 days prior to Cycle 1 Day 1 
21. Ongoing graft-versus-host disease 
22. Uncontrolled hypertension or uncontrolled diabetes 
23. Significant neuropathy (≥ Grade 3) within 14 days prior to Cycle 1 Day 1 
24. Known cirrhosis 
25. Known human immunodeficiency virus (HIV) seropositivity, hepatitis C infection, 
or hepatitis B infection (subjects with hepatitis B surface antigen [SAg] or core 
antibody receiving and responding to antiviral therapy directed at hepatitis B are 
allowed) 
26. Participation in another interventional study within 28 days prior to Cycle 1 Day 1 
27. Major surgery (except kyphoplasty) within 28 days prior to Cycle 1 Day 1 
28. Female subjects who are pregnant or lactating  
29. 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. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 8 of 108 
CONFIDENTIAL 
Treatment and 
assessments: 
Treatment cycles are 28 days in duration and consist of KRd combination treatment as 
described above. 
 
 
Criteria for evaluation: 
Safety 
variables: 
Safety and tolerability will be assessed by incidence and severity of AEs and changes 
from baseline of all relevant parameters, including laboratory values, vital signs, 
electrocardiogram (ECG), and ECHO.  Severity of AEs will be assessed according to the 
National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events 
(CTCAE; version 4.03).  All subjects will be monitored for AEs for 30 days after the last 
administration of study treatment.   
Efficacy 
variables: 
Disease assessments according to the IMWG-Uniform Response Criteria (URC) will be 
conducted at Screening (within 21 days before dosing on Cycle 1 Day 1) and then at 
Cycle 2 Day 1 and on Day 1 ± 3 days of every cycle thereafter for up to 18 cycles.  
Minimal residual disease (MRD) status will be assessed by using flow cytometry (FC) of 
cell surface markers and Next Generation Sequencing (NGS) of DNA and/or RNA from 
the Ig locus.  The MRD analysis by FC will be performed on bone marrow aspirated at 
2 time points:  Cycle 8 Day 1, and upon achieving a CR or sCR.  The MRD analysis by 
NGS will be performed using blood and bone marrow aspirates collected at 3 time points:  
baseline, Cycle 8 Day 1, and upon achieving a CR or sCR. 
PK: 
For both the Dose-evaluation and the Dose-expansion Components, blood samples will be 
collected from all subjects on Day 8 of Cycle 1 for determination of plasma 
concentrations of carfilzomib.  On the day of blood collection, blood will be collected at 
predose, 15 minutes after the start of the infusion, immediately prior to (within 2 minutes 
before) the end of the infusion, and 15 and 60 minutes after the end of the infusion. 
PDn: 
Whole blood will be collected from all subjects in the Dose-evaluation Component, and 
the first 8 subjects enrolled in Dose-expansion Arm 3, on Days 1, 8, 9, and 11 of 
Cycle 1.  On Days 1 and 8 of Cycle 1 whole blood will be collected pre-carfilzomib dose 
and post-carfilzomib dose.  On Days 9 and 11 of Cycle 1, when carfilzomib is not 
administered, one PDn sample will be collected at approximately the same time as when 
the pre-infusion sample was taken on Day 8. 
 
Genomics: 
Analysis of genetics, gene expression, and cell surface biomarkers that may predict for 
response and resistance to treatment with proteasome inhibitors will be performed.  
Exploratory studies will be conducted on all subjects who consent to optional genomic 
biomarker analysis.  These analyses will be performed on bone marrow aspirate (the 
remaining portion of the bone marrow aspirate sample left after the amount required for 
fluorescent in situ hybridization (FISH) analysis has been collected at baseline), as well as 
a sample of blood and saliva also collected at the time of baseline.  At progression, an 
optional additional bone marrow sample for biomarker analysis may be collected from all 
subjects who consent. 
Whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome 
sequencing (RNA-Seq), and/or other methods of nucleic acid and protein quantification 
will be conducted on isolated tumor (CD138+) cells from these bone marrow aspirate 
samples.  In addition, WGS or WES will be performed on a normal tissue sample (eg, 
CD3+ T cells isolated from peripheral blood or saliva) to distinguish germ line mutations 
from somatic mutations in tumor cell samples. 
Other: 
Subject convenience and satisfaction with the carfilzomib dosing schedule will be 
assessed by questionnaire at Cycle 3 Day 1 and Cycle 18 Day 1. 
Statistical 
methods and 
analyses: 
All safety and efficacy analyses will be based upon the Safety Population, defined as 
subjects receiving treatment with at least 1 dose of carfilzomib.  In addition, response data 
(overall response rate [ORR], complete response rate [CRR], progression-free survival 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 9 of 108 
CONFIDENTIAL 
Statistical 
methods and 
analyses 
(cont’d): 
[PFS], duration of response [DOR]) may also be analyzed based on the 
Response-evaluable Population, defined as subjects who are included in the Safety 
Population, have a baseline disease assessment and at least 1 postbaseline disease 
assessment, or dropped out due to AE prior to the first postbaseline disease assessment. 
Primary Endpoints
• 
Safety and tolerability of carfilzomib administered once weekly in combination 
with lenalidomide and dexamethasone, as defined by the type, incidence, and 
severity of AEs, and changes from baseline in key laboratory analyses, 
including immunoglobulin levels, vital signs, and the extent and duration of 
exposure to study drugs.   
: 
All treatment-emergent AEs will be summarized by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term, NCI CTCAE grade, and 
investigator assessment of causality.  In addition, all serious adverse events 
(SAEs), including deaths, will be listed separately.  Extent of exposure to the 
study treatment will be summarized using descriptive statistics.  Laboratory 
parameters will be summarized using descriptive statistics and by postdose 
shifts relative to baseline.  Vital signs will also be summarized descriptively for 
each scheduled protocol time point.   
Secondary Endpoints
• 
Pharmacokinetics (PK) of carfilzomib 
: 
• 
Overall Response Rate (ORR), defined as the proportion of subjects who 
achieve a best overall response of stringent complete response (sCR), CR, very 
good partial response (VGPR), or PR in accordance with IMWG-URC  
• 
Complete Response Rate (CRR), defined as the proportion of subjects who 
achieve a best overall response of either sCR or CR in accordance with 
IMWG-URC  
• 
Progression-free Survival (PFS), defined as the time from the first day of study 
treatment to the earlier of disease progression or death due to any cause  
• 
Duration of Response (DOR), defined as the time from the first evidence of 
confirmed PR or better to disease progression or death due to any cause among 
subjects who respond  
Point estimates for ORR and CRR along with their exact 2-sided 95% confidence intervals 
will be calculated.  The distribution of time-to-event endpoints (PFS and DOR) will be 
summarized descriptively using the Kaplan-Meier method.   
Safety and efficacy analyses will be performed by dose levels and by populations (newly 
diagnosed and relapsed). 
Pharmacokinetics
The PK parameter estimates for carfilzomib will be summarized, including total plasma 
exposure (expressed as area under the curve; AUC), maximum plasma concentration 
(Cmax), time to maximum plasma concentration (Tmax), total plasma clearance, and plasma 
terminal half-life (as appropriate for data collected).  Estimates for these parameters will 
be tabulated and summarized (ie, mean, standard deviation).  The PK parameters will be 
summarized descriptively. 
:  
Exploratory Endpoints
• 
Pharmacodynamics (PDn) of proteasome inhibition by carfilzomib measured in 
whole blood 
: 
• 
MRD[-] rate, defined as the proportion of subjects who have negative MRD at 
Cycle 8 Day 1.  Point estimates for MRD[-] rate along with exact 2-sided 95% 
confidence intervals will be calculated for both MRD assessment methods   
• 
Subject convenience and satisfaction with the carfilzomib dosing schedule.   
• 
WGS, WES, whole transcriptome sequencing, and other nucleic acid and 
protein quantification data and immunoglobulin levels in tumor cells 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 10 of 108 
CONFIDENTIAL 
WGS, WES, RNA-Seq, and/or other nucleic acid and protein quantification data will be 
analyzed to characterize whether drug response is related to alterations in genes regulated 
by or involved in activation of nuclear factor kappa light chain enhancer of activated B 
cells (NF-Kappa B) transcription factors as well as in genes involved in immunoglobulin 
production and protein homeostasis.  Immunoglobulin levels in tumor cells will be 
quantified by enzyme-linked immunosorbent assay (ELISA) and/ or other protein 
quantification methods.  The genomic data as a whole will also be used to derive new 
hypotheses about mechanisms of drug response, resistance, and safety. 


Onyx Therapeutics, Inc. 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 11 of 108 
CONFIDENTIAL 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL .........................................................................................1
Page 
 
PROTOCOL ACCEPTANCE PAGE ....................................................................................2 
1 
SYNOPSIS ....................................................................................................................3 
TABLE OF CONTENTS ......................................................................................................11 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................17 
3 
BACKGROUND INFORMATION .........................................................................21 
3.1 
Introduction ......................................................................................................21 
3.2 
Multiple Myeloma ...........................................................................................21 
3.3 
Novel Therapies for Multiple Myeloma ..........................................................22 
3.3.1 
Proteasome Background ...................................................................22 
3.3.2 
Carfilzomib Background (Nonclinical) ............................................22 
3.3.3 
Carfilzomib Background (Clinical) ..................................................23 
3.3.4 
Combinations of Immunomodulatory Agents and Proteasome 
Inhibitors ...........................................................................................25 
3.4  
Dose Rationale .................................................................................................27 
3.5 
Study Rationale ................................................................................................29 
4 
STUDY OBJECTIVES ..............................................................................................30 
4.1 
Primary Objectives...........................................................................................30 
4.2 
Secondary Objectives.......................................................................................30 
4.3 
Exploratory Objectives ....................................................................................31 
5 
STUDY DESIGN ........................................................................................................31 
5.1 
Study Population ..............................................................................................33 
5.2 
Definition of Dose-limiting Toxicity ...............................................................34 
5.2.1 
Nonhematologic DLT .......................................................................34 
5.2.2 
Hematologic DLT .............................................................................34 
5.3 
Cohort Safety Review Committee ...................................................................35 
5.4 
Part 1:  Dose-evaluation Component ...............................................................35 
5.5 
Part 2:  Dose-expansion Component................................................................36 
5.6 
Active Follow-up .............................................................................................36 
5.7 
Estimated Study Duration and Study Closure .................................................37 


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5.8 
Minimizing Bias...............................................................................................37 
5.8.1 
Randomization ..................................................................................37 
5.8.2 
Blinding.............................................................................................37 
6 
SUBJECT SELECTION ...........................................................................................37 
6.1 
Inclusion Criteria .............................................................................................38 
6.2 
Exclusion Criteria ............................................................................................39 
7 
SUBJECT SCREENING ...........................................................................................41 
8 
STUDY TREATMENT .............................................................................................42 
8.1 
Carfilzomib ......................................................................................................42 
8.1.1 
Physical Description .........................................................................42 
8.1.2 
Packaging and Labeling ....................................................................42 
8.1.3 
Storage ..............................................................................................42 
8.2 
Lenalidomide ...................................................................................................43 
8.3 
Dexamethasone ................................................................................................43 
8.4 
Study Drug Accountability ..............................................................................44 
9 
DOSAGE AND TREATMENT ADMINISTRATION ...........................................44 
9.1 
Treatment Regimen ..........................................................................................44 
9.2 
Intravenous Hydration .....................................................................................44 
9.2.1 
Study Treatment Administration.......................................................45 
9.2.1.1 
Carfilzomib .....................................................................45 
9.2.1.2 
Lenalidomide ..................................................................46 
9.2.1.3 
Dexamethasone ...............................................................46 
9.2.2 
Carfilzomib and Lenalidomide Dose Modification Guidelines ........47 
9.2.2.1 
Hematologic Toxicity .....................................................48 
9.2.2.2 
Nonhematologic Toxicity ...............................................49 
9.2.2.3 
Conditions Not Requiring Dose Reduction ....................53 
9.2.3 
Dexamethasone Dose Modification Guidelines................................53 
9.3 
Concomitant Medications ................................................................................56 
9.3.1 
Required Concomitant Medications .................................................56 
9.3.1.1 
Antiviral Prophylaxis ......................................................56 
9.3.1.2 
Anticoagulant Prophylaxis ..............................................56 
9.3.1.3 
Tumor Lysis Syndrome Prophylaxis ..............................57 
9.3.1.4 
Contraception ..................................................................57 


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9.3.2 
Optional and Allowed Concomitant Medications .............................58 
9.3.3 
Excluded Concomitant Medications .................................................58 
10 
STUDY PROCEDURES ...........................................................................................59 
10.1 
Study-specific Procedures ................................................................................59 
10.1.1 
Baseline Procedures ..........................................................................59 
10.1.2 
Vital Signs .........................................................................................59 
10.1.3 
Physical Examination........................................................................60 
10.1.4 
Disease Assessments .........................................................................60 
10.1.4.1 
Laboratory Evaluations of Disease Status ......................60 
10.1.4.2 
Bone Marrow Aspirate Assessments of Disease 
Status ...............................................................................61 
10.1.4.3 
Imaging Assessments of Disease Status .........................62 
10.1.5 
Myeloma Response Assessment .......................................................63 
10.1.6 
Clinical Laboratory Tests ..................................................................63 
10.1.7 
Electrocardiogram .............................................................................64 
10.1.8 
Echocardiogram ................................................................................64 
10.1.9 
Subject Convenience and Satisfaction ..............................................64 
10.2 
Correlative Studies ...........................................................................................64 
10.2.1 
Pharmacokinetic Measurements .......................................................64 
10.2.2 
Pharmacodynamic Measurements ....................................................65 
10.2.3 
Fluorescent In Situ Hybridization (FISH) Testing ............................65 
10.2.4 
Minimal Residual Disease ................................................................66 
10.2.5 
Optional Genomic Biomarkers .........................................................66 
11 
STUDY DISCONTINUATION ................................................................................67 
11.1 
Withdrawal of Subjects from Treatment..........................................................67 
11.2 
Withdrawal of Subjects from Study .................................................................68 
11.3 
Study Termination ...........................................................................................68 
12 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING...............68 
12.1 
Definition of Safety Events ..............................................................................68 
12.1.1 
Adverse Events .................................................................................68 
12.1.2 
Serious Adverse Events ....................................................................70 
12.2 
Safety Event Reporting Procedures .................................................................70 
12.2.1 
Adverse Events .................................................................................70 


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12.2.1.1 
Reporting Procedures for Adverse Events That do 
not Meet Serious Criteria ................................................70 
12.2.1.2 
Reporting Procedures for Serious Adverse Events .........72 
12.2.1.3 
Reporting Serious Adverse Events After the 
Protocol-required Reporting Period ................................73 
12.2.1.4 
Serious Adverse Events That are not to be Reported 
by the Sponsors to Regulatory Agencies in an 
Expedited Manner ...........................................................73 
12.3 
Pregnancy and Lactation Reporting .................................................................74 
13 
STATISTICS ..............................................................................................................75 
13.1 
Study Endpoints ...............................................................................................75 
13.1.1 
Primary Endpoints ............................................................................75 
13.1.2 
Secondary Endpoints ........................................................................75 
13.1.3 
Other Endpoints ................................................................................76 
13.2 
Analysis of the Conduct of the Study ..............................................................76 
13.3 
Independent Review Committee ......................................................................76 
13.4 
Data Monitoring Committee ............................................................................76 
13.5 
Statistical Methods ...........................................................................................76 
13.5.1 
Efficacy Analyses .............................................................................76 
13.5.2 
Safety Analysis .................................................................................77 
13.5.3 
Pharmacokinetic Analyses ................................................................77 
13.5.4 
Exploratory Analyses ........................................................................78 
13.6 
Handling of Missing Data ................................................................................78 
13.7 
Determination of Sample Size .........................................................................79 
13.8 
Interim Analysis ...............................................................................................80 
14 
ETHICAL AND ADMINISTRATIVE CONSIDERATIONS ...............................81 
14.1 
Compliance Statement .....................................................................................81 
14.2 
Institutional Review Board or Independent Ethics Committee .......................81 
14.3 
Informed Consent and Human Subject Protection...........................................82 
14.4 
Direct Access to Source Data, Source Documents, and Study Records ..........82 
14.5 
Data Collection and Handling ..........................................................................83 
14.6 
Confidentiality .................................................................................................84 
14.7 
Publication Policy ............................................................................................84 
15 
REFERENCES ...........................................................................................................86 


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APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS ..................................89 
APPENDIX B 
ECOG PERFORMANCE STATUS ..............................................93 
APPENDIX C 
INTERNATIONAL UNIFORM RESPONSE CRITERIA 
FOR MULTIPLE MYELOMA ................................................................................94 
APPENDIX D 
SUBJECT CONVENIENCE AND SATISFACTION 
QUESTIONNAIRE....................................................................................................97 
APPENDIX E 
FIGURES FROM PROTOCOL AMENDMENT 1...................100 
APPENDIX F 
ADDITIONAL SAFETY ASSESSMENT INFORMATION....101 
APPENDIX G 
SAMPLE ESERIOUS EVENT CONTINGENCY FORM .......102 
APPENDIX H 
PREGNANCY AND LACTATION NOTIFICATION 
WORKSHEETS .......................................................................................................105 
APPENDIX I  
SUMMARY OF CHANGES IN STUDY CFZ013 
AMENDMENT 3 .....................................................................................................107 
List of Tables 
Table 1 
Combination Studies of Proteasome Inhibitors and 
Immunomodulatory Agents ...................................................................................26 
Table 2 
Carfilzomib Combination Regimens .....................................................................29 
Table 3 
Stability of Reconstituted Carfilzomib for Injection (60 mg/vial) .........................43 
Table 4 
Carfilzomib/lenalidomide/dexamethasone Dosing Regimen ................................45 
Table 5 
Dose Decrements for Carfilzomib .........................................................................47 
Table 6 
Dose Decrements for Lenalidomide ......................................................................47 
Table 7 
Treatment Guidelines for Thrombocytopenia ........................................................48 
Table 8 
Treatment Guidelines for Neutropenia ..................................................................49 
Table 9 
Treatment Guidelines for Nonhematologic Toxicity .............................................50 
Table 10 Dose Decrements for Dexamethasone ...................................................................53 
Table 11 Treatment Guidelines for Dexamethasone-related Toxicity ..................................54 
Table 12 95% Credible Intervals for the Dose-limiting Toxicity Rate and Probabilities 
of Dose-limiting Toxicity Rate Being Larger Than 0.33 .......................................80 
Table 13 Boundaries for Number of Responding Subjects (Relapsed Disease Arm) ..........81 
Table 14 Toxicity Grading for Adverse Events Not Covered in the 
NCI-CTCAE (Version 4.03) ................................................................................101 


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List of Figures 
Figure 1 
Study Schema.........................................................................................................33 
Figure 2 
Design Schematic for the Dose-evaluation Component for RRMM subjects 
(prior to Protocol Amendment 2) .........................................................................100 
Figure 3 
Design Schematic for the Dose-expansion Component (prior to Protocol 
Amendment 2) .....................................................................................................100 
 


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2 
Abbreviation 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ARDS 
acute respiratory distress syndrome 
ASCT 
autologous stem cell transplant 
AST 
aspartate aminotransferase  
AUC 
area under the curve  
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CBR 
clinical benefit rate  
Cmax 
maximum plasma concentration  
CMP 
carfilzomib, melphalan, and prednisone 
CR 
complete response 
CR/nCR 
complete response/near complete response 
CRA 
Clinical Research Associate 
CrCl 
creatinine clearance 
CRF 
case report form 
CRR 
complete response rate 
CSRC 
Cohort Safety Review Committee 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
D5W 
5% Dextrose Injection 
DBP 
diastolic blood pressure 
Dex 
Dexamethasone 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
ECG 
electrocardiogram  
ECHO 
echocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EOT 
end of treatment 
FDA 
Food and Drug Administration 


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Abbreviation 
Definition 
FISH 
fluorescent in situ hybridization 
FCBP 
Females of childbearing potential 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HSCT 
hematopoietic stem cell transplantation 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IMiD 
immunomodulatory drug 
IMWG 
International Myeloma Working Group 
IMWG-URC 
International Myeloma Working Group-Uniform Response Criteria 
IND 
Investigational New Drug 
IP 
investigational product 
IPIM 
investigational product instruction manual 
IRB 
Institutional Review Board 
IST 
investigator-sponsored trial 
IUD 
intrauterine device 
IV 
intravenous (ly) 
K 
Kyprolis®(carfilzomib) 
KRd 
Kyprolis (carfilzomib)/Revlimid® (lenalidomide)/dexamethasone 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction  
MedDRA 
Medical Dictionary for Regulatory Activities  
MR 
minimal response 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging  
MTD 
maximum tolerated dose  
MUGA 
multigated acquisition  
NDMM 
newly diagnosed multiple myeloma 
nCR 
near complete response 
NCI 
National Cancer Institute (US) 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NF kappa B 
nuclear factor kappa light chain enhancer of activated B cells 
NGS 
Next Generation Sequencing 


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Abbreviation 
Definition 
NYHA 
New York Heart Association 
ORR 
overall response rate  
OS 
overall survival 
PD 
progressive disease 
PDn 
pharmacodynamic(s) 
PET 
positron emission tomography 
PK 
pharmacokinetic(s) 
PFS 
progression-free survival 
PN 
peripheral neuropathy 
PO 
oral(ly) 
POEMS 
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
PS 
performance status  
PSA 
prostate-specific antigen 
qIgA 
quantitative immunoglobulin A 
QTc 
corrected QT (interval) 
R 
Revlimid (lenalidomide) 
RBC 
red blood cell 
RNA-Seq 
whole transcriptome sequencing 
RRMM 
relapsed and refractory multiple myeloma 
SAE 
serious adverse event 
SAg 
surface antigen 
SBP 
systolic blood pressure 
SC 
subcutaneous(ly) 
sCR 
stringent complete response 
SFLC 
serum free light chain 
SmPC 
Summary of Product Characteristics 
SPEP 
serum protein electrophoresis 
SWI 
Sterile Water for Injection 
t1/2 
terminal half-life  
TLS 
tumor lysis syndrome 
tmax 
time to maximum plasma concentration  
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
URC 
Uniform Response Criteria 
USP 
United States Pharmacopeia 


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Abbreviation 
Definition 
VGPR 
very good partial response 
VRd 
Velcade (bortezomib)/Revlimid (lenalidomide)/dexamethasone 
WBC 
white blood cell 
WES 
whole exome sequencing  
WGS 
whole genome sequencing  


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3 
3.1 
INTRODUCTION 
BACKGROUND INFORMATION 
Kyprolis (Carfilzomib for Injection [carfilzomib]) is a proteasome inhibitor that received 
accelerated approval from the United States (US) Food and Drug Administration (FDA) in 
July 2012 for the treatment of patients with multiple myeloma who have received at least 2 
prior therapies, including bortezomib and an IMiD and have demonstrated disease 
progression on or within 60 days of completion of the last therapy.  The approval was based 
on the results of the Study PX-171-003 – Part 2 (A1) in 266 subjects with relapsed and/or 
refractory multiple myeloma.  Subsequent full approval in the US and European Union was 
based on two phase 3 trials: PX-171-009 (ASPIRE) and 2011-003 (ENDEAVOR).  
Following these approvals, Kyprolis in combination with either lenalidomide and 
dexamethasone or dexamethasone alone is indicated for treatment of relapsed and refractory 
multiple myeloma (RRMM). 
The study detailed in the current protocol will evaluate several dose levels of carfilzomib in 
combination with lenalidomide and dexamethasone.   
RRMM and newly diagnosed multiple myeloma (NDMM) subjects will be treated with 
carfilzomib given once weekly in combination with lenalidomide (Revlimid) and 
dexamethasone as part of a carfilzomib (K), lenalidomide (R) and dexamethasone (d) 
regimen (KRd).  Carfilzomib will be given as a 30-minute infusion once weekly for the first 
3 weeks of a 4-week (28-day) cycle as part of a KRd regimen.   
This study will evaluate the safety and tolerability of once-weekly carfilzomib regimens in 
subjects with relapsed multiple myeloma or newly diagnosed multiple myeloma.   
3.2 
MULTIPLE MYELOMA 
Multiple myeloma, a clonal neoplastic proliferation of plasma cells, is the second most 
common hematologic malignancy and is responsible 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, 


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renal failure, hypercalcemia, and increased susceptibility to infections.  The disease is 
systemic and chemotherapy is indicated for management of symptomatic myeloma.   
Current treatment options for people with newly diagnosed multiple myeloma commonly 
include combination chemotherapy with regimens consisting of melphalan (Alkeran), 
bortezomib (Velcade), thalidomide (Thalomid), and lenalidomide (Revlimid) with or without 
corticosteroids such as dexamethasone or prednisone.  For people whose tolerance is not 
limited by age or co-morbidities, the preferred treatment is standard chemotherapy or VRd 
followed by high dose, myeloablative chemotherapy and autologous stem cell 
transplantation (ASCT).  
Despite improvements in progression-free survival (PFS) and overall survival (OS) over the 
past 15 years, essentially all patients eventually relapse even with the best available approved 
treatments.   
3.3 
NOVEL THERAPIES FOR MULTIPLE MYELOMA 
3.3.1 
PROTEASOME BACKGROUND 
Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma 
(Moreau 2012).  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 
activity, a trypsin-like activity, and a caspase-like activity.  
3.3.2 
CARFILZOMIB BACKGROUND (NONCLINICAL) 
Carfilzomib is a tetrapeptide epoxyketone-based inhibitor of the chymotrypsin-like activity 
of the 20S proteasome.  It is structurally and mechanistically different from the dipeptide 
boronic acid proteasome inhibitor bortezomib and 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 


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be responsible for the reductions in myelosuppression and neuropathy observed in 
nonclinical studies comparing carfilzomib with bortezomib. 
Based upon in vitro and in vivo studies, it is anticipated that a more intense and sustained 
proteasome inhibition can be achieved with carfilzomib relative to bortezomib, resulting in 
enhanced antitumor activity.  Continuous 72-hour exposure to carfilzomib was associated 
with potent cytotoxic and pro-apoptotic activity across a broad panel of tumor-derived cell 
lines in culture (Demo 2007).  Incubation of hematologic tumor cell lines with carfilzomib 
for as little as 1 hour led to rapid inhibition of proteasome activity followed by accumulation 
of polyubiquitinated proteins and induction of apoptotic cell death.  Carfilzomib was also 
cytotoxic in bortezomib-resistant tumor cell lines (Suzuki 2011; Kuhn 2007). 
Nonclinical studies in rats and monkeys have been performed administering carfilzomib IV 
for 5 consecutive days followed by 9 days of rest for 2 cycles.  Proteasome inhibition of more 
than 80% was achieved, suggesting that high-level inhibition of the proteasome with the 
epoxyketone class is possible, affording new opportunities to escalate dose to optimize 
antitumor effects (Yang 2011).  This finding was in contrast to nonclinical testing with the 
boronate class of inhibitors that prohibited uninterrupted daily dosing due to substantial 
morbidity and mortality.  Carfilzomib has also been administered to rats and monkeys for 6 
and 9 months, respectively (once daily × 2:  once daily dosing for 2 consecutive days for 
3 weeks on a 28-day cycle).  Carfilzomib was well tolerated at doses resulting in more than 
80% proteasome inhibition, with no behavioral or histological evidence of peripheral 
neuropathy (PN) and no neutropenia (current Carfilzomib Investigator’s Brochure [IB]).  In 
contrast, rats and monkeys treated with bortezomib in chronic toxicity studies were shown to 
have reduced motor activity, convulsions, tremors, and hind-limb paralysis accompanied by 
histological degeneration in peripheral nerves, as well as significant neutropenia (Velcade 
[bortezomib] full prescribing information [Millennium Pharmaceuticals 2012]; Velcade 
Summary of Product Characteristics [SmPC] 2012 [High Wycombe, Bucks, UK 2012]). 
3.3.3 
CARFILZOMIB BACKGROUND (CLINICAL) 
Carfilzomib entered clinical studies in September 2005.   


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As of 10 July 2016, an estimated 4833 subjects and 4114 subject-years have been exposed to 
carfilzomib in clinical trials conducted by Onyx Therapeutics, Inc. since the beginning of the 
development program.   
Carfilzomib has been administered on 2 consecutive days weekly for 3 weeks in a 28-day 
cycle in most studies conducted to date.   
Study PX-171-006 was the first to explore the option of combination therapy using 
carfilzomib and lenolidamide (the IMiD most widely employed for the treatment of multiple 
myeloma; Wang 2013).  This investigation was the model for another Phase 2 study of the 
carfilzomib, lenalidomide, dexamethasone (KRd) combination conducted by the Multiple 
Myeloma Research Consortium, and it used a maximum planned dose of 36 mg/m2 twice 
weekly in patients with newly diagnosed multiple myeloma (Jakubowiak 2012).  The Phase 3 
ASPIRE study compared the efficacy of KRd versus lenalidomide and dexamethasone alone 
in a much larger trial that enrolled 792 RRMM subjects.  ASPIRE showed an improved 
overall response rate and PFS with KRd therapy and provides a strong incentive to optimize 
the KRd regimen (Stewart 2015).  
The Phase 1/Phase 2 CHAMPION 1 trial of subjects with relapsed or progressing multiple 
myeloma who had received 1 to 3 prior regimens evaluated the safety and efficacy of 
carfilzomib administered once weekly at doses higher than the 56 mg/m2 maximum tolerated 
dose (MTD) previously established for the twice-weekly administration routine 
(Berenson 2016).  All subjects received carfilzomib (20 mg/m2) on Cycle 1 Day 1 but 
received the cohort-assigned test dose on Cycle 1 Days 8 and 15.  Testing started at 
45 mg/m2 in the first cohort and was escalated to 56, 70, and 88 mg/m2 in successive cohorts 
until the MTD was determined.  Subjects received dexamethasone 40 mg (IV or orally) on 
Days 1, 8, 15, and 22 of Cycles 1 through 8 and on Days 1, 8, and 15 from Cycle 9 onward. 
No dose-limiting toxicities (DLTs) were observed during dose escalation in the cohorts at 45, 
56, or 70 mg/m2.  At a carfilzomib dose of 88 mg/m2, 2 DLTs were observed during Cycle 1:  
Grade 3 dyspnea (Days 9–11) and Grade 3 vomiting (Day 15).  Therefore, the MTD of 
once-weekly carfilzomib in combination with dexamethasone was determined to be 


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70 mg/m2; a total of 104 subjects were treated at 70 mg/m2 carfilzomib dose level on the 
phase 1/2 CHAMPION-1 study. 
Five treatment-emergent serious adverse events (SAEs) were reported.  One subject had 
2 treatment-emergent SAEs (Grade 3 increased blood creatinine and Grade 4 hyponatremia), 
1 subject had Grade 3 pneumonia, 1 subject had Grade 3 dyspnea, and 1 subject had Grade 3 
chronic obstructive pulmonary disease.  The Grade 3 dyspnea event occurred in a subject 
receiving 88 mg/m2 carfilzomib and was considered to be related to carfilzomib treatment.  
All other SAEs were determined to be unrelated to carfilzomib or dexamethasone treatment.  
The treatment regimen showed promising efficacy with an overall response rate (ORR) of 
81% and a clinical benefit rate (CBR) of 93% (Berenson 2016), raising the question of 
whether weekly carfilzomib administered in combination with other antimyeloma agents 
might provide even greater patient benefit.  
3.3.4 
COMBINATIONS OF IMMUNOMODULATORY AGENTS AND 
PROTEASOME INHIBITORS  
Nonclinical studies showing that the IMiD lenalidomide sensitizes multiple myeloma cells to 
the proteasome inhibitor bortezomib suggested that combination therapy may enhance 
clinical activity (Mitsiades 2002).  The treatment paradigm involving proteasome inhibitor, 
immunomodulatory agent, and dexamethasone now forms the core of other treatment 
approaches aimed at improving either efficacy or tolerability (Kumar 2010).  The results of 
selected trials of proteasome inhibitors, lenalidomide and dexamethasone in subjects with 
multiple myeloma are summarized in Table 1. 
 


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Table 1 
Combination Studies of Proteasome Inhibitors and 
Immunomodulatory Agents 
 
Regimen 
Response 
Richardson (2009) 
Phase 1/ n = 38 
Relapsed/Refractory 
• 
VRd; 21-day cycle 
• 
Bortezomib 1.0 mg/m2, Days 1, 4, 8, 11 
• 
Lenalidomide 5, 10 or 15 mg, Days 1−14 
• 
Dexamethasone 20 or 40 mg, Days 1, 2, 4, 5, 8, 9, 11, 
12 
• ≥ MR:  61% 
• CR/nCR:  8% 
Richardson (2014) 
Phase 2/ n = 64 
Relapsed/Refractory 
• 
VRd; 21-day cycle 
• 
Bortezomib 1.0 mg/m2, Days 1, 4, 8, 11 
• 
Lenalidomide 15 mg, Days 1−14 
• 
Dexamethasone 20 or 40 mg (Cycles 1−4) or  
10 or 20 mg (Cycles 5− 8), Days 1, 2, 4, 5, 8, 9, 11, 12 
• ≥ MR:  78% 
• ≥ PR:  64% 
• CR/nCR:  25% 
Dimopoulos (2010) 
Phase 2/ n = 49 
Relapsed/Refractory 
• 
VRd; 21-day cycle 
• 
Bortezomib 1.0 mg/m2, Days 1, 4, 8, 11 
• 
Lenalidomide 15 mg, Days 1−14 
• 
Dexamethasone 40 mg, Days 1−4 
• ≥ PR:  63% 
• VGPR:  14% 
• CR:  6% 
Richardson (2010) 
Phase 1, 2/ n = 66 
Newly Diagnosed 
• 
VRd; 21-day cycle 
• 
Bortezomib 1.0 or 1.3 mg/m2, Days 1, 4, 8, 11 
• 
Lenalidomide 15–25 mg, Days 1−14 
• 
Dexamethasone 20 or 40 mg, Days 1, 2, 4, 5, 8, 9, 11, 
12 
• CR/nCR:  40% 
• VGPR:  27% 
• PR:  33% 
Niesvizky (2013) 
Phase 1b/ n = 40 
Relapsed/Refractory 
• 
KRd; 28-day cycle 
• 
Carfilzomib, Days 1, 2, 8, 9, 15, 16 
doses- 15, 20, 27 mg/m2 
• 
Lenalidomide 10 to 25 mg, Days 1−21 
• 
Dexamethasone 40 mg, Days 1, 8, 15, 22 
• sCR:  2.5% 
• VGPR:  32.5% 
• PR:  27.5% 
Jakubowiak (2012) 
Phase 1, 2/ n = 53 
Newly Diagnosed 
• 
KRd; 28-day cycle 
• 
Carfilzomib 36 mg/m2, Days 1, 2, 8, 9, 15, 16 
• 
Lenalidomide 25 mg, Days 1−21 
• 
Dexamethasone 20 or 40 mg, Days 1−4 
• sCR:  42% 
• ≥ nCR:  62% 
• ≥ VGPR:  81% 
• ≥ PR:  98% 
Korde (2013) 
Phase 2/ n = 45 
Newly Diagnosed 
• 
KRd; 28-day cycle 
• 
Carfilzomib 36 mg/m2, Days 1, 2, 8, 9, 15, 16 
• 
Lenalidomide 25 mg, Days 1−21 
• 
Dexamethasone 10 mg (IV) or 20 mg (PO), Days 1, 2, 
8, 9, 15, 16, 22, 23 
• ORR:  98% 
• CR/nCR:  51% 
• ≥ VGPR:  88% 
• PR:  9% 
CR = complete response; IV = intravenous (ly); KRd = Kyprolis/Revlimid/dexamethasone; MR = minimal 
response; nCR = near complete response; ORR = overall response rate; PO = oral(ly); PR = partial response; 
sCR = stringent complete response; VGPR = very good partial response; 
VRd = Velcade/Revlimid/dexamethasone. 
 


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These studies demonstrated the efficacy of regimens that combine lenalidomide with 
proteasome inhibitors (bortezomib or carfilzomib).  The regimens are effective and well 
tolerated both in patients newly with diagnosed multiple myeloma as well as those who have 
relapsed.   
3.4  
DOSE RATIONALE 
The dose rationale for this study derives from considerations of carfilzomib, lenalidomide, 
and dexamethasone dose combinations that are currently in use, as shown in Table 1.  Dose 
combinations for this study are shown in Table 2.  Prior to protocol amendment 2, 
dose-evaluation cohorts were planned only for RRMM subjects (Cohorts 1, 2, and 3).  
Schemas for enrollment prior to protocol amendment 2 are shown in Appendix E (Figure 2 
and Figure 3).  With protocol amendment 2, a Dose-evaluation cohort is added for NDMM 
subjects.   
The initial dosing for the proposed weekly KRd combinations (Cohorts 1, 2, and 3) in this 
study reflects a triangulation of the individual components of the studies listed in 
Cohorts 1, 2, and 3 
Table 1.  
The Dose-evaluation Component of the study begins with carfilzomib 56 mg/m2, 
lenalidomide 25 mg, and dexamethasone 40 mg in RRMM subjects  
(Cohort 1, Table 2).  As shown in Table 1, carfilzomib, in combination with dexamethasone, 
has been administered at weekly doses as high as 70 mg/m2/day given once weekly and 
56 mg/m2 given on 2 consecutive days (total weekly exposure of 112 mg/m2).  Carfilzomib 
given as part of a KRd regimen has been administered safely at doses as high as 36 mg/m2 
given on 2 consecutive days each week (total weekly exposure of 72 mg/m2).  Of note, no 
DLTs were identified at this dose in the Phase 1 study; dose escalation was stopped at 
36 mg/m2 twice-weekly because it was the maximum dose planned in the protocol.  The 
safety information from these trials supports a starting dose for Cohort 1 of carfilzomib 
56 mg/m2, lenalidomide 25 mg, and dexamethasone 40 mg.  


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A 2-step-up KRd regimen will be evaluated in NDMM subjects: carfilzomib will be given at 
20 mg/m2 on Day 1 of Cycle 1, 56 mg/m2 on Days 8 and 15 of Cycle 1, then 70 mg/m2 on 
Days 1, 8, and 15 beginning with Cycle 2 (Cohort 4; 
Cohort 4 
Table 2).  This regimen was selected by 
the Cohort Safety Review Committee (CSRC) for Dose-evaluation in NDMM subjects, after 
the occurrence of 2 SAEs in NDMM subjects during Cycle 1 of treatment at Cohort 2 dose-
level (Arm 1). 


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Table 2 
Carfilzomib Combination Regimens 
d = dexamethasone, K = carfilzomib; KRd = Kyprolis (carfilzomib)/Revlimid (lenalidomide)/dexamethasone; 
R = lenalidomide.   
3.5 
STUDY RATIONALE 
Exploration of therapeutic variations aimed at improving tolerance, patient convenience, 
efficacy, and treatment adherence are important considerations for treatment outcomes.  A 
study comparing routes of bortezomib administration showed no loss of efficacy with the 
more convenient subcutaneous (SC) route relative to that seen with the established IV route 
of administration (Moreau 2011).  Likewise, twice-weekly bortezomib IV administration was 
 
Regimen 
Maximum Weekly 
Exposure 
Drug 
Dosing 
Schedule 
K 
mg/m2 
R 
mg 
d 
mg 
Cohort 1 
KRd 
Carfilzomib 
20 mg/m2 
Day 1 of Cycle 1 
56 
175 
40 
56 mg/m2 
Days 8, 15 of Cycle 1 
Days 1, 8, 15 of Cycles 2-18 
Lenalidomide 
25 mg 
Days 1–21 
Dexamethasone 
40 mg 
Days 1, 8, 15, 22 of Cycles 1-8 
Days 1, 8, 15 of Cycles 9-18 
Cohort 2 
KRd 
Carfilzomib 
20 mg/m2 
Day 1 of Cycle 1 
70 
175 
40 
70 mg/m2 
Days 8, 15 of Cycle 1 
Days 1, 8, 15 of Cycles 2-18 
Lenalidomide 
25 mg 
Days 1–21 
Dexamethasone 
40 mg 
Days 1, 8, 15, 22 of Cycles 1-8 
Days 1, 8, 15 of Cycles 9-18 
Cohort 3 
(optional) 
KRd 
Carfilzomib 
20 mg/m2 
Day 1 of Cycle 1 
70 
70 
40 
70 mg/m2 
Days 8, 15 of Cycle 1 
Days 1, 8, 15 of Cycles 2-18 
Lenalidomide 
10 mg 
Days 1–21 
Dexamethasone 
40 mg 
Days 1, 8, 15, 22 of Cycles 1-8 
Days 1, 8, 15 of Cycles 9-18 
Cohort 4 
2-step-up 
KRd 
Carfilzomib 
20 mg/m2 
Days 1 of Cycle 1 
70 
175 
40 
56 mg/m2 
Days 8, 15 of Cycle 1 
70 mg/m2 
Days 1, 8, 15 of Cycles 2-18 
Lenalidomide 
25 mg 
Days 1–21 
Dexamethasone 
40 mg 
Days 1, 8, 15, 22 of Cycles 1-8 
Days 1, 8, 15 of Cycles 9-18 


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used in the early trials of this agent (Richardson 2009).  A later study comparing 
once-weekly with twice-weekly bortezomib administration demonstrated improved safety, in 
particular a reduction in the rate of peripheral neuropathy, with no apparent effect on efficacy 
(Bringhen 2010). 
The combination of carfilzomib (twice-weekly), lenalidomide, and dexamethasone is a 
highly efficacious regimen in RRMM and NDMM subjects (Stewart 2015; Jakubowiak 2012; 
Korde 2013).  Of specific note, 23 of 26 subjects who reached nCR/CR achieved negative 
minimal residual disease (MRD[-]) status in one study (Jakubowiak 2012), while in another 
trial 27 of 27 subjects who reached nCR/CR achieved MRD[-] status (Korde 2013), further 
emphasizing the efficacy of this combination.  A favorable safety profile and promising 
preliminary efficacy for once-weekly carfilzomib in RRMM subjects was observed in the 
CHAMPION 1 study (Berenson 2016).   
This study will explore the safety and tolerability of once-weekly carfilzomib administered 
with lenalidomide and dexamethasone as part of a KRd regimen for RRMM and NDMM 
subjects.  Once-weekly carfilzomib is expected to improve tolerance, convenience, and 
treatment adherence.  The results will help inform decisions on future efficacy studies 
involving once-weekly carfilzomib administration. 
4 
4.1 
PRIMARY OBJECTIVES 
STUDY OBJECTIVES 
• The primary objective of the study is to evaluate the safety and tolerability of a 
once-weekly KRd regimen in RRMM and NDMM subjects. 
4.2 
SECONDARY OBJECTIVES 
Secondary objectives are the following: 
• To evaluate the pharmacokinetics (PK) of carfilzomib when administered once-weekly in 
a KRd regimen in RRMM and NDMM subjects  
• To evaluate the clinical activity (efficacy) of a once-weekly KRd regimen in RRMM and 
NDMM subjects 


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4.3 
EXPLORATORY OBJECTIVES 
Exploratory objectives include:  
• To explore the genomic and transcriptional biomarkers that might predict response and 
resistance to a once-weekly KRd regimen 
• To characterize the pharmacodynamics (PDn) of proteasome inhibition with a 
once-weekly KRd regimen in RRMM and NDMM subjects 
• To assess MRD status with a once-weekly KRd regimen in RRMM and NDMM subjects 
• To assess subject convenience and satisfaction with a once-weekly KRd regimen using 
subject questionnaire in RRMM and NDMM subjects 
5 
This is an open-label, multicenter, Phase 1b, dose-finding study of carfilzomib administered 
once-weekly in combination with lenalidomide and dexamethasone (KRd) in 28-day cycles 
to subjects with multiple myeloma.   
STUDY DESIGN 
Subjects may continue to receive study treatment for up to 18 cycles or until 1 or more of the 
following events occurs: 
• Disease progression 
• Allogeneic stem cell transplant 
• Withdrawal from the study for any reason 
• Study termination by the sponsor 
• Death 
Disease assessments will be conducted at Screening (within 21 days before dosing on 
Cycle 1 Day 1) and then on Day 1, ± 3 days, of every cycle beginning with Cycle 2.  
Response will be evaluated using the International Myeloma Working Group (IMWG) - 
Uniform Response Criteria (URC; Rajkumar, 2011; Appendix C).   
NDMM subjects may interrupt study treatment to proceed to hematopoietic stem cell 
collection, or stem cell collection and ASCT.  The investigator will communicate transplant 
plans with the clinical study team.  Upon completion of collection, subjects may resume 
study treatment (for up to the total of 18 cycles).  Study treatment interruption for autologous 
hematopoietic stem cell collection may not exceed 42 days.  Subjects with interruptions 
longer than 42 days may resume therapy on trial only with the written permission of the 


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sponsor study medical monitor.  Subjects may interrupt study treatment and proceed to 
ASCT at any time after Cycle 4.  Subjects who undergo ASCT may resume study treatment 
at any time up to posttransplant day 100, as elected by the investigator.   
There will be 2 parts in the study.   
The first part is the Dose-evaluation Component during which carfilzomib combination 
regimens will be evaluated (Table 2 and Figure 1).  Approximately 8 dose-limiting toxicity 
evaluable subjects will be enrolled into each opened Dose-evaluation cohort.  Before opening 
Dose-expansion arms, it must be determined that there are not more than 2 dose-limiting 
toxicities in 8 DLT-evaluable subjects at the dose selected for Dose-expansion.  
Dose-expansion arms may open once all safety data for at least 1 cycle at maximal dose 
carfilzomib is reviewed by the CSRC.   
The second part is the Dose-expansion Component.  
Prior to protocol amendment 2, dose evaluation was performed on RRMM subjects treated at 
Cohort 1 and Cohort 2 dosing (Table 2).  Cohort 2 dosing was selected for expansion with a 
plan for approximately 30 RRMM subjects and 30 NDMM subjects to be treated in the 
Dose-expansion Component (Arms 1 and 2; Appendix E; Figure 2 and Figure 3).   
In the first 8 NDMM subjects treated in Dose-expansion Arm 1 at Cohort 2 dosing, 2 SAEs 
were observed during Cycle 1 (Table 2).  Thus, with protocol amendment 2, Dose-evaluation 
Cohort 4 is added for NDMM subjects (Table 2 and Figure 1).  A Dose-expansion arm for 
NDMM subjects may open once all safety data for at least 1 cycle at maximal planned 
carfilzomib dose is reviewed by the CSRC as described in Section 5.4.   
All subjects will be evaluated for safety at an End of Treatment (EOT) visit, 28 ± 7 days after 
the last study treatment, and with an EOT echocardiogram (ECHO), done within 28 ± 7 days 
of the last study treatment.  The EOT visit will include a pregnancy test for females of 
childbearing potential (FCBP).  Following the EOT, subjects who have not had disease 
progression or allogeneic stem cell transplant will enter Active Follow-up.  For details 
regarding Active Follow-up, please refer to Section 5.6.  


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5.1 
STUDY POPULATION 
Subjects with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy for 
multiple myeloma will be included in the Dose-evaluation Component and the 
Dose-expansion Component of the study.   
Figure 1 Study Schema 
Dose Evaluationa, b 
Up to 18 Cycles -> Active Follow Up (all subjects) 
Arm 2 Expansion 
RRMM N = 30  
Cohort 1 Evaluation 
RRMM KRd 20/56 N = 8 
Arm 1 Expansionc 
NDMM N = 30 
Cohort 2 Evaluation 
RRMM KRd 20/70 N = 8 
Arm 3 Expansiond 
NDMM N = 30 
Cohort 4 Evaluation 
NDMM KRd 20/56/56/70 N = 8  
Dose Expansion 
N = number; NDMM = newly diagnosed multiple myeloma; RRMM = relapsed refractory multiply myeloma; 
KRd = Kyprolis (carfilzomib)/Revlimid® (lenalidomide)/dexamethasone’ 
 
a Optional Cohort 3 was not opened. 
b Full dosing information is presented in Table 2.  
c Twenty out of 30 planned NDMM subjects were enrolled in Dose expansion, at cohort 2 dosing, prior to protocol 
amendment 2. 
d Subjects in dose-expansion Arm 3 will be treated with KRd at 20/56 (full dosing regimen as shown for Cohort 1 
in Table 2). 


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Prior to protocol amendment 2, subjects with newly diagnosed, previously untreated multiple 
myeloma were included only in the Dose-expansion Component 
(Appendix E; Figure 2, Arm 1).  After protocol amendment 2, NDMM subjects will be 
enrolled into a NDMM Dose-evaluation cohort, which may be expanded after safety 
evaluation by the CSRC (Arm 3, Figure 1).  
Complete eligibility criteria are described in Section 6. 
5.2 
DEFINITION OF DOSE-LIMITING TOXICITY 
Dose-limiting toxicity (DLT) of the KRd regimens will be evaluated during Cycle 1 
(Cohorts 1, 2, and 3), or Cycles 1 and 2 (Cohort 4), of the Dose-evaluation Component.   
Subjects in the Dose-evaluation Component of the study who do not complete the dose 
evaluation period for reasons unrelated to toxicity will be considered unevaluable for DLT 
and may be replaced.  DLT are the toxicities defined below and attributable to carfilzomib, 
lenalidomide, or dexamethasone. 
5.2.1 
NONHEMATOLOGIC DLT 
• ≥ Grade 3 nonhematological toxicity (excluding nausea, vomiting, diarrhea, alopecia, 
fatigue lasting < 14 days, increased serum creatinine or electrolyte abnormalities that are 
not clinically significant and require no treatment)  
• ≥ Grade 3 acute kidney injury (creatinine > 3 × baseline or > 4.0 mg/dL) lasting 
> 72 hours 
• ≥ Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal 
therapy 
5.2.2 
HEMATOLOGIC DLT 
• Grade 4 neutropenia (absolute neutrophil count [ANC] < 500/mm3) lasting for > 7 days 
• Febrile neutropenia (ANC < 1000/mm3 with a fever ≥ 38.3ºC) of any duration 
• Grade 4 thrombocytopenia (platelet count < 25,000/mm3) that persists for > 14 days with 
or without platelet transfusion, despite holding treatment 
• Grade 3 or 4 thrombocytopenia (platelet count < 50,000/mm3) associated with > Grade 1 
bleeding 


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5.3 
COHORT SAFETY REVIEW COMMITTEE  
A CSRC comprised of the lead investigator, selected additional investigators, the sponsor 
study medical monitor, and sponsor’s drug safety representative will review all available 
safety data and make recommendations regarding ongoing enrollment and opening of 
subsequent cohorts during the Dose-evaluation Components.  The CSRC will also select the 
KRd regimens to be evaluated in the Dose-expansion Components.   
5.4 
PART 1:  DOSE-EVALUATION COMPONENT  
Approximately 8 dose-evaluable subjects will be enrolled into each Dose-evaluation cohort 
(Table 2, Figure 1).  Enrollment will be gated such that the first 4 subjects in Cohort 1 will 
complete Cycle 1 and undergo a safety evaluation prior to further enrollment.   
• If ≥ 2 of the first 4 subjects of Cohort 1 experience a DLT, enrollment to that cohort will 
stop and the study will terminate 
• If ≤ 1 of the first 4 subjects experience a DLT, the cohort will recommence enrollment of 
an additional 4 subjects for up to 8 dose-evaluable subjects total 
• Cohort 2 (n = approximately 8) will open to enrollment 
When both Cohorts 1 and 2 are open for concurrent enrollment, subjects will be assigned to a 
cohort on an alternating basis.  Safety will be evaluated in both cohorts on an ongoing basis. 
• If ≥ 2 of the first 4 subjects experience DLTs or ≥ 3 subjects experience DLTs at any time 
in Cohort 2, enrollment to that cohort will be stopped, and the optional third cohort 
(Cohort 3) may be opened to enrollment of an additional 8 subjects (approximately). 
• The CSRC will review all evaluable safety data (Section 5.3).  If < 3 subjects experience 
a DLT in an opened cohort, that dose may be selected for dose expansion. 
• For NDMM subjects evaluated in Cohort 4, the CSRC will review all safety data from the 
first 2 cycles and may elect to expand NDMM enrollment 
To be DLT evaluable, subjects must have received all planned doses of carfilzomib, at least 
80% of planned doses of lenalidomide, and at least 75% of planned doses of dexamethasone 
or received at least 1 dose of carfilzomib and experienced a DLT prior to completion of study 
treatment for Cycle 1 (Cohorts 1-3) or Cycle 2 (Cohort 4).  Subjects who withdraw from 
treatment after receiving a dose of carfilzomib but before completing the first 28-day cycle 
(Cohorts 1-3) or the first two 28-day cycles (Cohort 4) for reasons unrelated to toxicity will 
be considered unevaluable for DLTs.  Subjects who are not DLT-evaluable may be replaced.  


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The schema for the Dose-evaluation Component of the study for RRMM subjects is 
presented in Figure 2 (Appendix E).   
A 2-step-up KRd regimen will be evaluated in NDMM subjects: carfilzomib will be given at 
20 mg/m2 on Day 1 of Cycle 1, 56 mg/m2 on Days 8 and 15 of Cycle 1, then at 70 mg/m2 on 
Days 1, 8, and 15 beginning with Cycle 2 (Cohort 4; 
Cohort 4 
Table 2).  This regimen was selected by 
the CSRC for dose-evaluation in NDMM subjects, after the occurrence of 2 SAEs in NDMM 
subjects during Cycle 1 of treatment at Cohort 2 dose level during the Arm 1 NDMM 
Dose-expansion (Figure 1). 
5.5 
PART 2:  DOSE-EXPANSION COMPONENT  
Per protocol amendment 2
Enrollment of NDMM into Dose-expansion Arm 1 will stop (Appendix E; 
: 
Figure 3).   
NDMM subjects will be enrolled into Dose-evaluation Cohort 4 (Figure 1; Table 2).  Arm 1 
subjects enrolled prior to protocol amendment 2 who are DLT evaluable at Cohort 4 dosing 
will be included in Dose-evaluation Cohort 4 (Figure 1; Table 2).   
The CSRC will evaluate all safety data for all NDMM subjects.  Following the DLT rules 
above, the CSRC may elect to open an NDMM Dose-expansion arm, and may enroll an 
additional 30 NDMM subjects (Section 5.4).    
5.6 
ACTIVE FOLLOW-UP 
Subjects who have terminated or completed study treatment (for reasons other than 
progressive disease, allogeneic stem cell transplant, death, or withdrawal of consent) will 
enter Active Follow-up for 1 year.  For subjects in Active Follow-up, tumor response and 
disease assessment measurements will be performed every 8 weeks (every 56 ± 4 days).  The 
investigators will make every reasonable effort to keep each patient in active follow-up for 
1 year, or until the subject has progressive disease (PD), begins treatment with any 
antimyeloma medication, has withdrawn consent for further participation, is lost to follow 
up, has died, or the study is closed, whichever is earliest.   


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5.7 
ESTIMATED STUDY DURATION AND STUDY CLOSURE 
The total study duration is expected to be a minimum of 60 months.  Approximately 
6 months will be required to enroll subjects in the RRMM Dose-evaluation Component of the 
study.  Approximately 9 months will be required to enroll subjects in the RRMM 
Dose-expansion Component of the study.  Subjects will be followed for up to 17 months in 
order to complete primary safety and efficacy evaluations with up to an additional 12 months 
of Active Follow-up.  
It will take up to approximately 12 months to enroll NDMM subjects into Dose-evaluation 
Cohort 4, review the safety data, and enroll NDMM subjects into the NDMM 
Dose-expansion Arm 3.  Subjects will be followed for up to 17 months on treatment (with an 
allowed interruption of up to 4.5 months for ASCT), and for 12 months for Active Follow up. 
Based on these assumptions, it is estimated that the final analysis will occur approximately 
60 months after the first subject is enrolled. 
The end of study will occur when the last subject leaves Active Follow-up. 
5.8 
MINIMIZING BIAS 
5.8.1 
RANDOMIZATION 
This is not a randomized study.  
Subjects in the RRMM Dose-evaluation Component will be assigned to the open cohort at 
time of enrollment; when/if Cohort 1 and Cohort 2 are both open to enrollment, enrollment 
will alternate between Cohort 1 and Cohort 2 until Cohort 1 is filled.   
5.8.2 
BLINDING 
This is an open-label study; there is no blinding. 
6 
Approximately 114 subjects will be enrolled in this study.  Subjects will be evaluated for 
study entry within the 21 days prior to Cycle 1 Day 1. 
SUBJECT SELECTION 


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Fifty-six RRMM subjects enrolled prior to protocol amendment 2.  Twenty NDMM subjects 
were enrolled prior to protocol amendment 2.  Protocol amendment 2 allows for enrollment 
of up to 38 additional NDMM subjects.  
6.1 
INCLUSION CRITERIA 
1. Age ≥ 18 years 
2. Able to provide written informed consent in accordance with federal, local, and 
institutional guidelines 
3. Newly diagnosed or relapsed multiple myeloma 
a. 
i. 1 to 3 prior lines of therapy for multiple myeloma (induction therapy 
followed by stem cell transplant and consolidation/maintenance therapy 
will be considered as one line of therapy), and  
For subjects with relapsed multiple myeloma: 
ii. Documented response of at least partial response (PR) to 1 line of prior 
therapy.  Investigator assessment is acceptable as PR documentation. 
b. For subjects with newly diagnosed, transplant-eligible or transplant-ineligible 
multiple myeloma:
i. Symptomatic multiple myeloma (per IMWG diagnostic criteria) and  
   
ii. No prior treatment for multiple myeloma 
4. Measurable disease with at least 1 of the following assessed within 21 days prior 
to Cycle 1 Day 1: 
a. Serum M-protein ≥ 0.5 g/dL, 
b. Urine M-protein ≥ 200 mg/24 hour,  
c. In subjects without detectable serum or urine M-protein, serum free light chain 
(SFLC) > 100 mg/L (involved light chain) and an abnormal serum kappa 
lambda ratio 
d. For immunoglobulin (Ig) A subjects whose disease can only be reliably 
measured by serum quantitative immunoglobulin (qIgA), a qIgA level of 
≥ 750 mg/dL (0.75 g/dL) 
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2 
6. Left ventricular ejection fraction (LVEF) ≥ 40% 
8. Absolute neutrophil count (ANC) ≥ 1000/mm3 within 21 days prior to Cycle 1 
Day 1 with (1) no nonpegylated growth factor support for ≥ 7 days and (2) no 
pegylated growth factor support for ≥ 14 days 


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9. Hemoglobin ≥ 8.0 g/dL within 21 days prior to Cycle 1 Day 1.  Use of 
erythropoietic stimulating factors and red blood cell (RBC) transfusions per 
institutional guidelines is allowed 
10. Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the bone 
marrow is > 50%) within 21 days prior to Cycle 1 Day 1 with no platelet 
transfusions for ≥ 7 days 
11. Calculated or measured creatinine clearance (CrCl) of ≥ 50 mL/min within 
21 days prior to Cycle 1 Day 1.  Calculation must be based on standard formula 
such as the Cockcroft and Gault. 
12. Females of childbearing potential (FCBP) must have a negative serum pregnancy 
test within the 10 to 14 days prior to study drug administration and a negative 
urine or serum pregnancy test within the 24 hours prior to the first study drug 
administration 
13. FCBP and male subjects who are sexually active with a FCBP must agree to use 
2 highly effective methods of contraception during the study.  FCBP subjects are 
required to continue use of 2 highly effective methods of contraception for 
30 days following discontinuation of study drugs.  Vasectomized male subjects 
who have received medical confirmation of surgical success are not required to 
use additional methods of contraception.  Otherwise, male subjects with a FCBP 
partner must agree to use 2 highly effective methods of contraception during 
study and for 90 days following discontinuation of study drugs 
14. Male subjects must agree to not donate sperm while taking study drugs and 
90 days after the last dose of study drugs 
15. Normal hepatic function within 21 days prior to Cycle 1 Day 1: 
a. Bilirubin ≤ the upper limit of normal (ULN) 
b. Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ the ULN 
6.2 
EXCLUSION CRITERIA 
1. Waldenström macroglobulinemia 
2. For newly diagnosed multiple myeloma:  multiple myeloma of IgM subtype 
3.  For relapsed disease: 
a. If treated with a lenalidomide and dexamethasone-containing combination, 
progression during the first 3 months after initiating treatment. 
b.  Any progression during treatment if the lenalidomide and 
dexamethasone-containing regimen was the most recent line of therapy. 
c.  Any prior treatment with carfilzomib. 


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4. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes)  
5. Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential) 
6. Myelodysplastic syndrome 
7. Second malignancy within the past 5 years except: 
a. Adequately treated basal cell or squamous cell skin cancer, or 
b. Carcinoma in situ of the cervix, or  
c. Prostate cancer < Gleason score 6 with undetectable prostate-specific antigen 
(PSA) over 12 months, or 
d. Ductal breast carcinoma in situ with full surgical resection (ie, negative 
margins), or 
e. Treated medullary or papillary thyroid cancer, or 
f. Similar condition with an expectation of > 95% five-year disease-free survival 
8. Amyloidosis 
9. Cytotoxic chemotherapy within 28 days prior to Cycle 1 Day 1 
10. Immunotherapy within 21 days prior to Cycle 1 Day 1 
11. Glucocorticoid therapy within 14 days prior to Cycle 1 Day 1 that exceeds a 
cumulative dose of 160 mg of dexamethasone  
12. Radiation therapy: 
a. Focal therapy within 7 days prior to Cycle 1 Day 1 
b. Extended field therapy within 21 days prior to Cycle 1 Day 1 
13. Prior treatment with carfilzomib or oprozomib 
14. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize 
carfilzomib) 
15. Contraindication to lenalidomide or dexamethasone 
16. Contraindication to any of the required concomitant drugs or supportive treatments, 
including hypersensitivity to antiviral drugs, or intolerance to hydration due to 
preexisting pulmonary or cardiac impairment 
17. Active congestive heart failure (New York Heart Association [NYHA] Class III to 
IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional 
intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or 
myocardial infarction within 6 months prior to Cycle 1 Day 1 
18. Active infection within 14 days prior to Cycle 1 Day 1 requiring systemic antibiotics 


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19. Pleural effusions requiring thoracentesis within 14 days prior to Cycle 1 Day 1 
20. Ascites requiring paracentesis within 14 days prior to Cycle 1 Day 1 
21. Ongoing graft-versus-host disease 
22. Uncontrolled hypertension or uncontrolled diabetes 
23. Significant neuropathy (≥ Grade 3) within 14 days prior to Cycle 1 Day 1 
24. Known cirrhosis 
25. Known human immunodeficiency virus (HIV) infection, hepatitis C infection, or 
hepatitis B infection (subjects with hepatitis B surface antigen [SAg] or core antibody 
receiving and responding to antiviral therapy directed at hepatitis B are allowed) 
26. Participation in another interventional study within 28 days prior to Cycle 1 Day 1 
27. Major surgery (except kyphoplasty) within 28 days prior to Cycle 1 Day 1 
28. Female subjects who are pregnant or lactating  
29. 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 
7 
A signed and dated informed consent form (ICF) will be obtained before any study-specific 
tests may be performed.  Evaluations obtained as part of routine medical care and performed 
during the screening period may be used in place of the study-specific evaluations, provided 
they meet the time windows described below.  It is recommended that study-specific tests 
unrelated to subject eligibility (including a bone marrow aspirate) be done only after 
screening tests confirm subject eligibility for the study.  Subjects will acknowledge and agree 
to the possible use of this information for the study by giving informed consent.   
SUBJECT SCREENING 
All subjects who sign 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 for a particular subject commences at the point at which the subject 
signs the ICF, and must be completed within 21 days before dosing on Cycle 1 Day 1. 


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8 
8.1 
CARFILZOMIB 
STUDY TREATMENT 
8.1.1 
PHYSICAL DESCRIPTION 
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.  It specifically 
functions as an inhibitor of the chymotrypsin-like activity of the 20S proteasome which leads 
to the accumulation of protein substrates within the cell and induction of apoptosis.   
Carfilzomib for Injection will be provided as a lyophilized powder which, when 
reconstituted, contains a 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM 
sodium citrate buffer (pH 3.5) containing 10% (w/v) sulfobutylether-beta-cyclodextrin 
(SBE beta CD, Captisol). 
8.1.2 
PACKAGING AND LABELING 
Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use vials 
packaged in multivial cartons.  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. 
Institutional pharmacies will be supplied with open stock vials with appropriate labels.  
Additional information on carfilzomib may be found in the IB. 
8.1.3 
STORAGE 
Study drugs should be stored in a securely locked area with access limited to appropriate 
study personnel.  Lyophilized Carfilzomib for Injection must be stored at 2°C to 8°C 
(36°F−46°F) in a refrigerator.  Vials must be kept in cartons in order to protect from light 
until ready for reconstitution.  
Once a drug vial is reconstituted and inspected, the clear solution can be stored in a 
refrigerator (recommended) controlled temperature from 2°C to 8°C (36°F–46°F) for up to 


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24 hours.  Once reconstituted, Carfilzomib for Injection must be used by the time points 
outlined in Table 3 below. 
Table 3 
Stability of Reconstituted Carfilzomib for Injection (60 mg/vial) 
Storage Conditions of Reconstituted Carfilzomib 
Stability (in Hours) per Container 
Vial 
Syringe 
IV Bag (D5W) 
Refrigerated (2°C to 8°C; 36°F to 46°F) 
24  
24  
24  
Room Temperature (15°C to 30°C; 59°F to 86°F) 
4 
4  
4 
D5W = 5% Dextrose Injection, USP; IV = intravenous(ly). 
8.2 
LENALIDOMIDE 
Lenalidomide is a thalidomide analogue indicated for the treatment of subjects with multiple 
myeloma, in combination with dexamethasone, in subjects who have received at least 1 prior 
therapy.  Lenalidomide is also indicated for transfusion-dependent anemia due to low- or 
intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q abnormality 
with or without additional cytogenetic abnormalities and those with mantle cell lymphoma 
whose disease has relapsed or progressed after 2 prior therapies, one of which included 
bortezomib. 
Lenalidomide is a commercially available drug, available for oral administration, depending 
upon local health authority approvals (Celgene Corporation 2013).  Sites are advised to refer 
to the prescribing information that is specific to the lenalidomide product used.   
All precautions and restrictions included in the Prescribing Information (eg, pregnancy 
testing and contraception) must be observed when dispensing and administering lenalidomide 
as part of this protocol. 
8.3 
DEXAMETHASONE 
Dexamethasone is a commercially available drug.  The description, how supplied, and 
storage instructions for dexamethasone product are found in the prescribing information.  
Sites are advised to refer to the prescribing information for information that is specific to the 
brand or formulation of the drug product they are using. 


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8.4 
STUDY DRUG ACCOUNTABILITY 
The sponsor (or designee) and the investigator will maintain records of each shipment of 
investigational product (IP).  Upon receipt of IP, the designated recipient at the study site will 
inspect the shipment, verify the number and condition of the vials, and prepare an inventory 
or 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. 
Sites will be required to record and document subject compliance regarding lenalidomide and 
dexamethasone dosing. 
Additional details are provided in the IPIM (Investigational Product Instruction Manual). 
9 
9.1 
TREATMENT REGIMEN 
DOSAGE AND TREATMENT ADMINISTRATION 
Carfilzomib, lenalidomide, and dexamethasone will be administered in 28-day cycles up to a 
total of 18 cycles.  All cycles will start 28 days (± 2) after the start of the prior cycle.  Cycle 
delays of more than 2 days must be discussed with the sponsor study medical monitor.  All 
carfilzomib infusions and dexamethasone administrations will be within the 2 days of the 
scheduled administration unless approved by the sponsor study medical monitor.   
9.2 
INTRAVENOUS HYDRATION 
Intravenous hydration will be given before each carfilzomib infusion during Cycle 1.  This 
will consist of 250 to 500 mL normal saline or other appropriate IV fluid.  Thereafter, 
pre-carfilzomib IV hydration should only be administered if the subject’s condition and/or 
risk factors require hydration.  The reason for hydration after Cycle 1 will be collected. 


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9.2.1 
STUDY TREATMENT ADMINISTRATION 
Weekly carfilzomib/lenalidomide/dexamethasone (KRd) will be given in 28-day cycles 
(see Table 4): 
• Carfilzomib will be administered once weekly IV on Days 1, 8, and 15 
• Lenalidomide will be administered once daily by mouth on Days 1–21 
• Dexamethasone will be administered once daily by mouth or by IV on Days 1, 8, and 15.  
Dexamethasone will also be given on Day 22 of Cycles 1–8.   
Table 4 
Carfilzomib/lenalidomide/dexamethasone Dosing Regimen  
28-day Cycles 
Week 1 
Week 2 
Week 3 
Week 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 
K CFZ Xa   
  
  
  
  
  
X 
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
R Len 
X X X X X X X X X X X X X X X X X X X X X 
  
  
  
  
  
  
  
d Dex 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
  
X 
  
  
  
  
  
  Xb   
  
  
  
  
  
CFZ= carfilzomib, Len = lenalidomide, Dex = dexamethasone. 
a Cycle 1 Day 1 carfilzomib dose level will be 20 mg/m2. 
b Dexamethasone will be administered on Day 22 of Cycles 1-8 only. 
9.2.1.1 
Carfilzomib will be administered onceweekly over 30 minutes (approximate) followed by a 
flush (see IPIM for details) on Days 1 (± 2), 8 (± 2), and 15 (± 2) of each cycle.  The dose 
can be calculated using the subject’s actual body surface area (BSA) at baseline; however, 
dosing adjustments for subsequent actual BSA determinations is 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 gains/losses of ≥ 20% of baseline body weight.  
Mechanical infusion pumps are recommended but gravity-dependent infusions are permitted 
if the 30-minute infusion duration can be reliably maintained.  
Carfilzomib 
Carfilzomib will be administered at 20 mg/m2 on Cycle 1 Day 1 and given once weekly.  
Beginning on Cycle 1 Day 8 the carfilzomib dose will be according to the assigned level of 
56 mg/m2 or 70 mg/m2.   
Cohorts 1, 2, and 3 


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Carfilzomib will be administered once-weekly at the following dosing schedule: 20 mg/m2 
on Day 1 of Cycle 1, 56 mg/m2 on Day 8 and Day 15 of Cycle 1, and 70 mg/m2 on Day 1 of 
Cycle 2 and beyond.   
Cohort 4: 
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. 
9.2.1.2 
Lenalidomide will be taken once-daily by mouth with or without food.  Lenalidomide 
capsules should be swallowed whole with water.  The capsules should not be opened, broken, 
or chewed.  Subjects will be instructed to take the lenalidomide dose at approximately the 
same time every day.  If a planned administration of lenalidomide is missed, it should be 
taken as soon as possible within the same calendar day with a return to schedule the 
following day.  If a calendar day of dosing is missed, subjects should not make up doses, but 
should resume the dosing regimen on schedule with the next course.  Missed doses must be 
reported.  
Lenalidomide 
For FCBP, nonpregnant state must be documented prior to the first dose of lenalidomide, 
every week for the first cycle, prior to the start of each subsequent cycle, and at EOT.   
Subjects must be advised to not donate blood during treatment with lenalidomide and for 
1 month following discontinuation of the drug because the blood might be given to a 
pregnant female subject whose fetus must not be exposed to lenalidomide. 
9.2.1.3 
Dexamethasone will be taken by mouth or by IV infusion once-daily on Days 1 (± 2), 8 (± 2), 
and 15 (± 2) for all cycles and on Day 22 (± 2) of Cycles 1 through 8.  Dexamethasone will 
be administered at least 30 minutes (but no more than 4 hours) prior to carfilzomib.  Subjects 
receiving dexamethasone IV on Days 1, 8, and 15 may receive dexamethasone orally on 
Day 22. 
Dexamethasone 


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9.2.2 
CARFILZOMIB AND LENALIDOMIDE DOSE MODIFICATION 
GUIDELINES 
Dose reduction levels of carfilzomib and lenalidomide for toxicity management of individual 
subjects are provided in Table 5 and Table 6, respectively: 
Table 5 
Dose Decrements for Carfilzomib 
Nominal Dose 
(mg/m2) 
Reduced Carfilzomib Doses (mg/m2) 
Dose -1 
Dose -2 
Dose -3 
20 
Discontinue 
 
 
56  
45  
36  
Discontinue 
70  
56  
45  
36  
 
Table 6 
Dose Decrements for Lenalidomide 
Nominal Dose 
(mg) 
Reduced Lenalidomide Doses (mg) 
Dose -1 
Dose -2 
Dose -3 
25  
15  
10  
5  
10  
5  
Discontinue 
— 
 
Treatment guidelines for specific hematologic toxicities are outlined in Section 9.2.2.1 and 
nonhematologic toxicities in Section 9.2.2.2.  In addition to dose reductions, administration 
of carfilzomib and/or lenalidomide may be held temporarily in the event of a 
treatment-related toxicity at the investigator’s discretion.  When administration of 
carfilzomib and/or lenalidomide is held, the reason must be documented in the case report 
form (CRF), and the medical monitor must be notified within 2 business days of the 
scheduled dose (Section 9.1). 
If either the lenalidomide or carfilzomib dose level is reduced during a given cycle, the 
reduced dose level will be continued for the next cycle.  If the reduced dose level is tolerated 
for a complete cycle, the subject may, at the investigator’s discretion, resume the dose level 
prior to the reduction at the start of the subsequent cycle. 


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Carfilzomib or lenalidomide can be discontinued in the event of a treatment-related toxicity 
that, in the opinion of the investigator, warrants discontinuation.  The subject will be 
considered still on protocol treatment as long as carfilzomib is being administered.   
9.2.2.1 
Guidelines for dose modification in the event of thrombocytopenia are summarized in 
Hematologic Toxicity 
Table 7 and those for neutropenia in Table 8. 
Table 7 
Treatment Guidelines for Thrombocytopenia 
When Platelets: 
Recommended Action 
Lenalidomide 
Carfilzomib 
Fall to < 30 × 109/La 
• Hold dose, follow CBC 
weekly 
• Hold prophylactic 
anticoagulation until 
platelets return to 
≥ 30 × 109/La 
• Then resume at 1 dose 
decrement 
If platelets 10–30 × 109/L 
without evidence of 
bleeding 
• Hold 
• With resolution restart 
at previous dose 
If evidence of bleeding or 
platelets < 10 × 109/L 
• Hold 
• With resolution restart 
at 1 dose decrement 
For each subsequent 
drop to < 30 × 109/La 
• Hold dose, follow CBC 
weekly  
• Hold prophylactic 
anticoagulation until 
platelets return to 
≥ 30 × 109/La  
• Then resume at 
additional dose 
decrement  
If platelets 10–30 × 109/L 
without evidence of 
bleeding 
• Hold 
• With resolution restart 
at previous dose  
If evidence of bleeding or 
platelets < 10 × 109/L 
• Hold 
• With resolution restart 
at 1 dose decrement 
CBC = complete blood count. 
a For subjects entering the study with myeloma involvement in the bone marrow > 50%, a lower threshold of 
20 × 109/L may be applied for lenalidomide dose reductions. 
 


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Table 8 
Treatment Guidelines for Neutropenia 
When ANC: 
Recommended Action 
Lenalidomide 
Carfilzomib 
Falls to < 0.75 × 109/L 
• Hold dose, administer 
myeloid growth factor 
• Follow CBC weekly 
• Resume at full dose when  
ANC ≥ 0.75 × 109/L  
If ANC 0.5–0.75 × 109/L • Continue at full dose 
If ANC < 0.5 × 109/L 
• Hold dose 
• Resume at 1 dose 
decrement when  
ANC ≥ 0.5 × 109/L 
For each subsequent 
drop to < 0.75 × 109/L 
• Hold dose, administer 
myeloid growth factor 
• Follow CBC weekly 
• Resume at 1 dose 
decrement when 
ANC ≥ 0.75 × 109/L  
If ANC 0.5–0.75 × 109/L • Continue at full dose 
If ANC < 0.5 × 109/L 
• Hold dose 
• Resume at 1 dose 
decrement when  
ANC ≥ 0.5 × 109/L 
ANC = absolute neutrophil count; CBC = complete blood count. 
 
9.2.2.2 
Guidelines for dose modification in the event of nonhematologic toxicities are summarized in 
Nonhematologic Toxicity  
Table 9. 


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Table 9 
Treatment Guidelines for Nonhematologic Toxicity 
Symptom 
Recommended Action 
Lenalidomide 
Carfilzomib 
Blood and Lymphatic System 
Thrombotic microangiopathy (TMA) Fever, 
microangiopathic hemolytic anemia, 
thrombocytopenia, renal failure, 
neurologic changes 
If the diagnosis is suspected, stop lenalidomide and 
carfilzomib and manage per standard of care including 
plasma exchange as clinically appropriate.  If TMA is 
confirmed and related to lenalidomide or carfilzomib, 
permanently discontinue.  If the diagnosis of TMA is 
excluded, lenalidomide and carfilzomib dosing may be 
resumed at full dose if clinically appropriate. 
Cardiac 
Congestive heart failure 
Full dose 
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. 
Hypertensive crisis 
Sustained or persistent  
SBP ≥ 180 mm Hg or  
DBP ≥ 110 mm Hg 
Full dose 
Hold carfilzomib until resolution to 
baseline, then resume at 1 dose 
decrement 
LVEF Reduction 
< 40% or 
< 55% if the drop is greater than 20% 
from baseline 
Full dose 
Hold carfilzomib until LVEF returns 
to ≥ 40% or, if held due to a drop to 
< 55%, to within 15% of baseline.  
Resume at 1 dose decrement. 
Infections and Infestations 
Infection 
Grade 3 or 4 
Hold both lenalidomide and carfilzomib until systemic 
treatment for infection is complete.  If ANC > 1,000/µL, 
resume both drugs at full dose.  If ANC < 1,000/µL, follow 
hematologic toxicities dosage guidelines. 
Hepatic Dysfunction and Related Investigations 
Mild liver dysfunction, defined as 
2 consecutive values, at least 28 days 
apart, of:  
(1) total bilirubin ( > 33% direct)  
> 1x ULN to < 1.5x ULN 
 OR  
(2) an elevation of AST and/or ALT with 
normal bilirubin 
Full dose. 
25% dose reduction.   
Dose may be re-escalated if liver 
function tests return to normal and 
drug-induced hepatotoxicity is 
excluded. 
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Table 9  Treatment Guidelines for Nonhematologic Toxicity (cont’d) 
Symptom 
Recommended Action 
Lenalidomide 
Carfilzomib 
Hepatic Dysfunction and Related Investigations (cont’d) 
Moderate liver dysfunction, 
defined as 2 consecutive 
values, at least 28 days 
apart, of total bilirubin 
( > 33% direct) > 
1.5x ULN to < 3x ULN 
Hold lenalidomide until resolution to 
baseline, then resume at full dose. 
25% dose reduction.   
Dose may be re-escalated if 
liver function tests return to 
normal and drug-induced 
hepatotoxicity is excluded. 
Grade 3 elevation in ALT 
and/or AST ( > 5x ULN) 
Hold lenalidomide until resolution to 
baseline, then resume at full dose. 
Hold carfilzomib until 
resolution to baseline.  
Monitor any abnormality 
weekly.  
Resume carfilzomib with a 
25% dose reduction if drug-
induced hepatotoxicity is 
excluded. 
Grade 3 elevation in total 
bilirubin 
Hold lenalidomide until resolution to 
baseline, then resume at full dose. 
Hold carfilzomib until 
resolution to baseline.   
Monitor total bilirubin and 
direct bilirubin weekly.  
Upon resolution of total 
bilirubin to normal, resume 
carfilzomib dosing with a 
25% dose reduction if drug-
induced hepatotoxicity is 
excluded. 
Renal Dysfunction 
CrCla  
≥ 30 and < 50 mL/min 
Reduce dose to 10 mg once daily. 
Full dose 
CrCla  
≥ 15 and < 30 mL/min 
(NCI-CTCAE Grade 3) 
Hold dose.  If CrCl recovers resume 
dose at 1 dose decrement.  If significant 
CrCl reduction reappears then reduce 
dose to 15 mg every 48 hours.  Further 
dose modification will be based on 
individual subject treatment tolerance. 
Full dose 
CrCla 
< 15 mL/min 
(NCI-CTCAE Grade 4) 
Hold dose.  If CrCl recovers to 
baseline, resume dose at 1 dose 
decrement.  If significant CrCl 
reduction reappears reduce dose to 
15 mg every 48 hours.  If dialysis 
required, reduce dose to 5 mg once 
daily (administer the lenalidomide after 
dialysis on dialysis days).  Further dose 
modification will be based on 
individual subject treatment tolerance. 
Hold dose.  When CrCl 
returns to ≥ 15 mL/ minute, 
resume same dose.  If dialysis 
required, contact the medical 
monitor. 
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Table 9  Treatment Guidelines for Nonhematologic Toxicity (cont’d) 
Symptom 
Recommended Action 
Lenalidomide 
Carfilzomib 
Metabolism 
Tumor Lysis Syndrome 
3 or more of the following: 
• increase in creatinine of ≥ 50% 
• increase in uric acid of ≥ 50% 
• increase in phosphate of ≥ 50% 
• increase in potassium of ≥ 30% 
• decrease in calcium, OR 
increase in LDH of ≥ 2-fold from 
baseline 
Hold both lenalidomide and carfilzomib until all abnormalities in 
serum chemistries have resolved; resume at full dose. 
Nervous System Disorders  
Neuropathy 
Treatment-emergent painful 
grade 2, or grade 3 
Full dose 
Hold carfilzomib until resolution 
to ≤ grade 2 without pain, then 
resume at 1 dose decrement 
Neuropathy 
Grade 4 
Discontinue 
Discontinue 
Posterior Reversible Encephalopathy 
Syndrome (PRES) 
 
headaches, altered mental 
 status, seizures, visual loss and 
 hypertension 
If PRES is suspected, hold lenalidomide and carfilzomib.  
Consider neuroradiographic imaging, specifically MRI, to evaluate 
onset of visual or neurological symptoms suggestive of PRES.  If 
the diagnosis of PRES is excluded lenalidomide and carfilzomib 
dosing may resume at the same dose, if clinically appropriate.  If 
condition recurs, permanently discontinue carfilzomib. 
Respiratory 
Dyspnea 
Grade 2, 3 or 4 
Full dose 
Hold carfilzomib until resolution 
to baseline, then resume at 1 dose 
decrement 
Pulmonary hypertension: (≥Grade 3) 
 
Full dose 
Hold carfilzomib until resolution 
to baseline, then resume at 1 dose 
decrement 
Pulmonary toxicity 
Interstitial lung disease, acute 
respiratory failure, ARDS 
(≥Grade 3) 
Hold lenalidomide until 
resolution to baseline then 
resume full dose 
Hold carfilzomib until resolution 
to baseline, then resume at 1 dose 
decrement 
Other Symptoms Not Listed Above 
Any other drug-related 
nonhematologic 
toxicity ≥ Grade 3b 
For lenalidomide attribution, 
hold dose. 
Resume at 1 dose decrement 
when toxicity has resolved to 
Grade 1 or less or to baseline 
grade. 
For carfilzomib attribution, hold 
dose. 
Resume at 1 dose decrement 
when toxicity has resolved to 
Grade 1 or less or to baselinec 
grade.   
Page 3 of 3 


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ALT = alanine aminotransferase; ANC = absolute neutrophil count; ARDS = acute respiratory distress 
syndrome; AST = aspartate aminotransferase; CrCl = creatinine clearance; DBP = diastolic blood pressure; 
KRd = carfilzomib/lenalidomide/dexamethasone; LDH = lactate dehydrogenase; LVEF = left ventricular 
ejection fraction; MRI = magnetic resonance imaging; NCI-CTCAE = National Cancer Institute-Common 
Terminology Criteria for Adverse Events; PRES = posterior reversible encephalopathy syndrome; 
SBP = systolic blood pressure; TMA = Thrombotic microangiopathy; ULN = upper limit of normal. 
a For a rapid fall from baseline in CrCl or an absolute fall of ≥ 60 mL/min, contact the medical monitor. 
b In the event of a possible drug-related nonhematologic toxicity, the investigator should, to the best of his/her 
ability, assess its relationship to lenalidomide, carfilzomib, dexamethasone, or the combination of KRd to the 
extent possible.  If both carfilzomib and lenalidomide are considered likely to be involved, then 
recommended actions for both should be instituted.  For nonhematologic toxicity likely due to 
dexamethasone, refer to Table 11 for treatment guidelines for dexamethasone-related toxicity. 
c For grade 3 hypertension, baseline refers to an average SBP < 140 mmHg or DPB < 90 mmHg on appropriate 
antihypertensive therapy. 
 
9.2.2.3 
The following conditions are exceptions to the above guidelines.  Carfilzomib, lenalidomide, 
and dexamethasone do not need to be held in the following cases: 
Conditions Not Requiring Dose Reduction 
• Grade 3 nausea, vomiting, or diarrhea (unless persisting more than 3 days with adequate 
treatment of antiemetics or antidiarrheal agents) 
• Grade 3 dexamethasone-related hyperglycemia 
• Grade 3 fatigue (unless persisting for > 14 days) 
• Alopecia 
9.2.3 
DEXAMETHASONE DOSE MODIFICATION GUIDELINES 
Two dose reduction levels are defined for dexamethasone, as illustrated in Table 10 below: 
Table 10 Dose Decrements for Dexamethasone 
Nominal Dose 
(mg) 
Reduced Dexamethasone Doses (mg) 
Dose -1 
Dose -2 
40  
20  
12  
Dexamethasone will be permanently discontinued after 2 dose reductions in the event of 
additional dexamethasone-related toxicities.  At the investigator’s discretion, dexamethasone 
may be tapered prior to complete discontinuation according to institutional practice.  The 
subject may continue on treatment with the other protocol-specified drug(s).  Guidelines for 
dexamethasone dose modifications are summarized in Table 11. 
 


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Table 11 Treatment Guidelines for Dexamethasone-related Toxicity 
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) 
• Hold dexamethasone until symptoms return to baseline.  
• Restart dexamethasone at 1 dose decrement along with concurrent therapy with H2 blockers, 
sucralfate, or omeprazole. 
• If symptoms persist despite above measures, discontinue dexamethasone permanently. 
Acute pancreatitis 
• Discontinue dexamethasone permanently. 
General 
Disorders 
Limb edema > Grade 3 (> 30% limb 
discrepancy in volume; gross deviation 
from normal anatomic contour; limiting 
self-care activities of daily living) 
• Hold dexamethasone until symptoms return to baseline. 
• Diuretics as needed, and restart dexamethasone at 1 dose decrement; if edema persists despite 
above measures, decrease dose by another dose decrement. 
• Discontinue dexamethasone permanently if symptoms persist despite second reduction. 
Psychiatric 
Disorders 
Confusion or mood alteration ≥ Grade 2 
(interfering with function ± interfering 
with activities of daily living) 
• Hold dexamethasone until symptoms return to baseline. 
• Restart dexamethasone at 1 dose decrement. 
• If symptoms persist despite above measures, reduce by another dose decrement. 
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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Table 11 Treatment Guidelines for Dexamethasone-related Toxicity (cont’d) 
Dexamethasone-related Toxicities, All Days and Cycles 
Symptom 
Findings 
Recommended Action 
Metabolism and 
Nutrition 
Disorders 
Hyperglycemia ≥ Grade 3 (fasting glucose 
> 250 mg /dL) 
• Hold dexamethasone until glucose is ≤ Grade 2 (< 250 mg/dL) and treat with insulin or other 
hypoglycemic agents as needed. 
• If uncontrolled despite above measures, decrease dose by 1 dose decrement until ≤ Grade 2 
(< 250 mg /dL). 
All Other 
Other toxicity ≥ Grade 3 felt related to 
dexamethasone 
• Hold dexamethasone dose.  Resume at 1 dose decrement when toxicity has resolved to 
≤ Grade 2. 
• If toxicity recurs, hold dexamethasone dose until toxicity has resolved to ≤ Grade 2 and 
resume dexamethasone dose by another dose decrement. 
• If toxicity recurs despite 2 dose decrements, discontinue dexamethasone permanently. 
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9.3 
CONCOMITANT MEDICATIONS 
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements.  All concomitant medications from signing of the 
informed consent until 30 days after the subject’s last dose of study drug must be recorded on 
the electronic case report form (eCRF).  Blood or blood products are not considered 
concomitant medications and must be recorded on the appropriate eCRF. 
9.3.1 
REQUIRED CONCOMITANT MEDICATIONS 
Required prophylactic medications should be initiated at least 24 hours prior to the first 
administration of carfilzomib.  Contraception must be in place at least 4 weeks prior to the 
first administration of carfilzomib and/or lenalidomide. 
9.3.1.1 
Valacyclovir (or equivalent antiviral) is a required concomitant medication.  Valacyclovir 
500 mg orally, daily (or equivalent antiviral) should continue for the duration of treatment.  
Additional prophylaxis is at the investigator’s discretion.   
Antiviral Prophylaxis 
9.3.1.2 
Aspirin (or other anticoagulant or antiplatelet medication such as clopidogrel bisulfate, 
low-molecular-weight heparin, or warfarin), is a required concomitant medication while 
taking lenalidomide.  In subjects with a prior history of deep vein thrombosis, 
low-molecular-weight heparin or therapeutic doses of warfarin (for a target international 
normalized ratio of 2–3) are required.  Enteric-coated aspirin once-daily by mouth at the 
standard prophylactic dose should be administered for the duration of treatment with 
lenalidomide.  Subjects with known high thrombotic risk, eg, prior deep vein thrombosis, 
should receive full anticoagulation at the investigator’s discretion.  Other antiplatelet or 
anticoagulation medications may be used in cases of intolerance to aspirin upon consultation 
with the sponsor study medical monitor. 
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9.3.1.3 
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.  Allopurinol dose should be prescribed according to the package insert. 
Tumor Lysis Syndrome Prophylaxis 
Subjects should be well hydrated (Section 9.2) to reduce the risk of TLS and decline in renal 
function; refer to the current Carfilzomib IB for safety guidance regarding TLS. 
9.3.1.4 
Females of childbearing potential (FCBP) must: 
Contraception 
• Avoid pregnancy for at least 4 weeks before beginning lenalidomide 
• Have 2 negative pregnancy tests prior to starting treatment, the first, a serum pregnancy 
test within 10 to 14 days and the second, a urine or serum pregnancy test within 24 hours 
before dosing on Cycle 1 Day 1 
• Pregnancy tests weekly for the first month of treatment 
• Pregnancy tests monthly during treatment after the first month or semimonthly for 
women of childbearing potential with irregular menstruation 
• Agree to abstain from heterosexual sexual intercourse or to use 2 methods of highly 
effective contraception beginning 4 weeks prior to initiating treatment with lenalidomide, 
during therapy, during dose interruptions and for 1 month following last dose of drug 
(more frequent pregnancy tests may be conducted if required per local regulations) 
An FCBP is defined as a sexually mature female who:  1) has not undergone a hysterectomy 
or bilateral oophorectomy, or 2) has not been naturally postmenopausal for at least 
24 consecutive months (ie, no menses at any time in the preceding 24 consecutive months).  
Amenorrhea following cancer therapy does not rule out childbearing potential. 
Male subjects whose partners are FCBP must use 1 highly effective method of birth control 
plus 1 additional effective method of birth control (contraception) at the SAME TIME during 
treatment and for 3 months following the last dose of drug, unless they have undergone a 
medically-confirmed successful vasectomy.  Male subjects must not donate sperm while 
taking study drugs and for 90 days after the last dose of study drugs.   


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Highly effective methods of contraception include: 
• Intrauterine device (IUD)  
• Hormonal therapy (birth control pills, injections, implants) 
• Tubal ligation 
• Vasectomy, with medical confirmation of success 
Additional effective methods include: 
• Latex condom 
• Diaphragm 
• Cervical Cap 
9.3.2 
OPTIONAL AND ALLOWED CONCOMITANT MEDICATIONS 
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 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. 
Palliative radiation for pain management is permitted with the written approval of the study 
medical monitor. 
Bisphosphonates are permitted as indicated and in accordance with institutional guidelines. 
9.3.3 
EXCLUDED CONCOMITANT MEDICATIONS 
Concurrent therapy with a marketed or investigational anticancer therapeutic or radiation to 
large marrow reserves for either a palliative or therapeutic intent is excluded.  Long term 
(≥ 14 days) corticosteroids for nonmalignant conditions (eg, asthma, inflammatory bowel 
disease) equivalent to a dexamethasone dose > 4.0 mg/day or prednisone > 20 mg/day are not 
permitted (other than as indicated in this protocol).  Higher steroid doses given short term for 
exacerbations of nonmalignant conditions (eg, asthma flare) are permitted with the approval 


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of the sponsor study medical monitor.  Investigational agents are not to be used during the 
study. 
Subjects requiring the use of excluded concomitant medications or procedures will be 
withdrawn from study treatment.  
10 
All protocol-required tests and observations, along with their chronology, are outlined in the 
Schedule of Assessments (
STUDY PROCEDURES 
Appendix A).  On-study tests and observations are summarized 
below. 
10.1 
STUDY-SPECIFIC PROCEDURES 
10.1.1 
BASELINE PROCEDURES 
To be completed prior to initiation of therapy: 
• Skeletal survey (all subjects) (Section 10.1.4.3) 
• Beta-2 microglobulin (Section 10.1.4.1) 
• Plasmacytoma evaluation (if clinically indicated) (Section 10.1.4.3) 
• Bone marrow aspirate and biopsy (all subjects, Section 10.1.4.2) 
10.1.2 
VITAL SIGNS 
Vital signs will include pulse, blood pressure, respiratory rate, and temperature and will be 
assessed at Screening, prior to and after administration of carfilzomib on treatment days, and 
at EOT.  Resting blood pressure readings will be taken before administration of carfilzomib 
on Days 1, 8, and 15 of each cycle.  Pre-carfilzomib blood pressure may be assessed either 
before or after dexamethasone administration, and for a given patient should be done 
consistently before dexamethasone, or consistently after dexamethasone.  The time of pre-
carfilzomib dosing blood pressure assessment will be recorded.  The time of Day 1, 8, and 
15 dexamethasone administration will also be recorded (per report by patient if self-
administered).  During Cycles 1 through 6, 12, and 18, pre-carfilzomib blood pressure 
readings will be taken in triplicate.  In addition to the predosing blood pressure assessments, 
postdosing resting blood pressure readings will be taken in triplicate on Days 1, 8, and 15 of 


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Cycles 1 through 6, 12, and 18.  Postdosing blood pressure will be assessed from 10 to 
60 minutes after completion of carfilzomib administration. 
The subject should be in a supine position in a rested and calm state for at least 5 minutes 
before blood pressure assessments are conducted.  If unable to be in a supine position, the 
subject should be in the most recumbent position possible.  The position selected for a 
subject should be the same that is uses throughout the study and documented on the vital sign 
CRF.  The arm should be supported at the level of the heart.  Every effort should be made to 
use the same instrument in measuring a subject’s blood pressure throughout the study.  When 
blood pressure measurements are taken in triplicate, readings should be taken a minute or 
more apart. 
10.1.3 
PHYSICAL EXAMINATION 
A physical examination will be performed during Screening, on Day 1 of Cycles 2 
through 18, and at the EOT.  Physical exam will include:   
• ECOG PS 
• Examination of cardiovascular and respiratory systems  
• Weight  
• BSA (at Screening and on Day 1 of Cycles 2–18 only) 
• Height (at Screening only) 
Abnormal physical examination findings during Screening will be captured as medical 
history.  Abnormal physical examination findings observed after signing of the informed 
consent will be recorded as AEs.   
10.1.4 
DISEASE ASSESSMENTS 
10.1.4.1 
Laboratory assessments of disease status will be performed at Screening (within 21 days 
before dosing on Cycle 1 Day 1); at Day 1 (± 3 days) of Cycle 2 and each cycle thereafter; at 
the EOT; and every 8 weeks (every 56 ± 4 days) during Active Follow-up. 
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Disease assessments at Screening (within 21 days before dosing on Cycle 1 Day 1) or 
baseline, include the following: 
• Serum protein electrophoresis (SPEP) with immunofixation 
• Urine protein electrophoresis (UPEP; 24-hour assessment, no substitute method is 
acceptable) with immunofixation 
• SFLC 
• Quantitative immunoglobulins 
• Beta-2 microglobulin 
Disease assessments at Day 1 (± 3 days) of Cycle 2 and each cycle thereafter, at the EOT, 
and during Active Follow-up include the following: 
• Serum protein electrophoresis (SPEP) with immunofixation 
• UPEP with immunofixation  
• SFLC 
• Quantitative immunoglobulins 
SPEP with immunofixation, UPEP with immunofixation, beta-2 microglobulin, SFLC, and 
quantitative immunoglobulin analyses will be performed at the local laboratory. 
10.1.4.2 
A bone marrow aspirate is required at baseline, on Cycle 8 Day 1 (± 3 days), and to confirm 
a CR or sCR.  An optional bone marrow aspirate may also be done upon progression of 
disease in subjects who consent to optional genomic biomarker studies.  Details of aspirate 
sampling and shipment are described in the central laboratory manual. 
Bone Marrow Aspirate Assessments of Disease Status 
At baseline, bone marrow aspirate will be evaluated by the local pathology lab to determine 
percent plasma cell involvement.  For subjects whose aspirate is unobtainable, a bone 
marrow core biopsy should be obtained for quantification of percent plasma cell 
involvement.  Bone marrow aspirate or biopsy samples (taken as part of standard of care) 
within 45 days prior to Cycle 1 Day 1 may be used to quantify percent plasma cell 
involvement. 
Baseline bone marrow aspirate samples are also sent to the central laboratories for 
fluorescent in situ hybridization (FISH; Section 10.2.3) and for Next Generation Sequencing 


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(NGS) to allow MRD analysis (Section 10.2.4); also referred to herein as “MRD”).  Subjects 
who consent to optional genomic biomarker evaluation will have the baseline genomic 
biomarker analyses performed on aspirate samples remaining after central FISH testing of 
baseline aspirate.  
Bone marrow aspirate will be collected for central MRD analysis on Cycle 8 Day 1 for all 
subjects regardless of response status (± 2 days; see Section 10.2.4). 
Subjects with laboratory evidence of CR require confirmatory bone marrow aspirate 
evaluation, by the central study laboratory, for MRD (Section 10.2.4), in addition to local 
bone marrow assessment for evaluation of CR per IMWG-URC (Appendix C).  
Consenting subjects with PD may have a bone marrow aspirate done for optional genomic 
biomarker studies (Section 10.2.5). 
In instances where sample availability is limited, samples for disease assessments take 
priority over those for correlative testing as specified in the laboratory manual. 
10.1.4.3 
All subjects will have a baseline skeletal survey.  Repeat skeletal survey is recommended as 
clinically indicated. 
Imaging Assessments of Disease Status 
Subjects with physical exam findings suggestive of plasmacytoma should undergo baseline 
imaging with computed tomography [CT] scan, magnetic resonance imaging [MRI], or 
positron emission tomography/CT [PET/CT]. 
Repeat plasmacytoma imaging is required only to confirm a response of PR or better, to 
confirm PD, or if clinically indicated.  The same imaging technique should be employed for 
each measurement. 
For study purposes, a plasmacytoma is considered measurable if the longest diameter is at 
least 1 cm and the product of the greatest orthogonal cross-diameters is at least 1 cm2. 


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10.1.5 
MYELOMA RESPONSE ASSESSMENT 
Response will be determined by the investigator based on the disease assessments described 
above and the IMWG-URC (see definitions in Appendix C).  Myeloma response laboratory 
studies will be drawn at the beginning of each cycle before treatment.  The following 
confirmatory assessments are required for all response categories (stringent complete 
response [sCR], CR, VGPR, and PR) and progressive disease: 
• All laboratory-based progressive disease and all responses require 2 consecutive 
assessments made at any time before initiation of any new (ie, off protocol) therapy.  
Confirmatory lab samples should be separated by at least 1 calendar day 
• Progressive disease by nonlaboratory-based assessment (ie, plasmacytoma or skeletal 
lesion) does not require confirmatory report 
• All response categories also require no evidence of progression including new bone 
lesions, if radiographic studies are performed 
• Confirmation of CR or sCR requires local pathology review of a bone marrow biopsy or 
aspirate (a repeat confirmatory bone marrow sample is not required) 
• Extramedullary plasmacytoma evaluation is required to confirm PR, CR, or sCR (if 
present at baseline; Rajkumar, 2011) 
10.1.6 
CLINICAL LABORATORY TESTS  
Clinical laboratory assessments will include the following: 
• Hematology:  hemoglobin, hematocrit, white blood cell (WBC) with complete 
differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils), RBCs, 
platelet count   
• Full serum chemistry panel:  sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen (BUN), creatinine, glucose, calcium, magnesium, phosphate, AST, ALT, total 
protein, albumin, alkaline phosphatase, total bilirubin, uric acid, and lactate 
dehydrogenase (LDH)  
• Abbreviated chemistry panel:  sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose 
• Coagulation tests:  prothrombin time, activated partial thromboplastin time, and 
international normalized ratio 
Hematology and serum chemistry (full or abbreviated) will be performed at Screening, on 
Days 1, 8, and 15 of each cycle, and at EOT.  On Days 8 and 15 of each cycle, from Cycle 2 
onwards, an abbreviated serum chemistry panel may be performed.  C oagulation will be 
performed at baseline and at EOT.  For screening laboratory samples, historical panel may be 
used if within 21 days prior to dosing on Cycle 1 Day 1.  Thereafter, hematology samples 


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may be obtained anytime within the 24 hours prior to the carfilzomib administration, and full 
or abbreviated chemistry panels may be performed up t o 72 hours prior to carfilzomib 
administration.  
10.1.7 
ELECTROCARDIOGRAM 
Twelve-lead electrocardiograms (ECGs) including corrected QT interval (QTc; representing 
the corrected duration of ventricular electrical activity) will be performed locally.  These will 
be required in all subjects at Screening only.  Additional ECG assessment is only required if 
clinically indicated 
10.1.8 
ECHOCARDIOGRAM 
A 2-D transthoracic ECHO to assess LVEF will be performed in all subjects at Screening and 
at EOT.  During the Dose-evaluation Component, an ECHO is also required at Cycle 2 
Day 15, ± 7 days.  Additional ECHO assessment is only required for subjects who develop 
clinically significant congestive heart failure.   
If transthoracic ECHO is not available, multigated acquisition (MUGA) will be acceptable 
for LVEF evaluation. 
10.1.9 
SUBJECT CONVENIENCE AND SATISFACTION 
Subject convenience and satisfaction will be assessed in all subjects by questionnaire at 
Cycle 3 Day 1 and Cycle 18 Day 1 (see Appendix D).  The questionnaire should be 
administered prior to treatment with carfilzomib.  
10.2 
CORRELATIVE STUDIES 
It is recommended that samples for correlative studies be collected only after screening 
laboratories confirm study eligibility for the subject. 
10.2.1 
PHARMACOKINETIC MEASUREMENTS 
For both the Dose-evaluation and the Dose-expansion Components, blood samples will be 
collected from all subjects on Day 8 of Cycle 1 for determination of plasma concentrations 
of carfilzomib. 


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Blood samples will be collected at the following time points: 
• Predose (within 5 minutes before start of carfilzomib infusion) 
• 15 minutes (± 5 minutes) after the start of carfilzomib infusion 
• Immediately prior to (within 2 minutes before) the end of carfilzomib infusion 
• 15 minutes (± 5 minutes) after the end of carfilzomib infusion  
• 60 minutes (± 5 minutes) after the end of carfilzomib infusion 
The actual time of PK sample collection will be recorded.  Samples should be collected 
within a ± 5 minute time window around the nominal time points (except for the time point 
immediately prior to the end of carfilzomib 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 constitute a protocol deviation.  These samples will be assessed at a central 
laboratory.  Directions for collection, processing, and shipping of PK blood samples are 
provided in the central laboratory manual.   
10.2.2 
PHARMACODYNAMIC MEASUREMENTS 
For pharmacodynamic measurements, whole blood will be collected from the subjects on the 
following schedule: 
For the Dose-evaluation component Cohorts 1 and 2, and the first 8 subjects enrolled into 
Dose-expansion Arm 3, whole blood will be collected.  On Days 1 and 8 of Cycle 1, whole 
blood will be collected pre-carfilzomib dose and post-carfilzomib dose.  On Days 9 and 
11 of Cycle 1, when carfilzomib is not administered, one PDn sample will be collected at 
approximately the same time as when the pre-infusion sample was taken on Day 8. 
Directions for collection, processing, and shipping of PDn samples are provided in the 
central laboratory manual.   
10.2.3 
FLUORESCENT IN SITU HYBRIDIZATION (FISH) TESTING 
Bone marrow aspirate from all subjects will be evaluated centrally, at baseline, by FISH.  
Directions for collection, processing, and shipping of FISH samples are provided in the 
central laboratory manual. 


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10.2.4 
MINIMAL RESIDUAL DISEASE 
Analysis of MRD status will be performed by the central laboratory on all subjects by 
2 methods:  
Flow cytometry (FC) of cell surface markers and  
NGS of DNA and/or RNA from the Ig locus.   
The MRD analysis by FC will be performed on bone marrow aspirate samples collected at 
2 time points:  Cycle 8 Day 1 and upon achieving a CR or sCR.  The MRD analysis by NGS 
will be performed on blood and bone marrow aspirate samples collected at 3 time points:  
baseline, Cycle 8 Day 1, and upon achieving a CR or sCR. 
Directions for collection, processing, and shipping of MRD samples are provided in the 
central laboratory manual. 
10.2.5 
OPTIONAL GENOMIC BIOMARKERS 
Analysis of genetics, gene expression, and cell surface biomarkers that may be predictive of 
response and resistance to treatment with proteasome inhibitors will be performed.  
Exploratory studies will be conducted on all subjects who consent to optional genomic 
biomarker analysis.  These analyses will be performed on bone marrow aspirate at baseline 
(the remaining portion of the bone marrow aspirate sample left after the amount required for 
FISH analysis has been collected at baseline), as well as a sample of blood and saliva also 
collected at baseline.  At disease progression, an additional bone marrow sample for 
biomarker analysis may be collected from all subjects who consent. 
Whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome 
sequencing (RNA-Seq), and/or other methods of nucleic acid and protein quantification will 
be conducted on isolated tumor (CD138+) cells from bone marrow samples taken at baseline 
and disease progression.  In addition, WGS or WES will be performed on a normal tissue 
sample (eg, CD3+ T cells isolated from peripheral blood or saliva) to distinguish germ line 
mutations from somatic mutations in tumor cell samples. 


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Directions for collection, processing, and shipping of optional genomic biomarker samples 
are provided in the central laboratory manual. 
11 
11.1 
WITHDRAWAL OF SUBJECTS FROM TREATMENT 
STUDY DISCONTINUATION 
Subjects may withdraw from study treatment at any time.  Reasons for discontinuation 
include: 
• Adverse event 
• Allogeneic stem cell transplant 
• Pregnancy 
• Death 
• Lost to follow-up 
• Noncompliance 
• Withdrawal by subject 
• Study terminated by the sponsor 
• Physician decision 
• Progression of disease 
• Other 
The primary reason for 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 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.  
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 12.2.1.4, 
then it should also be recorded as a serious adverse event (SAE) in the AE eCRF. 
Sponsor or designee must be notified within 24 hours if a subject is withdrawn from 
treatment. 


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All subjects who withdraw or are withdrawn from study treatment will be encouraged to 
complete all relevant safety assessments and continue in the Active Follow-up period.  
11.2 
WITHDRAWAL OF SUBJECTS FROM STUDY 
Reasons for complete withdrawal from the study (treatment and all follow-up) before 
documentation of subject death include: 
• Withdrawal of consent by subject for all study procedures 
• Lost to follow-up 
• Sponsor decision 
The reason for complete withdrawal from study will be documented in the eCRF. 
11.3 
STUDY TERMINATION 
The sponsor has the right to terminate this study or a study site from participating in a study 
at any time.  Reasons for study termination may include: 
• 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 
12 
12.1 
DEFINITION OF SAFETY EVENTS 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
12.1.1 
ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence in a clinical trial subject.  The event 
does not necessarily have a causal relationship with study treatment.  The investigator is 
responsible for ensuring that any AEs observed by the investigator or reported by the subject 
are recorded in the subject’s medical record.   
The definition of AEs includes worsening of a pre-existing medical condition.  Worsening 
indicates that the pre-existing medical condition or underlying disease (eg, diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration more than would be 


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expected, and/or has an association with a significantly worse outcome than expected.  A 
pre-existing condition that has not worsened more than anticipated (ie, more than usual 
fluctuation of disease) during the study or involves an intervention such as elective cosmetic 
surgery or a medical procedure while on study, is not considered an AE.   
For situations when an AE or SAE is due to multiple myeloma, report all known signs and 
symptoms.  Death due to disease progression in the absence of signs and symptoms should be 
reported as the primary tumor type (eg, multiple myeloma).  
Note:  The term “disease progression” should not be used to describe the disease-related 
event or AE.   
The investigator’s clinical judgment is used to determine whether a subject is to be removed 
from treatment due to an AE.  In the event a subject, or subject’s legally acceptable 
representative requests to withdraw from protocol-required therapies or the study due to an 
AE, refer to Section 11 for additional instructions on the procedures recommended for safe 
withdrawal from protocol-required therapies or the study.   


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12.1.2 
SERIOUS ADVERSE EVENTS 
A serious adverse event is defined as an AE that meets at least 1 of the following serious 
criteria: 
• fatal 
• life threatening (places the subject at immediate risk of death) 
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• other medically important serious event 
An AE would meet the criterion of “requires hospitalization”, if the event necessitated an 
admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any of the 
serious criteria, the event could be classified as a SAE under the criterion of “other medically 
important serious event”.  Examples of such events could include allergic bronchospasm, 
convulsions, blood dyscrasias, drug induced liver injury, or events that necessitate an 
emergency room visit, outpatient surgery, or urgent intervention.   
12.2 
SAFETY EVENT REPORTING PROCEDURES  
12.2.1 
ADVERSE EVENTS 
12.2.1.1 
The investigator is responsible for ensuring that all AEs observed by the investigator or 
reported by the subject that occur after signing the informed consent form through 30 days 
after receiving the last dose of study drugs are reported using the Event CRF.   
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
If initiation of new anticancer therapy occurs within 30 days following the last dose of study 
drugs, 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. 
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 


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subject’s source file.  AEs 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. 
The investigator must assign the following AE attributes: 
• AE diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• Dates of onset and resolution (if resolved), 
• Severity (and/or toxicity per protocol), 
• Assessment of relatedness to carfilzomib and/or other protocol-required therapies 
• Action taken. 
The adverse event grading scale used will be the Common Terminology Criteria for Adverse 
Events (CTCAE).  The grading scale used in this study is described in Appendix F.   
The investigator must assess whether the AE is possibly related to carfilzomib and/or other 
protocol-required therapies.  This relationship is indicated by a “yes” or “no” response to the 
question:  Is there a reasonable possibility that the event may have been caused by 
carfilzomib and/or other protocol-required therapies?   
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, lenalidomide, and/or 
dexamethasone. 
The investigator is responsible for reviewing laboratory test results and determining whether 
an abnormal value in an individual study subject represents a clinically significant change 
from the subject’s baseline values.  In general, abnormal laboratory findings without clinical 
significance (based on the investigator's judgment) are not to be recorded as AEs.  However, 
laboratory value changes that require treatment or adjustment in current therapy are 
considered AEs.  Where applicable, clinical sequelae (not the laboratory abnormality) are to 
be recorded as the AE. 
The Investigator is expected to follow reported AEs until stabilization or reversibility.  


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12.2.1.2 
The investigator is responsible for ensuring that all SAEs observed by the investigator or 
reported by the subject that occur after through 30 days after the last day of the study drug 
are recorded in the subject’s medical record and are submitted to Amgen.  All SAEs must be 
submitted to Amgen within 24 hours following the investigator’s knowledge of the event via 
the Event CRF.   
Reporting Procedures for Serious Adverse Events 
If the electronic data capture (EDC) system is unavailable to the site staff to report the SAE, 
the information is to be reported to Amgen via an electronic SAE Contingency Report Form 
within 24 hours of the investigator’s knowledge of the event.  See Appendix G for a sample 
of the SAE Worksheet /electronic SAE Contingency Report Form.  For EDC studies where 
the first notification of a SAE is reported to Amgen via the electronic SAE Contingency 
Report Form, the data must be entered into the EDC system when the system is again 
available. 
The investigator must assess whether the SAE is possibly related to carfilzomib and/or other 
protocol-required therapies.  This relationship is indicated by a “yes” or “no” response to the 
question: Is there a reasonable possibility that the event may have been caused by carfilzomib 
and/or other protocol-required therapies?  Relatedness means that there are facts or reasons to 
support a relationship between investigational product and the event. 
The investigator is expected to follow reported SAEs until stabilization or reversibility.  
New information relating to a previously reported SAE must be submitted to Amgen.  All 
new information for SAEs must be sent to Amgen within 24 hours following knowledge of 
the new information.  If specifically requested, the investigator may need to provide 
additional follow-up information, such as discharge summaries, medical records, or extracts 
from the medical records. Information provided about the SAE must be consistent with that 
recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a SAE, 
this information must be submitted to Amgen. 


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Amgen will report SAEs and/or suspected unexpected serious adverse reactions as required 
to regulatory authorities, investigators/institutions, and Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) in compliance with all reporting requirements 
according to local regulations and good clinical practice.  
The investigator is to notify the appropriate IRB/IEC of SAEs occurring at the site and other 
AE reports received from Amgen, in accordance with local regulatory requirements and 
procedures. 
12.2.1.3 
There is no requirement to monitor study subjects for SAEs following the protocol-required 
reporting period or after end of study.  However, these SAEs can be reported to Amgen.  In 
some countries (eg, European Union [EU] member states), investigators are required to 
report SAEs that they become aware of after end of study.  If SAEs are reported, the 
investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge of the event. 
Reporting Serious Adverse Events After the Protocol-required Reporting 
Period 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
12.2.1.4 
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 
(eg, 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).  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. 
Serious Adverse Events That are not to be Reported by the Sponsors to 
Regulatory Agencies in an Expedited Manner  


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12.3 
PREGNANCY AND LACTATION REPORTING 
If a female subject becomes pregnant, or a male subject fathers a child, while the subject is 
taking carfilzomib report the pregnancy to Amgen Global Patient Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur in female subjects 30 days after the last study drug 
administration, and in a male subject’s spouse or partner while enrolled in this clinical study 
through 90 days following the last study drug administration. 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of the 
investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the Pregnancy 
Notification Worksheet (Appendix H) Amgen Global Patient Safety will follow-up with the 
investigator regarding additional information that may be requested.  
If a female subject becomes pregnant during the study, the investigator should attempt to 
obtain information regarding the birth outcome and health of the infant.  Newborns should be 
followed for a minimum of 12 weeks.   
If the outcome of the pregnancy meets a criterion for immediate classification as a SAE 
(eg, female subject experiences a spontaneous abortion, stillbirth, or neonatal death or there 
is a fetal or neonatal congenital anomaly) the investigator will report the event as a SAE.  
If a female breastfeeds while taking protocol-required therapies report the lactation case to 
Amgen as specified below.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of the 
investigator’s knowledge of event.  Report a lactation case on the Lactation Notification 
Worksheet (Appendix H).   
Amgen Global Patient Safety will follow-up with the investigator regarding additional 
information that may be requested. 


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If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the pregnant 
partner. 
13 
The final analysis will be based upon subject data collected through discontinuation of the 
final subject from study participation or until study discontinuation by the sponsor, 
whichever occurs first.  All efficacy and safety analyses will be based upon the Safety 
Population, defined as subjects receiving at least 1 dose of study drug.  All summaries will be 
presented by the assigned dose cohort level, by RRMM and NDMM population, as well as 
for the overall Safety Population.  In addition, response data (ORR, complete response rate 
[CRR], PFS, DOR) may also be analyzed based on the Response-evaluable Population, 
defined as subjects who are included in the Safety Population, have a baseline disease 
assessment and at least 1 postbaseline disease assessment, or dropped out due to AE prior to 
the first postbaseline disease assessment.  
STATISTICS 
13.1 
STUDY ENDPOINTS 
13.1.1 
PRIMARY ENDPOINTS 
Safety and tolerability of carfilzomib administered once weekly in combination with 
lenalidomide and dexamethasone, as defined by the type, incidence, and severity of AE, and 
changes from baseline in key laboratory analyses, including immunoglobulin levels, vital 
signs, and the extent and duration of exposure to study drugs.   
13.1.2 
SECONDARY ENDPOINTS 
The secondary endpoints of this study are: 
• Pharmacokinetics (PK) of carfilzomib 
• Overall Response Rate (ORR), defined as the proportion of subjects who achieve a best 
overall response of sCR, CR, VGPR, or PR in accordance with IMWG-URC  
• Complete Response Rate (CRR), defined as the proportion of subjects who achieve a best 
overall response of either sCR or CR in accordance with IMWG-URC 
• Progression-free survival (PFS), defined as the time from the first day of study treatment 
to the earlier of disease progression or death due to any cause 


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• Duration of Response (DOR), defined as the time from the first evidence of confirmed 
PR or better to disease progression or death due to any cause among subjects who 
respond 
13.1.3 
OTHER ENDPOINTS 
The exploratory endpoints include: 
• Pharmacodynamics (PDn) of proteasome inhibition by carfilzomib measured in whole 
blood 
• MRD[-] rate, defined as the proportion of subjects who are negative for MRD at Cycle 8 
Day 1.  Point estimates for MRD[-] rate along with exact 2-sided 95% confidence 
intervals will be calculated for both MRD assessment methods.   
• Subject convenience and satisfaction with the carfilzomib dosing schedule.  
• WGS, WES, whole transcriptome sequencing, and other nucleic acid and protein 
quantification data and immunoglobulin levels in tumor cells 
13.2 
ANALYSIS OF THE CONDUCT OF THE STUDY 
Enrollment, major protocol violations, study drug administration, and discontinuations from 
the study will be summarized by the assigned dose cohort and for all subjects.  Demographic 
and baseline characteristics, such as age, sex, race, weight, number of prior therapies, and 
baseline ECOG PS (Appendix B), will be summarized using means, standard deviations, 
medians, and ranges for continuous variables, and proportions for categorical variables.  
13.3 
INDEPENDENT REVIEW COMMITTEE 
All efficacy interpretation will be based on investigator assessment.  An independent review 
committee will not be employed for this study. 
13.4 
DATA MONITORING COMMITTEE  
A data monitoring committee will not be employed for this study. 
13.5 
STATISTICAL METHODS 
13.5.1 
EFFICACY ANALYSES 
The primary analysis of efficacy will be based on the Safety Population.  Additionally, 
response data (ORR, CRR, PFS, and DOR) may also be analyzed based on the 
Response-evaluable Population.  Response assessment data, PFS, and DOR will be listed for 


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all subjects by dose cohort level.  Point estimates for ORR and CRR along with their exact 
2-sided 95% confidence intervals will be calculated.  Summary statistics for DOR and PFS 
will be calculated using the Kaplan-Meier method.  The follow-up time for PFS will be 
summarized by reverse Kaplan-Meier method (Schemper 1996). 
13.5.2 
SAFETY ANALYSIS 
Safety will be assessed through summaries of AEs, changes from baseline in laboratory test 
results, including immunoglobulin levels, and vital signs, and the extent and duration of 
exposure to study drugs.  All treatment-emergent AEs will be summarized by MedDRA 
preferred term, NCI-CTCAE (version 4.03) toxicity grade, and investigator assessment of 
causality.  In addition, all SAEs and DLTs, including deaths, will be listed separately.  Extent 
of exposure to the study treatment will be summarized using descriptive statistics.  
Laboratory parameters will be summarized using descriptive statistics and by postdose shifts 
relative to baseline.  Vital signs will also be summarized descriptively for each scheduled 
protocol time point.    
13.5.3 
PHARMACOKINETIC ANALYSES  
Actual collection times will be 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 estimates for carfilzomib will be summarized, including total plasma exposure 
(expressed as area under the curve [AUC]), maximum plasma concentration (Cmax), time to 
maximum plasma concentration (Tmax), total plasma clearance, and plasma terminal half-life 
(as appropriate for data collected).  Estimates for these parameters will be tabulated and 
summarized (ie, mean, standard deviation). 
Unless otherwise specified, the PK parameter will be estimated based on noncompartmental 
methods.  These estimates will be summarized descriptively by dose cohort and population.  
Exploratory analyses may be performed to evaluate the relationship between the estimated 
PK parameters and selected safety, biomarker, or clinical effect endpoints. 
In addition to noncompartmental PK analysis, the population modeling program may be used 
to fit a nonlinear mixed effects model to estimate PK parameters including clearance and 


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volume of distribution, the inter- and intra-subject variability and the population variability in 
the parameter estimates.  The PK concentrations obtained from subjects in the 
Dose-expansion portion, along with results from the Dose-evaluation Component of the 
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.  Results from the population PK modeling will be reported separately. 
13.5.4 
EXPLORATORY ANALYSES  
Exploratory analyses of MRD[-] rate, PDn, and genomic biomarkers may be conducted.  
Point estimates for MRD[-] rate along with exact 2-sided 95% confidence intervals will be 
calculated.  MRD measurements will be correlated with ORR, CRR, PFS, and other clinical 
variables to explore the relationship of MRD to disease response and progression. 
PDn will be determined from whole blood. 
For genomic biomarker analyses, WGS, WES, RNA-Seq, and/or other forms of nucleic acid 
and protein data will be analyzed to characterize whether drug response is related to 
alterations in genes regulated by or involved in activation of nuclear factor kappa light chain 
enhancer of activated B cells (NF-Kappa B) transcription factors as well as in genes involved 
in immunoglobulin production and protein homeostasis.  Immunoglobulin levels in tumor 
cells will be quantified by enzyme-linked immunosorbent assay (ELISA) and/or other protein 
quantification methods.  The genomic data as a whole will also be used to derive new 
hypotheses about mechanisms of drug response, resistance, and safety. 
Results from the subject convenience and satisfaction questionnaire will be summarized 
descriptively. 
13.6 
HANDLING OF MISSING DATA 
Missing data for partial dates for AEs or concomitant medication may be imputed according 
to prespecified, conservative imputation rules.  Details of missing data handling and 
imputation rules will be specified in the statistical analysis plan. 


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Subjects with no postbaseline response assessments will be classified as nonresponders in the 
estimation of ORR and CRR.  
Progression and survival data will be collected for all subjects on study.  For subjects who 
discontinue without having experienced progression or death, progression will be censored at 
the time of the last on-study disease assessment demonstrating lack of progression.  Details 
of censoring rules will be specified in the statistical analysis plan.  
13.7 
DETERMINATION OF SAMPLE SIZE 
Sample sizes are determined to provide preliminary information on safety, clinical activity, 
PDn, and PK.  
For the Dose-evaluation Component of the study, it is anticipated that approximately 
8 subjects will be enrolled in each dose cohort with 16 subjects total, should both cohorts be 
fully enrolled.  Assuming beta (0.5, 0.5) prior distribution for the DLT rate, 95% credible 
intervals for the DLT rate and the posterior probability of DLT rate being larger than 0.33 for 
each toxicity scenario are provided in Table 12.  For example, when 3 out of 8 subjects have 
DLTs, the posterior probability of the DLT rate being > 0.33 is 0.62. 


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Table 12 95%  Credible Intervals for the Dose-limiting Toxicity Rate and Probabilities 
of Dose-limiting Toxicity Rate Being Larger Than 0.33 
Cohort Size 
# DLTs 
Observed 
95% Credible Interval 
for the DLT Rate 
8 
0 
0 
0.26 
8 
1 
0.01 
0.45 
8 
2 
0.06 
0.59 
8 
3 
0.12 
0.71 
8 
4 
0.20 
0.80 
8 
5 
0.29 
0.88 
8 
6 
0.41 
0.94 
8 
7 
0.55 
0.99 
8 
8 
0.74 
1 
DLT = dose-limiting toxicity. 
With combined number of subjects in both dose finding and expansion components, 
38 RRMM subjects and 38 NDMM subjects will allow an approximately 86% probability to 
detect an occurrence of an AE with 5% incidence rate.   
13.8 
INTERIM ANALYSIS  
No formal interim analyses with the purpose of stopping the study early for efficacy or 
futility will be conducted for this study.  However, the following nonbinding boundaries are 
calculated to provide more information about the distribution of ORR for subjects with 
relapsed disease.  
For subjects with relapsed disease, under the null hypothesis of ORR ≤ 55%, the alternative 
hypothesis of ORR ≥ 75%, and the beta (0.65, 0.35) prior distribution for the true ORR, the 
boundaries for number of subjects with overall responses based on Bayesian predictive 
probability (Lee 2008) are listed below in Table 13. 


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Table 13 Boundaries for Number of Responding Subjects (Relapsed Disease Arm) 
Interim looks 
(# of subjects finishing 
4 cycles of treatment) 
Predictive probability 
of success < 0.05 
Predictive probability 
of success > 0.95 
8 
≤ 2 
≥ 8 
18 
≤ 8 
≥ 15 
28 
≤ 16 
≥ 21 
38 
≤ 25 
≥ 26 
Frequentist operating characteristics of the above boundaries are evaluated by simulations, 
which show that the overall type I error rate is controlled under 0.1 and the power is 
approximately 87%. 
14 
14.1 
COMPLIANCE STATEMENT 
ETHICAL AND ADMINISTRATIVE CONSIDERATIONS 
This study will be conducted in accordance with the protocol and with International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, as well as all 
applicable country and regional legal and regulatory requirements.  The investigator is 
responsible for ensuring that this protocol, the site’s ICF, and any other information that will 
be presented to potential subjects are reviewed and approved by the appropriate Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) prior to the enrollment of any 
study subjects. 
14.2 
INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the informed consent, investigator’s brochure (IB), 
and any other relevant supporting information to the appropriate IRB or IEC and the local 
regulatory agency (where required) for review and approval prior to study initiation. 
Amendments to the protocol must also be approved by the IRB/IEC and the local regulatory 
agency, as appropriate, prior to the implementation of changes in this study.  No protocol 
deviations are allowed.  However, the investigator may implement a deviation from, or a 
change of, the protocol to eliminate an immediate hazard(s) to the study subjects without 
prior IRB/IEC/sponsor approval/favorable opinion.  As soon as possible, the implemented 


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deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment, 
should be submitted to the IRB/IEC/sponsor.  Any deviations from the protocol must be fully 
explained and documented by the investigator. 
14.3 
INFORMED CONSENT AND HUMAN SUBJECT PROTECTION 
No investigator may involve a human being as a subject in research unless the investigator 
has obtained the legally effective informed consent of the subject or the subject’s legally 
authorized representative.  An investigator shall seek such consent only under circumstances 
that provide the prospective subject or the subject’s legally authorized representative 
sufficient opportunity to consider whether or not to participate, and that minimize the 
possibility of coercion or undue influence.  The information that is given to the subject or the 
representative shall be in a language understandable to the subject or representative. 
The sponsor or its designated representative will provide the investigator with a sample 
consent form.  Local and/or institutional requirements may require disclosure of additional 
information in the ICF.  Any changes to the consent form must be submitted to the sponsor or 
its designated representative for acceptance, prior to submission to the IRB/IEC.  
The IRB/IEC will review the consent form for approval.  A copy of the approved form must 
be submitted to the sponsor or its designated representative for its acceptance prior to 
initiation of the study.  Before implementing any study procedure on a particular subject, 
informed consent shall be documented in such subject’s case histories and by the use of a 
written consent form approved by the sponsor and 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. 
14.4 
DIRECT ACCESS TO SOURCE DATA, SOURCE DOCUMENTS, AND 
STUDY RECORDS 
The study will be carried out in keeping with applicable local laws and regulations.  
This may include an inspection by sponsor representatives/designees, and/or regulatory 


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authority representatives at any time.  The investigator/institution must agree to the 
inspection of study-related records by the regulatory authority/sponsor 
representatives/designees, and must allow direct access to source documents to the regulatory 
authority/sponsor representatives/ designees/IRB/IEC.  The investigator must allocate time 
(investigator and study staff) to discuss findings and relevant issues with the regulatory 
authority/sponsor representatives. 
14.5 
DATA COLLECTION AND HANDLING 
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 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, and other documents.  The sponsor will supply the eCRF, which will be completed in 
English. 
Data collection will involve the use of the EDC system, to which only authorized personnel 
will have access. 
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.  Detailed instructions may be found in the other study-specific documents. 
All entries made on the eCRF, must be verifiable against source documents.  In addition to 
periodic monitoring occurring within the system by study monitors, programmatic edit 
checks and data listings will be used to review the data for completeness, logic, and 
adherence to study protocol.  As a result of this monitoring and these checks, queries may be 
electronically issued to the clinical study sites and electronically resolved by those sites. 
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records.  Also, data will be stored and 
evaluated in such a way as to assure subject confidentiality in accordance with the legal and 
regulatory requirements applying to protected health information.  Study records (eg, copies 


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of eCRFs, regulatory documents) will be retained at the study site, along with adequate 
source documentation.  The study file and all source data should be retained for the time 
period required by applicable regulatory requirements and will not be destroyed until written 
notification is given by the sponsor or designee for destruction. 
14.6 
CONFIDENTIALITY 
All records identifying the subject will be kept confidential and, in accordance with the 
applicable laws and/or regulations, will not be made publicly available. 
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
on the case report form (CRF).  If the subject name appears on any other document 
(eg, pathologist report) or study materials (eg, biopsy tissue slides), then that information 
must be redacted before a copy of the document is supplied to the sponsor.  Study data stored 
on a computer will be stored in accordance with local data protection laws and regulations.  
Subjects will be informed in writing that representatives of the sponsor, IRB/IEC, or 
regulatory authorities may inspect their medical records to verify the information collected, 
and that all personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection laws and regulations. 
If the results of the study are published, the subject’s identity will remain confidential. 
The investigator will maintain a list to enable subjects’ records to be identified in accordance 
with applicable laws and regulations and according to the terms and agreed upon in such 
subjects’ signed consent forms. 
14.7 
PUBLICATION POLICY 
To coordinate dissemination of data from this study, Amgen may facilitate the formation of a 
publication committee consisting of several investigators and appropriate Amgen staff, the 
governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does not 
guarantee authorship.  The criteria described below are to be met for every publication. 


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Authorship of any publications resulting from this study will be determined on the basis of 
the International Committee of Medical Journal Editors Recommendations for the Conduct 
of Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states: 
• Authorship credit 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. 
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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15 
American Cancer Society. Cancer facts and figures 2014. American Cancer Society 2014. 
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Korde N, Zingone A, Kwok M, et al.  Phase II clinical and correlative study of carfilizomib, 
lenalidomide, and dexamethasone followed by lenalidome extended dosing (CRD-R) induces 
high rates of MRD negativity in newly diagnosed multiple myeloma (MM) patients. Blood. 
2013;122(21). ASH Annual Meeting 2013. Abstract 3220. 
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, Flinn I, Noga SJ, et al. Bortezomib, dexamethasone, cyclophosphamide and 
lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the 
multicenter EVOLUTION study. Leukemia. 2010;24(7):1350–56. 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clinical 
Trials. 2008;5(2):93–106.  
Millennium Pharmaceuticals, Inc. Velcade (bortezomib) full prescribing information. 2012. 
Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by 
immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic 
implications. Blood. 2002;99(12):4525–30. 
Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of 
bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-
inferiority study. Lancet Oncol. 2011;12(5):431–40. 
Moreau P, Richardson P, Cavo M, et al. Proteasome inhibitors in multiple myeloma: 10 years 
later. Blood. 2012;120:947-59. 
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. 
Niesvizky R, Martin TG III, Bensinger WI, et al. Phase Ib Dose-Escalation Study 
(PX-171-006) of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or 
Progressive Multiple Myeloma. Clin Cancer Res, 2013; 19(8); 1–9. 
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. 
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. 
Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase I, dose-escalation trial of 
lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin 
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combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010; 
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Richardson PG, Xie W, Jagannath S, et al. A phase 2 trial of lenalidomide, bortezomib, and 
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Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and 
dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142-52. 
Suzuki E, Demo S, Deu E, et al. Molecular mechanisms of bortezomib resistant 
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Wang M, Martin T, Bensinger W, et al. Phase 2 dose-expansion study (PX-171-006) of 
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APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS 
Assessment 
Screeninga 
Baselineb 
Cycles 1 through 18 
EOTc 
Active 
Follow-up 
D1 
D8 
D9 
D11 
D15 
D21 
D22 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical and treatment history 
X 
 
 
 
 
 
 
 
 
 
 
Time of pre-carfilzomib resting BP and time of 
dexamethasone administration (Cycles 1-6, 12, and 18) 
 
 
X 
X 
 
 
X 
 
 
 
 
Vital signs 
X 
 
X 
X 
 
 
X 
 
 
X 
 
Post-carfilzomib BP (Cycles 1-6, 12, and 18) 
 
 
X 
X 
 
 
X 
 
 
 
 
Physical examinationd and ECOG Performance Score 
X 
 
X 
 
 
 
 
 
 
X 
 
Hematology 
X 
 
X 
X 
 
 
X 
 
 
X 
 
Full serum chemistry panele 
X 
 
X 
 
 
 
 
 
 
X 
 
Abbreviated serum chemistry panelf 
 
 
 
X 
 
 
X 
 
 
 
 
Coagulation 
 
X 
 
 
 
 
 
 
 
X 
 
ECG (repeat if clinically indicated) 
X 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGA 
Dose–evaluation cohorts 
(Cycle 2 and as clinically indicated) 
X 
 
 
 
 
 
X 
 
 
X 
 
Dose–expansion arms 
(repeat if clinically indicated) 
X 
 
 
 
 
 
 
 
 
X 
 
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APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS (CONT’D) 
Assessment 
Screeninga 
Baselineb 
Cycles 1 through 18 
EOTc 
Active 
Follow-up 
D1 
D8 
D9 
D11 
D15 
D21 
D22 
Pregnancy testing 
(for FCBP) 
Serum (10–14 days prior to C1D1) 
X 
 
 
 
 
 
 
 
 
X 
 
Urine or serum Cycle 1 (predose) 
 
 
X 
X 
 
 
X 
 
X 
 
 
Urine or serum Cycle 2–18 
(predose; no menses) 
 
 
X 
 
 
 
 
 
 
 
 
Urine or serum Cycle 2–18 
(predose; irregular menses) 
 
 
X 
 
 
 
X 
 
 
 
 
SPEP/UPEP/immunofixation (except Cycle 1) 
X 
 
X 
 
 
 
 
 
 
X 
X 
Serum free light chains (except Cycle 1) 
X 
 
X 
 
 
 
 
 
 
X 
X 
Quantitative immunoglobulins (except Cycle 1) 
X 
 
X 
 
 
 
 
 
 
X 
X 
Beta-2 microglobulin 
 
X 
 
 
 
 
 
 
 
 
 
Skeletal survey (repeat if clinically indicated) 
 
X 
 
 
 
 
 
 
 
 
 
Plasmacytoma evaluation (if clinically indicated at 
baseline and repeat to confirm response) 
 
X 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate 
Percent plasma cell involvement (local 
lab):  Baseline and upon CR 
 
X 
 
 
 
 
 
 
 
 
 
FISH testing (central lab):  Baseline 
 
X 
 
 
 
 
 
 
 
 
 
MRD (central lab):  Baseline; Cycle 8 
Day 1; and upon achieving CR or sCR 
 
X 
Xg 
 
 
 
 
 
 
 
 
Genomics (optional; central lab; 
baseline is run on remaining sample 
after FISH):  Baseline, EOT, and active 
follow-up, if PD in subjects consenting 
to genomics evaluation 
 
X 
 
 
 
 
 
 
 
Xh 
Xh 
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APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS (CONT’D) 
Assessment 
Screeninga 
Baselineb 
Cycles 1 through 18 
EOTc 
Active 
Follow-up 
D1 
D8 
D9 
D11 
D15 
D21 
D22 
Blood for MRD/NGS (central lab): Baseline;  
Cycle 8  Day 1; and upon achieving CR or sCR 
 
X 
Xg 
 
 
 
 
 
 
 
 
Genomic Biomarkers blood and saliva (optional) 
 
X 
 
 
 
 
 
 
 
 
 
Plasma PK (Cycle 1 only) 
 
 
 
X 
 
 
 
 
 
 
 
Blood for PDn  
Cohorts 1-2 and first 8 subjects in Arm 3 (Cycle 1 
only) 
 
 
Xi 
Xi 
Xj 
Xj 
 
 
 
 
 
Questionnaire: patient convenience/satisfaction  
(Cycles 3 and 18 only) 
 
 
X 
 
 
 
 
 
 
 
 
IV hydration (Cycle 1 only) 
 
 
X 
X 
 
 
X 
 
 
 
 
Carfilzomib administration  
 
 
X 
X 
 
 
X 
 
 
 
 
Dexamethasone 
administrationk 
Cycles 1 to 8 
 
 
X 
X 
 
 
X 
 
X 
 
 
Cycles 9 to 18 
 
 
X 
X 
 
 
X 
 
 
 
 
Lenalidomide administration 
 
 
 
 
 
 
Adverse events 
 
Concomitant medications 
 
Footnotes defined on last page of table  
Page 3 of 3 
 
 
 
 
 
 
 


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BP = blood pressure; BSA = body surface area; CR = complete response; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end 
of treatment; FCBP = females of childbearing potential; FISH = fluorescent in situ hybridization; IV = intravenous (ly); MRD = minimal residual disease; 
MUGA = multigated acquisition; PD = progressive disease; PDn = pharmacodynamic(s); PK = pharmacokinetic(s); sCR = stringent complete response; 
SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis  
Details of Assessments are in the protocol body.  
a Screening samples can be collected within 21 days of Cycle 1 Day 1. 
b It is recommended that baseline samples are collected only after subject is enrolled. 
c EOT visit must be scheduled 28 ± 7 days after the last study treatment.  EOT ECHO must be performed within 28 ± 7 days after the last study treatment. 
d Height is only measured once at screening.  BSA is not calculated on Day1 of Cycle 1 or at EOT visit. 
e Full serum chemistry panel will also be collected on Days 8 and 15 of Cycle 1. 
f 
Abbreviated serum chemistry panel will be collected Cycle 2 onwards, Days 8 and 15 (as listed in table). 
g After baseline, collect aspirate and blood for MRD only on Day 1 Cycle 8, all subjects, and upon achieving a CR or sCR in all subjects. 
h Optional bone marrow aspirate to be collected upon progression of disease in subjects consenting to optional genomic biomarker analysis. 
i 
Predose and postdose.  
j 
On Days 9 and 11, when carfilzomib is not administered, collect 1 PDn sample at approximately the same time as when the pre-infusion sample was taken on 
Day 8. 
k Dexamethasone should be administered 30 minutes to 4 hours prior to initiation of carfilzomib infusion.   


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APPENDIX B 
ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Normal activity, fully active, able to carry on all predisease 
performance without restriction. 
1 
Symptoms, but fully ambulatory, restricted in physically 
strenuous but ambulatory and able to carry out work of a light or 
sedentary nature (eg, light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours. 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead 
Source:  Oken 1982. 
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 
 


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APPENDIX C 
INTERNATIONAL UNIFORM RESPONSE CRITERIA FOR 
MULTIPLE MYELOMA 
Summary of International Myeloma Working Group Uniform Response Criteria 
(IMWG-URC) 
Response 
Subcategory 
Multiple Myeloma Response Criteria 
sCR 
• Negative immunofixation on the serum and urine and
• Disappearance of any soft tissue plasmacytomas 
  
• < 5% plasma cells in bone marrow 
and 
and
• Normal SFLC ratio 
  
and
• Absence of clonal plasma cells in bone marrow by 
immunohistochemistry or 2- to 4-color flow cytometry  
  
CR 
• Negative immunofixation on the serum and urine and
• Disappearance of any soft tissue plasmacytomas 
  
• < 5% plasma cells in bone marrow  
and 
• In patients with measurable disease only by SFLC, normal SFLC ratio 
VGPR 
• Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or
• ≥ 90% reduction in serum M-component with urine M-component 
< 100 mg per 24 hours 
  
• In patients with measurable disease only by SFLC, a decrease ≥ 90% in 
the difference between involved and uninvolved FLC levels, in addition 
to VGPR criteria, is required 
PR 
• ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary 
M-protein by ≥ 90% or to < 200 mg per 24 hours (if both are 
measurable at baseline)  
• In patients with measurable disease only by SFLC, a decrease ≥ 50% in 
the difference between involved and uninvolved FLC levels is required 
in place of the M-protein criteria. 
• In addition to the above criteria, if present at baseline, ≥ 50% reduction 
in the size of soft tissue plasmacytomas is also required.  
Stable 
Disease 
• Not meeting criteria for CR, VGPR, PR, or PD 
 


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Summary of International Myeloma Working Group Uniform Response Criteria 
(IMWG-URC) (cont’d) 
PD 
• Increase of 25% from lowest response value in any of the following: 
o Serum M-component (absolute increase must be ≥ 0.5 g/dL) 
o Urine M-component (absolute increase must be ≥ 200 mg per 
24 hours) 
and/or 
o Only in patients without measurable serum and urine M-protein 
levels:  the difference between involved and uninvolved FLC 
levels (absolute increase must be >10 mg/dL) 
and/or 
• Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in size of existing bone lesions or 
soft tissue plasmacytomas  
• Development of hypercalcemia (corrected serum calcium 
> 11.5 mg/dL or 2.875 mmol/L) attributed solely to the plasma cell 
proliferative disorder 
CR = complete response; sCR = stringent complete response; FLC = serum free light chain; PD = progressive 
disease; PR = partial response; SFLC = serum free light chain; VGPR = very good partial response. 
 
All response categories (CR, sCR, VGPR, PR, PD) 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. 
For sCR:  presence/absence of clonal cells is based upon the kappa lambda (κ/λ) ratio.  An 
abnormal ratio reflecting presence of an abnormal clone is κ/λ > 4:1 or < 1:2. An abnormal 
kappa lambda ratio by immunohistochemistry and/or immunofluorescence requires a 
minimum of 100 plasma cells for analysis.  For CR:  A normal SFLC kappa lambda ratio is 
0.26 to 1.65. 
“Measurable” disease is defined by at least one of SPEP ≥ 0.5 g/dL, UPEP ≥ 200 mg per 
24 hours, or in subjects without detectable serum or urine M-protein, SFLC > 100 mg/L 
(involved light chain) and an abnormal kappa lambda ratio.  


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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.  
Plasmacytomas:  A definite increase in the size is defined as a ≥ 50% increase as measured 
serially by the sum of the products of the greatest orthogonal cross-diameters of the 
measurable lesions. A plasmacytoma is considered measurable if the longest diameter is at 
least 1 cm and the product of the greatest orthogonal cross-diameters is at least 1 cm2.  
Plasmacytomas of lesser size will be considered non-measurable. The requirement for bi-
directional measurements applies only to plasmacytomas. The plasmacytoma specifications 
for PD are based on the sponsor’s interpretation of the IMWG-URC and practical 
considerations for study execution. 
Sources: Durie 2006; Rajkumar 2011. 
 


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APPENDIX D 
SUBJECT CONVENIENCE AND SATISFACTION 
QUESTIONNAIRE 
 


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APPENDIX E 
FIGURES FROM PROTOCOL AMENDMENT 1 
Figure 2 Design Schematic for the Dose-evaluation Component for RRMM subjects 
(prior to Protocol Amendment 2) 
 
 
Figure 3 Design Schematic for the Dose-expansion Component (prior to Protocol 
Amendment 2) 
 


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APPENDIX F 
ADDITIONAL SAFETY ASSESSMENT INFORMATION 
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 (National Cancer Institute 2010).  For AEs not adequately addressed in the 
NCI-CTCAE version 4.03, Table 14 may be used. 
Table 14 Toxicity Grading for Adverse Events Not Covered in the 
NCI-CTCAE (Version 4.03) 
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 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 
ADL = activities of daily living; NCI-CTCAE = National Cancer Institute-Common Terminology 
Criteria for Adverse Events. 
 


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APPENDIX G 
SAMPLE eSERIOUS EVENT CONTINGENCY FORM 
 
 
 
 


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APPENDIX H 
PREGNANCY AND LACTATION NOTIFICATION 
WORKSHEETS 
 
 


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APPENDIX I  
SUMMARY OF CHANGES IN STUDY CFZ013 
AMENDMENT 3 
This Summary of Changes outlines noteworthy changes from protocol amendment 2.0 to 
protocol amendment 3.0, and includes rationales for the changes.  Administrative updates, 
typographical and formatting changes were made throughout the protocol.  The main 
purposes for revising the CFZ013 (20140241) protocol are listed below. 
Protocol amendment 3 specifies the dosing selected for newly diagnosed multiple 
myeloma (NDMM) Dose-expansion Arm 3.  The carfilzomib, lenalidomide, and 
dexamethasone (KRd) dosing for Arm 3 is as follows: carfilzomib 20 mg/m2 on Day 1 of 
Cycle 1, then 56 mg/m2 on Days 8 and 15 of Cycle 1, and Days 1, 8, and 15 of Cycles 
2-18.  Lenalidomide will be given at 25 mg on Days 1-21, and dexamethasone at 40 mg 
on Days 1, 8, 15, 22 of Cycles 1-8, and on Days 1, 8, and 15 of Cycles 9-18 (see Cohort 1 
dosing in Table 2). 
The pharmacokinetics (PK) and pharmacodynamics (PDn) sample collection schedule 
was modified to reflect the dosing selected.  Cycle 2 sampling that was introduced in 
protocol amendment 2, in anticipation of a 2-step-up dosing regimen, has been removed 
as it is not required for the dosing selected for Dose-expansion Arm 3. 
Two revisions were made in response to the carfilzomib US Prescribing Information 
(USPI) labelling change approved by FDA in November 2016, which required a 25% 
dose reduction in patients with mild or moderate hepatic impairment: 
• Table 9 (Treatment Guidelines for Nonhematologic Toxicity) has been modified 
to align with requested changes.  Specifically, NCI Organ Dysfunction Working 
Group definition of mild, moderate and severe hepatic impairment were used 
(Shibata et al, 2013): 
o mild: total bilirubin (>33% direct) > the upper limit of normal (ULN) 
and ≤ 1.5x ULN OR total bilirubin (>33% direct) ≤ ULN and alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) > ULN;  
o moderate: total bilirubin  .5x ULN and ≤ 3x ULN, any ALT or AST;  
o severe: total bilirubin > 3x ULN, any ALT or AST.   
Subjects with treatment-emergent mild or moderate hepatic impairment, per 
this definition, are to have a 25% carfilzomib dose reduction.  In cases of severe 


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hepatic impairment, carfilzomib is to be held.  In moderate or severe hepatic 
impairment, lenalidomide is to be held. 
• Inclusion criteria have been modified in Section 6.1.  Previous protocol 
amendments allowed enrollment of subjects with baseline mild hepatic 
insufficiency.  With protocol amendment 3 (under which only the NDMM dose-
expansion Arm 3 subjects will be enrolled), subjects will be required to have 
normal hepatic function.  The intent of this modification is to maximize the 
ability to give full, protocol-specified 20/56 mg/m2 carfilzomib dosing to the 
enrolled NDMM subjects. 
Other minor changes: 
• To maintain internal consistency of the document, Dose-expansion groups are 
uniformly referred to “Arms” with the term “Cohort” reserved for Dose-
evaluation groups.  
• 
Changed the duration of enrollment from 8 to 12 months. 


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Description of Changes  
Section: Global 
Change:   
Minor typographic and formatting errors were corrected throughout the protocol.   
Section: Title page 
Add:  
Amendment 3: 
13 December 2016 
Section: Protocol Acceptance Page 
Replace:   
CFZ013 Amendment 2/14 October 2016 
With: 
CFZ013 Amendment 3/13 December 2016 
Section: Synopsis (Study design)  
Paragraph 7 
Delete: 
All subjects will be evaluated for safety at an End of Treatment (EOT) visit, 28 ± 7 days 
after the last study treatment, and with an EOT echocardiogram (ECHO), done within 
scheduled 28 ± 7 days after the last study treatment. 
Section: Synopsis (Treatment regimen[s]) 
Paragraph 4 
Delete: 
Cohort 2 (RRMM and NDMM): 


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Section: Synopsis (Treatment regimen[s]) 
Paragraph 11 
Replace: 
If a regimen evaluated during the Dose-evaluation Component is safe and tolerable, 
approximately 30 additional subjects may be enrolled for treatment with that regimen in 
the Dose-expansion Component. 
Dose-expansion Component 
With: 
If a regimen evaluated during the Dose-evaluation Component is safe and tolerable, 
approximately 30 additional subjects may be enrolled for treatment with that regimen in a 
Dose-expansion arm. 
Dose-expansion Component 
Section: Synopsis (Inclusion criteria) and Section 6.1 
Inclusion criterion 7 
Delete:  
7. 
Adequate hepatic function within 21 days prior to Cycle 1 Day 1: 
a. 
Bilirubin < 1.5 times the upper limit of normal (ULN) 
b. 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 
3 times the ULN 
Section: Synopsis (Inclusion criteria) and Section 6.1 
Add: 
15. Normal hepatic function within 21 days prior to Cycle 1 Day 1: 
a. Bilirubin ≤ the upper limit of normal (ULN) 
b. Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ the ULN 
Section: Synopsis (PK)  
Replace: 
For both the Dose-evaluation and the Dose-expansion Components, blood samples will 
be collected from all subjects for determination of plasma concentrations of carfilzomib.  
For NDMM subjects, blood will be collected on Day 1 of Cycle 2; for the remaining 


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subjects, blood will be collected on Day 8 of Cycle 1.   
With: 
For both the Dose-evaluation and the Dose-expansion Components, blood samples will 
be collected from all subjects on Day 8 of Cycle 1 for determination of plasma 
concentrations of carfilzomib.  For NDMM subjects, blood will be collected on Day 1 of 
Cycle 2; for the remaining subjects, blood will be collected on Day 8 of Cycle 1.   
Section: Synopsis (PDn)  
Replace: 
Whole blood will be collected from all subjects in the Dose evaluation Component on 
Days 1, 8, 9, and 11 of Cycle 1.  On Days 1 and 8 of Cycle 1 whole blood will be 
collected pre-carfilzomib dose and post-carfilzomib dose.  On Days 9 and 11 of Cycle 1, 
when carfilzomib is not administered, one PDn sample will be collected at approximately 
the same time as when the pre-infusion sample was taken on Day 8. 
For the first 8 NDMM subjects enrolled under protocol amendment 2, whole blood will 
be collected pre-carfilzomib dose and post-carfilzomib dose on Cycle 1 Day 1 and Cycle 
2 Day 1; post-carfilzomib dose on Days 8 and 15 of Cycles 1-2. 
Per protocol amendment 2: 
With: 
Whole blood will be collected from all subjects in the Dose-evaluation Component, and 
the first 8 subjects enrolled in Dose-expansion Arm 3, on Days 1, 8, 9, and 11 of Cycle 
1.  On Days 1 and 8 of Cycle 1 whole blood will be collected pre-carfilzomib dose and 
post-carfilzomib dose.  On Days 9 and 11 of Cycle 1, when carfilzomib is not 
administered, one PDn sample will be collected at approximately the same time as when 
the pre-infusion sample was taken on Day 8. 
Per protocol amendment 2: 
For the first 8 NDMM subjects enrolled under protocol amendment 2, whole blood will 
be collected pre-carfilzomib dose and post-carfilzomib dose on Cycle 1 Day 1 and Cycle 
2 Day 1; post-carfilzomib dose on Days 8 and 15 of Cycles 1-2. 


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Section: 3.4 DOSE RATIONALE 
Paragraph 1 
Replace: 
The dose rationale for this study derives from considerations of carfilzomib, 
lenalidomide, and dexamethasone dose combinations that are currently in use, as shown 
in Table 1.  Dose combinations for this study are shown in Table 2.  Prior to protocol 
amendment 2, dose-evaluation cohorts were planned only for RRMM subjects (Cohorts 
1, 2, and 3).  Schemas for enrollment prior to protocol amendment 2 are shown in 
Appendix E (Figure 2 and Figure 3).  Per protocol amendment 2, Dose-evaluation cohorts 
are added for NDMM subjects. 
With: 
The dose rationale for this study derives from considerations of carfilzomib, 
lenalidomide, and dexamethasone dose combinations that are currently in use, as shown 
in Table 1.  Dose combinations for this study are shown in Table 2.  Prior to protocol 
amendment 2, dose-evaluation cohorts were planned only for RRMM subjects (Cohorts 
1, 2, and 3).  Schemas for enrollment prior to protocol amendment 2 are shown in 
Appendix E (Figure 2 and Figure 3).  With protocol amendment 2, a Dose-evaluation 
cohort is added for NDMM subjects.   
Section: 3.4 DOSE RATIONALE 
Paragraph 3 
Replace: 
A 2-step-up KRd regimen will be evaluated in NDMM subjects: carfilzomib will be 
given at 20 mg/m2 on Day 1 of Cycle 1, 56 mg/m2 on Days 8 and 15 of Cycle 1, then 
70 mg/m2 on Days 1, 8, and 15 beginning with Cycle 2 (Cohort 4; Table 2).  This 
regimen was selected by the Cohort Safety Review Committee (CSRC) for Dose-
evaluation in NDMM subjects, after the occurrence of 2 SAEs in NDMM subjects during 
Cycle 1 of treatment at Cohort 2 dose-level during the Dose-expansion Component. 
Cohort 4 


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With: 
A 2-step-up KRd regimen will be evaluated in NDMM subjects: carfilzomib will be 
given at 20 mg/m2 on Day 1 of Cycle 1, 56 mg/m2 on Days 8 and 15 of Cycle 1, then 
70 mg/m2 on Days 1, 8, and 15 beginning with Cycle 2 (Cohort 4; Table 2).  This 
regimen was selected by the Cohort Safety Review Committee (CSRC) for Dose-
evaluation in NDMM subjects, after the occurrence of 2 SAEs in NDMM subjects during 
Cycle 1 of treatment at Cohort 2 dose-level (Arm 1). 
Cohort 4 
Section: 5 STUDY DESIGN 
Paragraph 7-10 
Replace: 
The first part is the Dose-evaluation Component during which carfilzomib combination 
regimens will be evaluated (Table 2 and Figure 1).  Approximately 8 dose-limiting 
toxicity evaluable subjects will be enrolled into each opened Dose-evaluation cohort.  
Before opening Dose-expansion cohorts, it must be determined that there are not more 
than 2 dose-limiting toxicities in 8 DLT-evaluable subjects at the dose selected for Dose-
expansion.  Dose-expansion cohorts may open once all safety data for at least 1 cycle at 
maximal dose carfilzomib is reviewed by the CSRC.   
The second part is the Dose-expansion Component.  
Prior to protocol amendment 2, dose evaluation was performed on RRMM subjects 
treated at Cohort 1 and Cohort 2 dosing (Table 2).  Cohort 2 dosing was selected for 
expansion with a plan for approximately 30 RRMM subjects and 30 NDMM subjects to 
be treated in the Dose-expansion Component (Appendix E; Figure 2 and Figure 3).   
In the first 8 NDMM subjects treated in Dose-expansion at Cohort 2 dosing, 2 SAEs were 
observed during Cycle 1 (Table 2).  Thus, per protocol amendment 2, a Dose-evaluation 
Cohort 4 is added for NDMM subjects (Table 2 and Figure 1).  A Dose-expansion cohort 
for NDMM subjects may open once all safety data for at least 1 cycle at maximal planned 
carfilzomib dose is reviewed by the CSRC as described in Section 5.4.  


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With: 
The first part is the Dose-evaluation Component during which carfilzomib combination 
regimens will be evaluated (Table 2 and Figure 1).  Approximately 8 dose-limiting 
toxicity evaluable subjects will be enrolled into each opened Dose-evaluation cohort.  
Before opening Dose-expansion arms, it must be determined that there are not more than 
2 dose-limiting toxicities in 8 DLT-evaluable subjects at the dose selected for 
Dose-expansion.  Dose-expansion arms may open once all safety data for at least 1 cycle 
at maximal dose carfilzomib is reviewed by the CSRC.   
The second part is the Dose-expansion Component.  
Prior to protocol amendment 2, dose evaluation was performed on RRMM subjects 
treated at Cohort 1 and Cohort 2 dosing (Table 2).  Cohort 2 dosing was selected for 
expansion with a plan for approximately 30 RRMM subjects and 30 NDMM subjects to 
be treated in the Dose-expansion Component (Arms 1 and 2; Appendix E; Figure 2 and 
Figure 3).   
In the first 8 NDMM subjects treated in Dose-expansion Arm 1 at Cohort 2 dosing, 
2 SAEs were observed during Cycle 1 (Table 2).  Thus, with protocol amendment 2, a 
Dose-evaluation Cohort 4 is added for NDMM subjects (Table 2 and Figure 1).  A 
Dose-expansion arm for NDMM subjects may open once all safety data for at least 
1 cycle at maximal planned carfilzomib dose is reviewed by the CSRC as described in 
Section 5.4.   


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Section: 5 STUDY DESIGN 
Figure 1 
Replace: 
 


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With: 
 
Section: 5.1 STUDY POPULATION 
Paragraph 2 
Add: 
Prior to protocol amendment 2, subjects with newly diagnosed, previously untreated 
multiple myeloma were included only in the Dose-expansion Component 
(Appendix E; Figure 2, Arm 1).  After protocol amendment 2, NDMM subjects will be 


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enrolled into a NDMM Dose-evaluation cohort, which may be expanded after safety 
evaluation by the CSRC (Arm 3, Figure 1). 
Section: 5.4 
PART 1:  DOSE-EVALUATION COMPONENT 
Paragraph 4 
Replace: 
A 2-step-up KRd regimen will be evaluated in NDMM subjects: carfilzomib will be 
given at 20 mg/m2 on Day 1 of Cycle 1, 56 mg/m2 on Days 8 and 15 of Cycle 1, then at 
70 mg/m2 on Days 1, 8, and 15 beginning with Cycle 2 (Cohort 4; Table 2).  This 
regimen was selected by the CSRC for dose-evaluation in NDMM subjects, after the 
occurrence of 2 SAEs in NDMM subjects during Cycle 1 of treatment at Cohort 2 dose 
level during the first NDMM Dose-expansion Component. 
With: 
A 2-step-up KRd regimen will be evaluated in NDMM subjects: carfilzomib will be 
given at 20 mg/m2 on Day 1 of Cycle 1, 56 mg/m2 on Days 8 and 15 of Cycle 1, then at 
70 mg/m2 on Days 1, 8, and 15 beginning with Cycle 2 (Cohort 4; Table 2).  This 
regimen was selected by the CSRC for dose-evaluation in NDMM subjects, after the 
occurrence of 2 SAEs in NDMM subjects during Cycle 1 of treatment at Cohort 2 dose 
level during the Arm 1 NDMM Dose-expansion (Figure 1). 
Section: 5.5 
PART 2:  DOSE-EXPANSION COMPONENT 
Paragraph 3 
Replace: 
The CSRC will evaluate all safety data for all NDMM subjects following the rules above.  
The CSRC may elect to open an NDMM Dose-expansion cohort for 2-step-up KRd 
dosing, and may enroll an additional 30 NDMM subjects (Section 5.4).    
With: 
The CSRC will evaluate all safety data for all NDMM subjects.  Following the DLT 
rules above, the CSRC may elect to open an NDMM Dose-expansion arm, and may 
enroll an additional 30 NDMM subjects (Section 5.4). 


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Section: 5.7 
ESTIMATED STUDY DURATION AND STUDY CLOSURE 
Paragraph 2 
Replace: 
It will take up to approximately 8 months to enroll NDMM subjects into Dose-evaluation 
Cohort 4, review the safety data, and enroll NDMM subjects into the NDMM 
Dose-expansion Component.  Subjects will be followed for up to 17 months on treatment 
(with an allowed interruption of up to 4.5 months for ASCT), and for 12 months for 
Active Follow up. 
With: 
It will take up to approximately 12 months to enroll NDMM subjects into Dose-
evaluation Cohort 4, review the safety data, and enroll NDMM subjects into the NDMM 
Dose-expansion Arm 3.  Subjects will be followed for up to 17 months on treatment 
(with an allowed interruption of up to 4.5 months for ASCT), and for 12 months for 
Active Follow up. 
Section: 9.2.1.2 
Lenalidomide 
Paragraph 2 
Replace: 
For FCBP, nonpregnant state must be documented prior to the first dose of lenalidomide, 
every week for the first cycle, and prior to the start of each subsequent cycle.   
With: 
For FCBP, nonpregnant state must be documented prior to the first dose of lenalidomide, 
every week for the first cycle, and prior to the start of each subsequent cycle, and at 
EOT.   


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Section: 9.2.2.2 
Nonhematologic Toxicity 
Replace: 
Table 9 
Treatment Guidelines for Nonhematologic Toxicity 
Symptom 
Recommended Action 
Lenalidomide 
Carfilzomib 
Blood and Lymphatic System 
Thrombotic microangiopathy 
(TMA) Fever, microangiopathic 
hemolytic anemia, 
thrombocytopenia, renal failure, 
neurologic changes 
If the diagnosis is suspected, stop lenalidomide and carfilzomib and 
manage per standard of care including plasma exchange as 
clinically appropriate.  If TMA is confirmed and related to 
lenalidomide or carfilzomib, permanently discontinue.  If the 
diagnosis of TMA is excluded, lenalidomide and carfilzomib 
dosing may be resumed at full dose if clinically appropriate. 
Cardiac 
Congestive heart failure 
Full dose 
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. 
Hypertensive crisis 
Sustained or persistent  
SBP ≥ 180 mm Hg or  
DBP ≥ 110 mm Hg 
Full dose 
Hold carfilzomib until 
resolution to baseline, then 
resume at 1 dose decrement 
LVEF Reduction 
< 40% or 
< 55% if the drop is greater than 
20% from baseline 
Full dose 
Hold carfilzomib until LVEF 
returns to ≥ 40% or, if held due 
to a drop to < 55%, to within 
15% of baseline.  Resume at 
1 dose decrement. 
Infections and Infestations 
Infection 
Grade 3 or 4 
Hold both lenalidomide and carfilzomib until systemic treatment 
for infection is complete.  If ANC > 1,000/µL, resume both drugs at 
full dose.  If ANC < 1,000/µL, follow hematologic toxicities 
dosage guidelines. 
Investigations 
Elevation of AST, ALT, or total 
bilirubin 
 Grade 3 or 4 
Hold lenalidomide until 
resolution to baseline, then 
resume at full dose. 
Hold carfilzomib until 
resolution to baseline, then 
resume at 1 dose decrement. 
Page 1 of 3 
Footnotes defined on last page of table 


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Table 9  Treatment Guidelines for Nonhematologic Toxicity (cont’d) 
Symptom 
Recommended Action 
Lenalidomide 
Carfilzomib 
Investigations (cont’d) 
CrCla  
≥ 30 and < 50 mL/min 
Reduce dose to 10 mg once 
daily. 
Full dose 
CrCla  
≥ 15 and < 30 mL/min 
(NCI-CTCAE Grade 3) 
Hold dose.  If CrCl recovers 
resume dose at 1 dose 
decrement.  If significant CrCl 
reduction reappears then 
reduce dose to 15 mg every 
48 hours.  Further dose 
modification will be based on 
individual subject treatment 
tolerance. 
Full dose 
CrCla 
< 15 mL/min 
(NCI-CTCAE Grade 4) 
Hold dose.  If CrCl recovers to 
baseline, resume dose at 1 dose 
decrement.  If significant CrCl 
reduction reappears reduce 
dose to 15 mg every 48 hours.  
If dialysis required, reduce 
dose to 5 mg once daily 
(administer the lenalidomide 
after dialysis on dialysis days).  
Further dose modification will 
be based on individual subject 
treatment tolerance. 
Hold dose.  When CrCl 
returns to ≥ 15 mL/ minute, 
resume same dose.  If dialysis 
required, contact the medical 
monitor. 
Metabolism 
Tumor Lysis Syndrome 
3 or more of the following: 
• increase in creatinine of ≥ 50% 
• increase in uric acid, of ≥ 50% 
• increase in phosphate of ≥ 50% 
• increase in potassium of ≥ 30% 
• decrease in calcium, OR 
• increase in LDH of ≥ 2-fold 
from baseline 
Hold both lenalidomide and carfilzomib until all abnormalities 
in serum chemistries have resolved; resume at full dose. 
Nervous System Disorders 
Neuropathy 
Treatment-emergent painful 
grade 2, or grade 3 
Full dose 
Hold carfilzomib until 
resolution to ≤ grade 2 
without pain, then resume at 
1 dose decrement 
Neuropathy 
Grade 4 
Discontinue 
Discontinue 
Page 2 of 3 
Footnotes defined on last page of table 
 


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Table 9  Treatment Guidelines for Nonhematologic Toxicity (cont’d) 
Symptom 
Recommended Action 
Lenalidomide 
Carfilzomib 
Nervous System Disorders (cont’d) 
Posterior Reversible 
Encephalopathy Syndrome (PRES)
  
headaches, altered mental 
 status, seizures, visual loss and 
 hypertension 
If PRES is suspected, hold lenalidomide and carfilzomib.  
Consider neuroradiographic imaging, specifically MRI, to 
evaluate onset of visual or neurological symptoms suggestive of 
PRES.  If the diagnosis of PRES is excluded lenalidomide and 
carfilzomib dosing may resume at the same dose, if clinically 
appropriate.  If condition recurs, permanently discontinue 
carfilzomib. 
Respiratory 
Dyspnea 
Grade 2, 3 or 4 
Full dose 
Hold carfilzomib until 
resolution to baseline, then 
resume at 1 dose decrement 
Pulmonary hypertension: (≥Grade 3) 
 
Full dose 
Hold carfilzomib until 
resolution to baseline, then 
resume at 1 dose decrement 
Pulmonary toxicity 
Interstitial lung disease, acute 
respiratory failure, ARDS 
(≥Grade 3) 
Hold lenalidomide until 
resolution to baseline then 
resume full dose 
Hold carfilzomib until 
resolution to baseline, then 
resume at 1 dose decrement 
Other Symptoms Not Listed Above 
Any other drug-related 
nonhematologic 
toxicity ≥ Grade 3b 
For lenalidomide attribution, 
hold dose. 
Resume at 1 dose decrement 
when toxicity has resolved to 
Grade 1 or less or to baseline 
grade. 
For carfilzomib attribution, 
hold dose. 
Resume at 1 dose decrement 
when toxicity has resolved to 
Grade 1 or less or to baselinec 
grade.   
Page 3 of 3 
 
With: 
 


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Table 1 
Treatment Guidelines for Nonhematologic Toxicity 
Symptom 
Recommended Action 
Lenalidomide 
Carfilzomib 
Blood and Lymphatic System 
Thrombotic microangiopathy (TMA) 
Fever, microangiopathic hemolytic 
anemia, thrombocytopenia, renal 
failure, neurologic changes 
If the diagnosis is suspected, stop lenalidomide and 
carfilzomib and manage per standard of care including 
plasma exchange as clinically appropriate.  If TMA is 
confirmed and related to lenalidomide or carfilzomib, 
permanently discontinue.  If the diagnosis of TMA is 
excluded, lenalidomide and carfilzomib dosing may be 
resumed at full dose if clinically appropriate. 
Cardiac 
Congestive heart failure 
Full dose 
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. 
Hypertensive crisis 
Sustained or persistent  
SBP ≥ 180 mm Hg or  
DBP ≥ 110 mm Hg 
Full dose 
Hold carfilzomib until resolution to 
baseline, then resume at 1 dose 
decrement 
LVEF Reduction 
< 40% or 
< 55% if the drop is greater than 20% 
from baseline 
Full dose 
Hold carfilzomib until LVEF 
returns to ≥ 40% or, if held due to a 
drop to < 55%, to within 15% of 
baseline.  Resume at 1 dose 
decrement. 
Infections and Infestations 
Infection 
Grade 3 or 4 
Hold both lenalidomide and carfilzomib until systemic 
treatment for infection is complete.  If ANC > 1,000/µL, 
resume both drugs at full dose.  If ANC < 1,000/µL, 
follow hematologic toxicities dosage guidelines. 
Hepatic Dysfunction and Related Investigations 
Mild liver dysfunction, defined as 
2 consecutive values, at least 28 days 
apart, of:  
(1) total bilirubin ( > 33% direct)  
> 1x ULN to < 1.5x ULN 
 OR  
(2) an elevation of AST and/or ALT 
with normal bilirubin 
Full dose. 
25% dose reduction.   
Dose may be re-escalated if liver 
function tests return to normal 
and drug-induced hepatotoxicity 
is excluded. 
Page 1 of 3 
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Table 9  Treatment Guidelines for Nonhematologic Toxicity (cont’d) 
Symptom 
Recommended Action 
Lenalidomide 
Carfilzomib 
Hepatic Dysfunction and Related Investigations (cont’d) 
Moderate liver 
dysfunction, defined as 
2 consecutive values, at 
least 28 days apart, of 
total bilirubin 
( > 33% direct) > 
1.5x ULN to < 3x ULN 
Hold lenalidomide until resolution to 
baseline, then resume at full dose. 
25% dose reduction.   
Dose may be re-escalated if 
liver function tests return 
to normal and 
drug-induced 
hepatotoxicity is excluded. 
Grade 3 elevation in ALT 
and/or AST 
( > 5x ULN) 
Hold lenalidomide until resolution to 
baseline, then resume at full dose. 
Hold carfilzomib until 
resolution to baseline.  
Monitor any abnormality 
weekly.  
Resume carfilzomib with a 
25% dose reduction if 
drug-induced 
hepatotoxicity is excluded. 
Grade 3 elevation in total 
bilirubin 
Hold lenalidomide until resolution to 
baseline, then resume at full dose. 
Hold carfilzomib until 
resolution to baseline.   
Monitor total bilirubin and 
direct bilirubin weekly.  
Upon resolution of total 
bilirubin to normal, resume 
carfilzomib dosing with a 
25% dose reduction if 
drug-induced 
hepatotoxicity is excluded. 
Renal Dysfunction 
CrCla  
≥ 30 and < 50 mL/min 
Reduce dose to 10 mg once daily. 
Full dose 
CrCla  
≥ 15 and < 30 mL/min 
(NCI-CTCAE Grade 3) 
Hold dose.  If CrCl recovers resume 
dose at 1 dose decrement.  If significant 
CrCl reduction reappears then reduce 
dose to 15 mg every 48 hours.  Further 
dose modification will be based on 
individual subject treatment tolerance. 
Full dose 
CrCla 
< 15 mL/min 
(NCI-CTCAE Grade 4) 
Hold dose.  If CrCl recovers to 
baseline, resume dose at 1 dose 
decrement.  If significant CrCl 
reduction reappears reduce dose to 
15 mg every 48 hours.  If dialysis 
required, reduce dose to 5 mg once 
daily (administer the lenalidomide after 
dialysis on dialysis days).  Further dose 
modification will be based on 
individual subject treatment tolerance. 
Hold dose.  When CrCl 
returns to ≥ 15 mL/ minute, 
resume same dose.  If 
dialysis required, contact the 
medical monitor. 
Page 2 of 3 
Footnotes defined on last page of table 


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Table 9  Treatment Guidelines for Nonhematologic Toxicity (cont’d) 
Symptom 
Recommended Action 
Lenalidomide 
Carfilzomib 
Metabolism 
Tumor Lysis Syndrome 
3 or more of the following: 
• increase in creatinine of ≥ 50% 
• increase in uric acid of ≥ 50% 
• increase in phosphate of ≥ 50% 
• increase in potassium of ≥ 30% 
• decrease in calcium, OR 
increase in LDH of ≥ 2-fold from 
baseline 
Hold both lenalidomide and carfilzomib until all abnormalities in 
serum chemistries have resolved; resume at full dose. 
Nervous System Disorders  
Neuropathy 
Treatment-emergent painful 
grade 2, or grade 3 
Full dose 
Hold carfilzomib until resolution 
to ≤ grade 2 without pain, then 
resume at 1 dose decrement 
Neuropathy 
Grade 4 
Discontinue 
Discontinue 
Posterior Reversible Encephalopathy 
Syndrome (PRES) 
 
headaches, altered mental 
 status, seizures, visual loss and 
 hypertension 
If PRES is suspected, hold lenalidomide and carfilzomib.  
Consider neuroradiographic imaging, specifically MRI, to 
evaluate onset of visual or neurological symptoms suggestive of 
PRES.  If the diagnosis of PRES is excluded lenalidomide and 
carfilzomib dosing may resume at the same dose, if clinically 
appropriate.  If condition recurs, permanently discontinue 
carfilzomib. 
Respiratory 
Dyspnea 
Grade 2, 3 or 4 
Full dose 
Hold carfilzomib until resolution 
to baseline, then resume at 1 dose 
decrement 
Pulmonary hypertension: (≥Grade 3) 
 
Full dose 
Hold carfilzomib until resolution 
to baseline, then resume at 1 dose 
decrement 
Pulmonary toxicity 
Interstitial lung disease, acute 
respiratory failure, ARDS 
(≥Grade 3) 
Hold lenalidomide until 
resolution to baseline then 
resume full dose 
Hold carfilzomib until resolution 
to baseline, then resume at 1 dose 
decrement 
Other Symptoms Not Listed Above 
Any other drug-related 
nonhematologic 
toxicity ≥ Grade 3b 
For lenalidomide attribution, 
hold dose. 
Resume at 1 dose decrement 
when toxicity has resolved to 
Grade 1 or less or to baseline 
grade. 
For carfilzomib attribution, hold 
dose. 
Resume at 1 dose decrement 
when toxicity has resolved to 
Grade 1 or less or to baselinec 
grade.   
Page 3 of 3 
 


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Section: 10.2.1 
PHARMACOKINETIC MEASUREMENTS 
Paragraph 1 
Replace: 
For both the Dose-evaluation and the Dose-expansion Components, blood samples will 
be collected from all subjects for determination of plasma concentrations of carfilzomib.  
Subjects enrolled prior to protocol amendment 2: PK samples will be collected on 
treatment Day 8 of Cycle 1.  Subjects enrolled under protocol amendment 2: PK samples 
will be collected on Day 1 of Cycle 2. 
With: 
For both the Dose-evaluation and the Dose-expansion Components, blood samples will 
be collected from all subjects on Day 8 of Cycle 1 for determination of plasma 
concentrations of carfilzomib.  Subjects enrolled prior to protocol amendment 2: PK 
samples will be collected on treatment Day 8 of Cycle 1.  Subjects enrolled under 
protocol amendment 2: PK samples will be collected on Day 1 of Cycle 2.   
Section: 10.2.2 
PHARMACODYNAMIC MEASUREMENTS 
Paragraphs 2 and 3 
Replace: 
For the Dose-evaluation component Cohorts 1 and 2 whole blood will be collected (pre-
carfilzomib dose and post-carfilzomib dose) from all subjects on Days 1 and 8 of Cycle 1.  
On Days 9 and 11 of Cycle 1, when carfilzomib is not administered, one PDn sample will 
be collected at approximately the same time as when the pre-infusion sample was taken 
on Day 8. 
For the first 8 NDMM subjects enrolled in Cohort 4 under protocol amendment 2, whole 
blood will be collected pre-carfilzomib dose and post-carfilzomib dose on Cycle 1 Day 1 
and Cycle 2 Day 1; post-carfilzomib dose on Days 8 and 15 of Cycles 1 and 2. 
With: 
For the Dose-evaluation component Cohorts 1 and 2, and the first 8 subjects enrolled 
into Dose-expansion Arm 3, whole blood will be collected (pre-carfilzomib dose and 
post-carfilzomib dose) from all subjects.  On Days 1 and 8 of Cycle 1, whole blood will 


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be collected pre-carfilzomib dose and post-carfilzomib dose.  On Days 9 and 11 of 
Cycle 1, when carfilzomib is not administered, one PDn sample will be collected at 
approximately the same time as when the pre-infusion sample was taken on Day 8. 
For the first 8 NDMM subjects enrolled in Cohort 4 under protocol amendment 2, whole 
blood will be collected pre-carfilzomib dose and post-carfilzomib dose on Cycle 1 Day 1 
and Cycle 2 Day 1; post-carfilzomib dose on Days 8 and 15 of Cycles 1 and 2. 
 
Section: 13.8 INTERIM ANALYSIS 
Delete: 
For subjects with relapsed disease, under the null hypothesis of ORR ≤ 55%, the 
alternative hypothesis of ORR ≥ 75%, and the beta (0.65, 0.35) prior distribution for the 
true ORR, the boundaries for number of subjects with overall responses based on 
Bayesian predictive probability (Lee 2008) are listed below in Table 13Table 13.  
Section: 15 
REFERENCES 
Add: 
Shibata S, Chung V, Synold TW, et al.  Phase I study of pazopanib in patients with 
advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ 
Dysfunction Working Group study. Clin Cancer Res. 2013;19(13):3631-3639. 
 


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Section: Appendix A SCHEDULE OF STUDY ASSESSMENTS 
Replace: 
APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS 
Assessment 
Screening
a 
Baselineb 
Cycles 1 through 18 
EOTc 
Active 
Follow-up 
D1 
D8 
D9 
D11 
D15 
D21 
D22 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical and treatment history 
X 
 
 
 
 
 
 
 
 
 
 
Time of pre-carfilzomib resting BP and time of 
dexamethasone administration (Cycles 1-6, 12, and 18) 
 
 
X 
X 
 
 
X 
 
 
 
 
Vital signs 
X 
 
X 
X 
 
 
X 
 
 
X 
 
Post-carfilzomib BP (Cycles 1-6, 12, and 18) 
 
 
X 
X 
 
 
X 
 
 
 
 
Physical examinationd and ECOG Performance Score 
X 
 
X 
 
 
 
 
 
 
X 
 
Hematology 
X 
 
X 
X 
 
 
X 
 
 
X 
 
Full serum chemistry panele 
X 
 
X 
 
 
 
 
 
 
X 
 
Abbreviated serum chemistry panelf 
 
 
 
X 
 
 
X 
 
 
 
 
Coagulation 
 
X 
 
 
 
 
 
 
 
X 
 
ECG (repeat if clinically indicated) 
X 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGA 
Dose–evaluation cohorts 
(Cycle 2 and as clinically indicated) 
X 
 
 
 
 
 
X 
 
 
X 
 
Dose–expansion cohorts 
(repeat if clinically indicated) 
X 
 
 
 
 
 
 
 
 
X 
 
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APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS (CONT’D) 
Assessment 
Screeninga 
Baselineb 
Cycles 1 through 18 
EOTc 
Active 
Follow-up 
D1 
D8 
D9 
D11 
D15 
D21 
D22 
Pregnancy testing 
(for FCBP) 
Serum (10–14 days prior to C1D1) 
X 
 
 
 
 
 
 
 
 
X 
 
Urine or serum Cycle 1 (predose) 
 
 
X 
X 
 
 
X 
 
X 
 
 
Urine or serum Cycle 2–18 
(predose; no menses) 
 
 
X 
 
 
 
 
 
 
 
 
Urine or serum Cycle 2–18 
(predose; irregular menses) 
 
 
X 
 
 
 
X 
 
 
 
 
SPEP/UPEP/immunofixation (except Cycle 1) 
X 
 
X 
 
 
 
 
 
 
X 
X 
Serumfree light chains (except Cycle 1) 
X 
 
X 
 
 
 
 
 
 
X 
X 
Quantitative immunoglobulins (except Cycle 1) 
X 
 
X 
 
 
 
 
 
 
X 
X 
Beta-2 microglobulin 
 
X 
 
 
 
 
 
 
 
 
 
Skeletal survey (repeat if clinically indicated) 
 
X 
 
 
 
 
 
 
 
 
 
Plasmacytoma evaluation (if clinically indicated at 
baseline and repeat to confirm response) 
 
X 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate 
Percent plasma cell involvement (local 
lab):  Baseline and upon CR 
 
X 
 
 
 
 
 
 
 
 
 
FISH testing (central lab):  Baseline 
 
X 
 
 
 
 
 
 
 
 
 
MRD (central lab):  Baseline; Cycle 8 
Day 1; and upon achieving CR or sCR 
 
X 
Xg 
 
 
 
 
 
 
 
 
Genomics (optional; central lab; 
baseline is run on remaining sample 
after FISH):  Baseline, EOT, and active 
follow-up, if PD in subjects consenting 
to genomics evaluation 
 
X 
 
 
 
 
 
 
 
Xh 
Xh 
Page 2 of 3 
Footnotes defined on last page of table 
 


Onyx Therapeutics, Inc. 
 
 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
 
 
Page 21 of 29 
 
CONFIDENTIAL 
APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS (CONT’D) 
Assessment 
Screeninga 
Baselineb 
Cycles 1 through 18 
EOTc 
Active 
Follow-up 
D1 
D8 
D9 
D11 
D15 
D21 
D22 
Blood for MRD/NGS (central lab): Baseline;  
Cycle 8  Day 1; and upon achieving CR or sCR 
 
X 
Xg 
 
 
 
 
 
 
 
 
Genomic Biomarkers blood and saliva (optional) 
 
X 
 
 
 
 
 
 
 
 
 
Plasma PK  
Cohorts 1-2 
NDMM subjects enrolled prior to 
protocol amendment 2 (Cycle 1) 
 
 
 
X 
 
 
 
 
 
 
 
Under protocol amendment 2: 
NDMM subjects (Cycle 2 only) 
 
 
X 
 
 
 
 
 
 
 
 
Blood for PDn  
Cohorts 1-2 (Cycle 1 only) 
 
 
Xi 
Xi 
Xj 
Xj 
 
 
 
 
 
First 8 NDMM subjects enrolled 
under protocol amendment 2 
(Cycle 1-2 only) 
 
 
Xi 
Xk 
 
 
Xk 
 
 
 
 
Questionnaire: patient convenience/satisfaction (Cycles 
3 and 18 only) 
 
 
X 
 
 
 
 
 
 
 
 
IV hydration (Cycle 1 only) 
 
 
X 
X 
 
 
X 
 
 
 
 
Carfilzomib administration  
 
 
X 
X 
 
 
X 
 
 
 
 
Dexamethasone 
administrationl 
Cycles 1 to 8 
 
 
X 
X 
 
 
X 
 
X 
 
 
Cycles 9 to 18 
 
 
X 
X 
 
 
X 
 
 
 
 
Lenalidomide administration 
 
 
 
 
 
 
Adverse events 
 
Concomitant medications 
 
Footnotes defined on last page of table  
Page 3 of 3 
 
 


Onyx Therapeutics, Inc. 
 
 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
 
 
Page 22 of 29 
 
CONFIDENTIAL 
BP = blood pressure; BSA = body surface area; CR = complete response; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end 
of treatment; FCBP = females of childbearing potential; FISH = fluorescent in situ hybridization; IV = intravenous (ly); MRD = minimal residual disease; 
MUGA = multigated acquisition; NDMM = newly diagnosed multiple myeloma; PD = progressive disease; PDn = pharmacodynamic(s); 
PK = pharmacokinetic(s); RRMM = relapsed and refractory multiple myeloma; sCR = stringent complete response; SPEP = serum protein electrophoresis; 
UPEP = urine protein electrophoresis  
Details of Assessments are in the protocol body.  
a Screening samples can be collected within 21 days of Cycle 1 Day 1. 
b It is recommended that baseline samples are collected only after subject is enrolled. 
c EOT visit must be scheduled 28 ± 7 days after the last study treatment.  EOT ECHO must be performed within 28 ± 7 days after the last study treatment. 
d Height is only measured once at screening.  BSA is not calculated on Day1 of Cycle 1 or at EOT visit. 
e Full serum chemistry panel will also be collected on Days 8 and 15 of Cycle 1. 
f 
Abbreviated serum chemistry panel will be collected Cycle 2 onwards, Days 8 and 15 (as listed in table). 
g After baseline, collect aspirate and blood for MRD only on Day 1 Cycle 8, all subjects, and upon achieving a CR or sCR in all subjects. 
h Optional bone marrow aspirate to be collected upon progression of disease in subjects consenting to optional genomic biomarker analysis. 
i 
Predose and postdose.  
j 
On Days 9 and 11, when carfilzomib is not administered, collect 1 PDn sample at approximately the same time as when the pre-infusion sample was taken on 
Day 8. 
k Postdose only. 
l 
Dexamethasone should be administered 30 minutes to 4 hours prior to initiation of carfilzomib infusion.   


Onyx Therapeutics, Inc. 
 
 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
 
 
Page 23 of 29 
 
CONFIDENTIAL 
With: 
APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS 
Assessment 
Screening
a 
Baselineb 
Cycles 1 through 18 
EOTc 
Active 
Follow-up 
D1 
D8 
D9 
D11 
D15 
D21 
D22 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical and treatment history 
X 
 
 
 
 
 
 
 
 
 
 
Time of pre-carfilzomib resting BP and time of 
dexamethasone administration (Cycles 1-6, 12, and 18) 
 
 
X 
X 
 
 
X 
 
 
 
 
Vital signs 
X 
 
X 
X 
 
 
X 
 
 
X 
 
Post-carfilzomib BP (Cycles 1-6, 12, and 18) 
 
 
X 
X 
 
 
X 
 
 
 
 
Physical examinationd and ECOG Performance Score 
X 
 
X 
 
 
 
 
 
 
X 
 
Hematology 
X 
 
X 
X 
 
 
X 
 
 
X 
 
Full serum chemistry panele 
X 
 
X 
 
 
 
 
 
 
X 
 
Abbreviated serum chemistry panelf 
 
 
 
X 
 
 
X 
 
 
 
 
Coagulation 
 
X 
 
 
 
 
 
 
 
X 
 
ECG (repeat if clinically indicated) 
X 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGA 
Dose–evaluation cohorts 
(Cycle 2 and as clinically indicated) 
X 
 
 
 
 
 
X 
 
 
X 
 
Dose–expansion arms 
(repeat if clinically indicated) 
X 
 
 
 
 
 
 
 
 
X 
 
Page 1 of 3 
Footnotes defined on last page of table 


Onyx Therapeutics, Inc. 
 
 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
 
 
Page 24 of 29 
 
CONFIDENTIAL 
APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS (CONT’D) 
Assessment 
Screeninga 
Baselineb 
Cycles 1 through 18 
EOTc 
Active 
Follow-up 
D1 
D8 
D9 
D11 
D15 
D21 
D22 
Pregnancy testing 
(for FCBP) 
Serum (10–14 days prior to C1D1) 
X 
 
 
 
 
 
 
 
 
X 
 
Urine or serum Cycle 1 (predose) 
 
 
X 
X 
 
 
X 
 
X 
 
 
Urine or serum Cycle 2–18 
(predose; no menses) 
 
 
X 
 
 
 
 
 
 
 
 
Urine or serum Cycle 2–18 
(predose; irregular menses) 
 
 
X 
 
 
 
X 
 
 
 
 
SPEP/UPEP/immunofixation (except Cycle 1) 
X 
 
X 
 
 
 
 
 
 
X 
X 
Serum free light chains (except Cycle 1) 
X 
 
X 
 
 
 
 
 
 
X 
X 
Quantitative immunoglobulins (except Cycle 1) 
X 
 
X 
 
 
 
 
 
 
X 
X 
Beta-2 microglobulin 
 
X 
 
 
 
 
 
 
 
 
 
Skeletal survey (repeat if clinically indicated) 
 
X 
 
 
 
 
 
 
 
 
 
Plasmacytoma evaluation (if clinically indicated at 
baseline and repeat to confirm response) 
 
X 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate 
Percent plasma cell involvement (local 
lab):  Baseline and upon CR 
 
X 
 
 
 
 
 
 
 
 
 
FISH testing (central lab):  Baseline 
 
X 
 
 
 
 
 
 
 
 
 
MRD (central lab):  Baseline; Cycle 8 
Day 1; and upon achieving CR or sCR 
 
X 
Xg 
 
 
 
 
 
 
 
 
Genomics (optional; central lab; 
baseline is run on remaining sample 
after FISH):  Baseline, EOT, and active 
follow-up, if PD in subjects consenting 
to genomics evaluation 
 
X 
 
 
 
 
 
 
 
Xh 
Xh 
Page 2 of 3 
Footnotes defined on last page of table 
 


Onyx Therapeutics, Inc. 
 
 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
 
 
Page 25 of 29 
 
CONFIDENTIAL 
APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS (CONT’D) 
Assessment 
Screening
a 
Baselineb 
Cycles 1 through 18 
EOTc 
Active 
Follow-up 
D1 
D8 
D9 
D11 
D15 
D21 
D22 
Blood for MRD/NGS (central lab): Baseline;  
Cycle 8  Day 1; and upon achieving CR or sCR 
 
X 
Xg 
 
 
 
 
 
 
 
 
Genomic Biomarkers blood and saliva (optional) 
 
X 
 
 
 
 
 
 
 
 
 
Plasma PK  
Cohorts 1-2 
NDMM subjects enrolled 
prior to protocol 
amendment 2 (Cycle 1 
only) 
 
 
 
X 
 
 
 
 
 
 
 
Under protocol 
amendment 2: 
NDMM subjects (Cycle 2 
only) 
 
 
X 
 
 
 
 
 
 
 
 
Blood for PDn  
Cohorts 1-2 and first 8 
subjects in Arm 3 
(Cycle 1 only) 
 
 
Xi 
Xi 
Xj 
Xj 
 
 
 
 
 
First 8 NDMM subjects 
enrolled under protocol 
amendment 2 (Cycle 1-2 
only) 
 
 
Xi 
Xk 
 
 
Xk 
 
 
 
 
Questionnaire: patient convenience/satisfaction  
 (Cycles 3 and 18 only) 
 
 
X 
 
 
 
 
 
 
 
 
IV hydration (Cycle 1 only) 
 
 
X 
X 
 
 
X 
 
 
 
 
Carfilzomib administration  
 
 
X 
X 
 
 
X 
 
 
 
 
Dexamethasone 
administrationk 
Cycles 1 to 8 
 
 
X 
X 
 
 
X 
 
X 
 
 
Cycles 9 to 18 
 
 
X 
X 
 
 
X 
 
 
 
 
Lenalidomide administration 
 
 
 
 
 
 


Onyx Therapeutics, Inc. 
 
 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
 
 
Page 26 of 29 
 
CONFIDENTIAL 
APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS (CONT’D) 
Assessment 
Screening
a 
Baselineb 
Cycles 1 through 18 
EOTc 
Active 
Follow-up 
D1 
D8 
D9 
D11 
D15 
D21 
D22 
Adverse events 
 
Concomitant medications 
 
Footnotes defined on last page of table  
Page 3 of 3 
 
BP = blood pressure; BSA = body surface area; CR = complete response; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end 
of treatment; FCBP = females of childbearing potential; FISH = fluorescent in situ hybridization; IV = intravenous (ly); MRD = minimal residual disease; 
MUGA = multigated acquisition; NDMM = newly diagnosed multiple myeloma; PD = progressive disease; PDn = pharmacodynamic(s); 
PK = pharmacokinetic(s); RRMM = relapsed and refractory multiple myeloma; sCR = stringent complete response; SPEP = serum protein electrophoresis; 
UPEP = urine protein electrophoresis  
Details of Assessments are in the protocol body.  
a 
Screening samples can be collected within 21 days of Cycle 1 Day 1. 
b It is recommended that baseline samples are collected only after subject is enrolled. 
c EOT visit must be scheduled 28 ± 7 days after the last study treatment.  EOT ECHO must be performed within 28 ± 7 days after the last study treatment. 
d Height is only measured once at screening.  BSA is not calculated on Day1 of Cycle 1 or at EOT visit. 
e Full serum chemistry panel will also be collected on Days 8 and 15 of Cycle 1. 
f 
Abbreviated serum chemistry panel will be collected Cycle 2 onwards, Days 8 and 15 (as listed in table). 
g After baseline, collect aspirate and blood for MRD only on Day 1 Cycle 8, all subjects, and upon achieving a CR or sCR in all subjects. 
h Optional bone marrow aspirate to be collected upon progression of disease in subjects consenting to optional genomic biomarker analysis. 
i 
Predose and postdose.  
j 
On Days 9 and 11, when carfilzomib is not administered, collect 1 PDn sample at approximately the same time as when the pre-infusion sample was taken on 
Day 8. 
k Postdose only. 
k Dexamethasone should be administered 30 minutes to 4 hours prior to initiation of carfilzomib infusion.   


Onyx Therapeutics, Inc. 
 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
 
 
Page 27 of 29 
 
CONFIDENTIAL 
Section: Appendix I 
Replace: 
APPENDIX I  SUMMARY OF CHANGES IN STUDY CFZ013 AMENDMENT 2 
 
 This Summary of Changes outlines noteworthy changes from protocol amendment 1.0 to 
protocol amendment 2.0, and includes rationales for the changes.  Administrative 
updates, typographical and formatting changes were made throughout the protocol.  
Updates have been implemented to align with the current template.  The main purposes 
for revising the CFZ013 (20140241) protocol are as follows: 
 
A Dose-evaluation Component is added for newly diagnosed multiple myeloma 
(NDMM) subjects.  During the conduct of the trial, NDMM subjects were enrolled into 
Dose-expansion Arm 1 (treated at Cohort 2 dosing; Table 2 and Appendix E). 
• When 2 serious adverse events were seen during Cycle 1 in the first 8 NDMM 
subjects, an ad hoc Cohort Safety Review Committee (CSRC) meeting was held.  
The CSRC elected to: 
o continue the study 
o evaluate NDMM subjects in Dose-evaluation cohorts prior to opening 
additional NDMM Dose-expansion cohorts 
o modify Cycle 1 dosing for NDMM subjects as shown in Table 2, Cohort 
4.  After the ad hoc CSRC meeting, investigators were instructed to treat 
NDMM subjects at dosing herein referred to as Cohort 4 dosing. 
• Dose-evaluation enrollment guideline text is modified.  The language was 
broadened, to apply to both relapsed and refractory multiple myeloma RRMM 
Dose-evaluation and the newly added NDMM Dose-evaluation components of the 
trial 
• Autologous stem cell transplant (ASCT) is now allowed for NDMM subjects 
while remaining on trial.  The previous version allowed enrollment of transplant-
eligible NDMM subjects and stem cell harvest but did not allow ASCT for 
subjects on trial.   
• Simplified study schema (Figure 1) 
• Revised blood collection schedule for pharmacokinetics and pharmacodynamics 
for NDMM cohort, to reflect dosing schedule 
• Added dose rationale for new dosing regimen 
• Modified study duration, given delay in enrollment of NDMM subjects  
 
• For treatment guidelines: 
o modified guidelines for thrombotic microangiopathy and Posterior 
Reversible Encephalopathy Syndrome to align with the current 
Carfilzomib Investigator’s Brochure Amgen/Onyx. Carfilzomib 
Investigator’s Brochure. Onyx Therapeutics, Inc. (a wholly owned 
subsidiary of Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary).  
o specified guidelines for pulmonary hypertension to align with the current 
Carfilzomib IB 


Onyx Therapeutics, Inc. 
 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
 
 
Page 28 of 29 
 
CONFIDENTIAL 
• For study procedures: 
o Added Section 10.1.1 Baseline Procedures 
o revised vital signs collection text to clarify post-dose blood pressure 
collection on treatment days 
o removed peripheral neuropathy assessment from physical examination 
assessments 
o required urine protein electrophoresis with immunofixation for every 
disease assessment 
o specified that local bone marrow pathology assessment will be done to 
evaluate for complete response 
• Modified Appendix C:  removed text referring to subjects without measurable 
serum M-protein, urine M-protein or serum free light chains at baseline, as these 
subjects are not eligible for enrollment. 
• To clarify changes to the protocol, added Appendix E APPENDIX E 
Figures 
from protocol amendment 1 
The following changes were done to align the protocol with the current Amgen Clinical 
Protocol Template: 
• Changed the language in Section 12 (Adverse Events and Serious Adverse 
Events)  
• Modified analysis of the conduct of the study  
• Added publication policy section 
• Added APPENDIX F Additional Safety Assessment Information  
• Added: APPENDIX G 
Sample eSerious Event Contingency Form 
• Added APPENDIX H Pregnancy and Lactation Notification Worksheets 
 
With: 
APPENDIX I  SUMMARY OF CHANGES IN STUDY CFZ013 AMENDMENT 3 
 This Summary of Changes outlines noteworthy changes from protocol amendment 2.0 to 
protocol amendment 3.0, and includes rationales for the changes.  Administrative 
updates, typographical and formatting changes were made throughout the protocol.  
Updates have been implemented to align with the current template.  The main purposes 
for revising the CFZ013 (20140241) protocol are listed below: 
Protocol amendment 3 specifies the dosing selected for newly diagnosed multiple 
myeloma (NDMM) Dose-expansion Arm 3.  The carfilzomib, lenalidomide, and 
dexamethasone (KRd) dosing for Arm 3 is as follows: carfilzomib 20 mg/m2 on 
Day 1 of Cycle 1, then 56 mg/m2 on Days 8 and 15 of Cycle 1, and Days 1, 8, and 15 
of Cycles 2-18.  Lenalidomide will be given at 25 mg on Days 1-21, and 
dexamethasone at 40 mg on Days 1, 8, 15, 22 of Cycles 1-8, and on Days 1, 8, and 15 
of Cycles 9-18 (see Cohort 1 dosing in Table 2). 


Onyx Therapeutics, Inc. 
 
Clinical Study Protocol No. CFZ013 
Carfilzomib 
 
 
Page 29 of 29 
 
CONFIDENTIAL 
The pharmacokinetics (PK) and pharmacodynamics (PDn) sample collection 
schedule was modified to reflect the dosing selected.  Cycle 2 sampling that was 
introduced in protocol amendment 2, in anticipation of a 2-step-up dosing regimen, 
has been removed as it is not required for the dosing selected for Dose-expansion 
Arm 3. 
Two revisions were made in response to the carfilzomib US Prescribing Information 
(USPI) labelling change approved by FDA in November 2016, which required a 
25% dose reduction in patients with mild or moderate hepatic impairment: 
• Table 9 (Treatment Guidelines for Nonhematologic Toxicity) has been 
modified to align with requested changes.  Specifically, NCI Organ 
Dysfunction Working Group definition of mild, moderate and severe hepatic 
impairment were used (Shibata et al, 2013): 
o mild: total bilirubin (>33% direct) > the upper limit of normal (ULN) 
and ≤ 1.5x ULN OR total bilirubin (>33% direct) ≤ ULN and alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) > ULN;  
o moderate: total bilirubin  .5x ULN and ≤ 3x ULN, any ALT or AST;  
o severe: total bilirubin > 3x ULN, any ALT or AST.   
Subjects with treatment-emergent mild or moderate hepatic impairment, per 
this definition, are to have a 25% carfilzomib dose reduction.  In cases of 
severe hepatic impairment, carfilzomib is to be held.  In moderate or severe 
hepatic impairment, lenalidomide is to be held. 
• Inclusion criteria have been modified in Section 6.1.  Previous protocol 
amendments allowed enrollment of subjects with baseline mild hepatic 
insufficiency.  With protocol amendment 3 (under which only the NDMM 
Dose-expansion Arm 3 subjects will be enrolled), subjects will be required to 
have normal hepatic function.  The intent of this modification is to maximize 
the ability to give full, protocol-specified 20/56 mg/m2 carfilzomib dosing to 
the enrolled NDMM subjects. 
Other minor changes: 
• To maintain internal consistency of the document, Dose-expansion groups 
are uniformly referred to “Arms” with the term “Cohort” reserved for Dose-
evaluation groups.  
• Changed the duration of enrollment from 8 to 12 months. 
 
 


Onyx Therapeutics, Inc.  
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 107 of 108 
CONFIDENTIAL 
APPENDIX I  
SUMMARY OF CHANGES IN STUDY CFZ013 
AMENDMENT 2 
 This Summary of Changes outlines noteworthy changes from protocol amendment 1.0 
to protocol amendment 2.0, and includes rationales for the changes.  Administrative 
updates, typographical and formatting changes were made throughout the protocol.  
Updates have been implemented to align with the current template.  The main purposes 
for revising the CFZ013 (20140241) protocol are as follows: 
 
A Dose-evaluation Component is added for newly diagnosed multiple myeloma 
(NDMM) subjects.  During the conduct of the trial, NDMM subjects were enrolled into 
Dose-expansion Arm 1 (treated at Cohort 2 dosing; Table 2 and Appendix E). 
• When 2 serious adverse events were seen during Cycle 1 in the first 8 NDMM 
subjects, an ad hoc Cohort Safety Review Committee (CSRC) meeting was held.  
The CSRC elected to: 
o continue the study 
o evaluate NDMM subjects in Dose-evaluation cohorts prior to opening 
additional NDMM Dose-expansion cohorts 
o modify Cycle 1 dosing for NDMM subjects as shown in Table 2, Cohort 4.  
After the ad hoc CSRC meeting, investigators were instructed to treat 
NDMM subjects at dosing herein referred to as Cohort 4 dosing. 
• Dose-evaluation enrollment guideline text is modified.  The language was 
broadened, to apply to both relapsed and refractory multiple myeloma RRMM 
Dose-evaluation and the newly added NDMM Dose-evaluation components of 
the trial 
• Autologous stem cell transplant (ASCT) is now allowed for NDMM subjects 
while remaining on trial.  The previous version allowed enrollment of 
transplant-eligible NDMM subjects and stem cell harvest but did not allow 
ASCT for subjects on trial.   
• Simplified study schema (Figure 1) 
• Revised blood collection schedule for pharmacokinetics and pharmacodynamics 
for NDMM cohort, to reflect dosing schedule 
• Added dose rationale for new dosing regimen 
• Modified study duration, given delay in enrollment of NDMM subjects  
 
• For treatment guidelines: 
o modified guidelines for thrombotic microangiopathy and Posterior 
Reversible Encephalopathy Syndrome to align with the current 
Carfilzomib Investigator’s Brochure Amgen/Onyx. Carfilzomib 
Investigator’s Brochure. Onyx Therapeutics, Inc. (a wholly owned 
subsidiary of Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary).  
o specified guidelines for pulmonary hypertension to align with the current 
Carfilzomib IB 


Onyx Therapeutics, Inc.  
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 108 of 108 
CONFIDENTIAL 
• For study procedures: 
o Added Section 10.1.1 Baseline Procedures 
o revised vital signs collection text to clarify post-dose blood pressure 
collection on treatment days 
o removed peripheral neuropathy assessment from physical examination 
assessments 
o required urine protein electrophoresis with immunofixation for every 
disease assessment 
o specified that local bone marrow pathology assessment will be done to 
evaluate for complete response 
• Modified Appendix C:  removed text referring to subjects without measurable 
serum M-protein, urine M-protein or serum free light chains at baseline, as these 
subjects are not eligible for enrollment. 
• To clarify changes to the protocol, added Appendix E APPENDIX E Figures 
from protocol amendment 1 
The following changes were done to align the protocol with the current Amgen Clinical 
Protocol Template: 
• Changed the language in Section 12 (Adverse Events and Serious Adverse 
Events)  
• Modified analysis of the conduct of the study  
• Added publication policy section 
• Added APPENDIX F 
Additional Safety Assessment Information  
• Added: APPENDIX G 
Sample eSerious Event Contingency Form 
• Added APPENDIX H 
Pregnancy and Lactation Notification Worksheets 
 
 
 


Onyx Therapeutics, Inc.  
Clinical Study Protocol No. CFZ013 
Carfilzomib 
Page 93 of 135 
CONFIDENTIAL 
APPENDIX E 
SUMMARY OF CHANGES IN STUDY CFZ013 
AMENDMENT 1 
Administrative updates, editorial changes, and style and formatting revisions have been made 
to improve clarity and consistency throughout the document.  Significant changes and their 
rationale are described in the table below. 
 
Main changes include the following: 
• Allow for replacement of non-DLT evaluable subjects 
• Define EOT visit window 
• Include information distributed in former “Protocol Clarification Letters” 
• Align with current Core Risk and Discomforts language 
• Update subject questionnaire forms 
• Align with current sponsor protocol SOP 
 

SAP_001.pdf: 
Product: Carfilzomib 
Protocol Number:  20140241 (CFZ013) 
Date:  15 October 2019 
Page 1 of 42 
CONFIDENTIAL       
Statistical Analysis Plan 
Protocol Title: 
Phase 1b Study of Carfilzomib Administered Once 
Weekly in Combination With Lenalidomide and 
Dexamethasone in Subjects With Multiple Myeloma 
Short Protocol Title: 
Weekly KRd 
Protocol Number: 
20140241 (CFZ013) 
Authors: 
, PhD 
Biostatistics Senior Manager, Amgen Inc. 
, MD, PhD, MS 
Biostatistics Manager, Amgen Inc. 
Sponsor: 
Onyx Therapeutics, Inc 
One Amgen Center Drive  
Thousand Oaks, CA 91320 
SAP Date: 
Document Version 
Original (v1.0) 
Date 
10 July 2018 
Amendment 1 (v2.0) 
15 October 2019 
NCT Number: NCT02335983
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


Product: Carfilzomib 
Protocol Number:  20140241 (CFZ013) 
Date:  15 October 2019 
Page 2 of 42 
 
CONFIDENTIAL            
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
10 July 2018 
 
Amendment 1 (v2.0) 
15 October 2019 
1. Section 2.1 Objectives and Endpoints: 
• Update MRD[-]CR definition “… MRD[-] 
at CR” to “… MRD[-] at CR or better” 
 
2. Section 3.1 Study Design: 
• updated number of subjects in NDMM 
cohorts in Figure 1 and Table 1 
• added superscripts in Table 1. 
 
3. Section 3.2 Sample Size: 
• add the summary for sample size 
justification 
 
4. Section 5 Definitions: 
• removed ‘and time’ in Baseline definition 
• updated FISH risk group definition 
(central lab data): ‘>10%’ to ‘>=10%’, 
‘>20%’ to ‘>=20%’ 
• add FISH risk group definition based on 
local lab data 
• add R-ISS per local lab FISH data 
• updated TEAE definition based on  
DES 6.0. 
5. Section 6 Analysis Sets: deleted MRD 
Analysis Set. Rationale: MRD[-] analyses will 
not be included in CSR. 
 
6. Section 9 Statistical Methods of Analysis: 
• updated number of subjects in NDMM 
cohorts in 9.1 General Considerations 
• removed ‘Number of screened subjects’ 
but added ‘Number of enrolled subjects’ 
in 9.2 Subject Accountability. Rationale: 
not able to separate number of subjects 
screened for RRMM and NDMM 
subjects 
• deleted definition and the ‘not done’ 
category for FISH in 9.4.3 Disease 
Characteristics. Rationale: FISH is 
already defined in section 5 Definitions, 
and ‘not done’ can be categorized into 
‘unknown’; add FISH risk group per 
local lab data 
• updated categorization for baseline 
beta2 microglobulin to ‘<3.5’,  
‘3.5 - <5.5’, ‘≥5.5’ in 9.4.3 Disease 
Characteristics 
 


Product: Carfilzomib 
Protocol Number:  20140241 (CFZ013) 
Date:  15 October 2019 
Page 3 of 42 
 
CONFIDENTIAL            
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
• added ‘unknown’ category to ISS and 
RISS at baseline in 9.4.3 Disease 
Characteristics; add RISS per local 
FISH lab data 
• corrected the conditions for PFS 
censoring: deleted ‘post’ in ‘no post 
baseline disease assessments’ in 9.5.2 
Progression-free Survival 
• updated the AEs determined to be DLTs 
included in the listings: deleted ‘during 
the first cycle’ in 9.6.1 Adverse Events 
and Disease-related Events. Rationale: 
AEs determined to be DLTs were found 
being evaluated in other cycles other 
than the cycles specified in Protocol 
• updated EOI list in 9.6.1 Adverse 
Events and Disease-related Events 
• removed ‘Examination of cardiovascular 
and respiratory systems’ in 9.6.4 
Physical Measurements. Rationale: 
heart rate, BP and respiratory rate are 
presented in vital sign section for 
examination of cardiovascular and 
respiratory system 
• removed summaries at unscheduled 
visits in 9.6.6 Echocardiogram 
• added ‘+1’ to the definition of duration of 
treatment in weeks; and added number 
of treatment cycles received prior to 
SCT for subjects who had SCT and 
number of treatment cycles received for 
subjects who did not have SCT in 9.6.7 
Exposure to Investigational Product 
• updated 9.7.2 Analyses of Minimal 
Residual Disease Negative Rate 
Endpoints: deleted detailed analyses 
and added ‘The analysis of MRD[-] rate 
will not be included in the clinical study 
report (CSR). The MRD analyses will be 
summarized in a separate analysis plan 
by Clinical Biomarkers & Diagnostics 
group’. 
• updated 9.7.3 Analyses of Patient 
Reported Outcomes and Other Health 
Related Quality of Life Endpoints by 
adding the specifications for 
denominator for percentage 
• updated 9.7.4 Analyses of Biomarker 
Endpoints: deleted detailed analyses 
and added ‘will not be included in CSR’. 


Product: Carfilzomib 
Protocol Number:  20140241 (CFZ013) 
Date:  15 October 2019 
Page 4 of 42 
 
CONFIDENTIAL            
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Introduction ............................................................................................................. 9 
2. 
Objectives,Endpoints and Hypotheses.................................................................. 10 
2.1 
Objectives and Endpoints .......................................................................... 10 
2.2 
Hypotheses and/or Estimations ................................................................. 11 
3. 
Study Overview .................................................................................................... 12 
3.1 
Study Design ............................................................................................. 12 
3.2 
Sample Size .............................................................................................. 13 
4. 
Covariates and Subgroups ................................................................................... 15 
4.1 
Planned Covariates ................................................................................... 15 
4.2 
Subgroups ................................................................................................. 15 
5. 
Definitions ............................................................................................................. 16 
6. 
Analysis Sets ........................................................................................................ 20 
6.1 
Safety Analysis Set ................................................................................... 20 
6.2 
Response-Evaluable Analysis Set ............................................................. 20 
6.3 
Pharmacokinetic Analysis Set ................................................................... 20 
6.4 
Pharmacodynamic Analyses Set ............................................................... 20 
7. 
Planned Analyses ................................................................................................. 21 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 21 
7.2 
Primary Analysis ....................................................................................... 21 
7.3 
Final Analysis ............................................................................................ 21 
8. 
Data Screening and Acceptance ........................................................................... 22 
8.1 
General Principles ..................................................................................... 22 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 22 
8.3 
Handling of Missing and Incomplete Data ................................................. 22 
8.4 
Detection of Bias ....................................................................................... 24 
8.5 
Outliers ..................................................................................................... 24 
8.6 
Distributional Characteristics ..................................................................... 25 
8.7 
Validation of Statistical Analyses ............................................................... 25 
9. 
Statistical Methods of Analysis.............................................................................. 26 
9.1 
General Considerations ............................................................................. 26 
9.2 
Subject Accountability ............................................................................... 27 
9.3 
Important Protocol Deviations ................................................................... 27 
9.4 
Demographic and Baseline Characteristics ............................................... 27 
9.4.1 
Demographics and Baseline Characteristics.............................. 27 
9.4.2 
Medical History .......................................................................... 28 
9.4.3 
Disease Characteristics ............................................................. 28 


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9.4.4 
Prior Cancer Therapies ............................................................. 28 
9.5 
Efficacy Analyses ...................................................................................... 28 
9.5.1 
Overall Response Rate and Complete Response Rate ............. 29 
9.5.2 
Progression-Free Survival ......................................................... 29 
9.5.3 
Duration of Response ................................................................ 30 
9.6 
Safety Analyses ........................................................................................ 30 
9.6.1 
Adverse Events and Disease-related Events ............................. 30 
9.6.2 
Laboratory Test Results ............................................................ 32 
9.6.3 
Vital Signs ................................................................................. 33 
9.6.4 
Physical Measurements ............................................................ 34 
9.6.5 
Electrocardiogram ..................................................................... 34 
9.6.6 
Echocardiogram ........................................................................ 34 
9.6.7 
Exposure to Investigational Product .......................................... 34 
9.6.8 
Exposure to Concomitant Medication ........................................ 35 
9.7 
Other Analyses ......................................................................................... 35 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 35 
9.7.2 
Analyses of Minimal Residual Disease Negative Rate 
Endpoints .................................................................................. 36 
9.7.3 
Analyses of Patient Reported Outcomes and Other 
Health Related Quality of Life Endpoints ................................... 36 
9.7.4 
Analyses of Biomarker Endpoints .............................................. 36 
10.
Changes From Protocol-specified Analyses.......................................................... 37 
11.
Literature Citations / References ........................................................................... 38 
12.
Appendices ........................................................................................................... 39
Appendix A.  Dose Intensity Calculations .............................................................. 40 
List of Tables 
Table 1.  KRd Dose Level Combinations ....................................................................... 13 
Table 2.  95% Credible Intervals for the Dose-limiting Toxicity Rate and 
Probabilities of Dose-limiting Toxicity Rate Being Larger 
Than 0.33 ............................................................................................... 14 
Table 3.  Imputation Rules for Partial or Missing Start Dates ......................................... 23 
Table 4.  Conventions for Censoring for PFS................................................................. 30 
List of Figures 
Figure 1.  Study Schema ............................................................................................... 12 


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List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Description/Explanation 
AE 
Adverse Event 
AMQ 
Amgen MedDRA Queries 
ANC 
Absolute Neutrophil Count 
ASCT 
Autologous Stem Cell Transplant 
ATC 
Anatomical Therapeutic Class 
BSA 
Body Surface Area 
CA 
Chromosomal Abnormalities 
CDM 
Clinical Data Management 
CI 
Confidence Interval 
cm 
Centimeter 
CR 
Complete Response 
CRR 
Complete Response Rate 
CSR 
Clinical Study Report 
CSRC 
Cohort Safety Review Committee 
d 
Dexamethasone 
DMC 
Data Monitoring Committee 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOI 
Event of Interest 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in situ Hybridization 
GSO-DM 
Global Study Operations-Data Management 
HLT 
High Level Term 
HRQOL 
Heath-related Quality of Life 
ICF 
Informed Consent Form 
IMWG-URC 
International Myeloma Working Group Uniform Response Criteria 
ISS 
International Staging System for Multiple Myeloma 
K 
Kyprolis® (carfilzomib) 


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Abbreviation or Term 
Description/Explanation 
kg 
Kilogram 
KM 
Kaplan-Meier 
KRd 
Kyprolis (carfilzomib), Revlimid (lenalidomide), and 
dexamethasone  
LDH 
Lactate Dehydrogenase 
LVEF 
Left Ventricular Ejection Fraction 
m2 
Square Meter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
MRD 
Minimal Residual Disease 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for 
Adverse Events 
NDMM 
Newly Diagnosed Multiple Myeloma 
ORCA 
Onyx Response Computational Assessment 
ORR 
Overall Response Rate 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PDn 
Pharmacodynamics 
PFS 
Progression-free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred Term 
QT Interval 
The time between the start of the Q wave and the end of the T 
wave in the heart's electrical cycle; QTc is corrected QT 
R 
Revlimid® (lenalidomide) 
R-ISS 
Revised ISS 
RRMM 
Relapsed and Refractory Multiple Myeloma 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sCR 
Stringent Complete Response 
SD 
Stable Disease; Standard Deviation 
SFLC 
Serum Free Light Chain 
SIFE 
Serum Immunofixation 
SMQ 
Standardized MedDRA Queries  
SOC 
System Organ Class 


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Abbreviation or Term 
Description/Explanation 
SPEP 
Serum Protein Electrophoresis 
TEAE 
Treatment-Emergent Adverse Event 
UIFE 
Urine Immunofixation 
UPEP 
Urine Protein Electrophoresis 
VGPR 
Very Good Partial response 
WBC 
White Blood Cell 
WES 
Whole Exome Sequencing 
WGS 
Whole Genome Sequencing 
WHO-DD 
World Health Organization – Drug Dictionary 
 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for carfilzomib study 20140241 
(CFZ013) amendment 3.0 dated 13 December 2016.  The scope of this plan includes 
the final analysis that is planned and will be executed by the Amgen Global Biostatistical 
Science department unless otherwise specified.  PK/PDn analyses and biomarker 
analyses will be provided by the Department of Clinical Pharmacology, Modeling & 
Simulation (CPMS) and Clinical Biomarkers & Diagnostics, respectively. 


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2. 
Objectives,Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety and tolerability of 
a once-weekly carfilzomib, lenalidomide, 
and dexamethasone (KRd) regimen in 
relapsed and refractory multiple 
myeloma (RRMM) and newly diagnosed 
multiple myeloma (NDMM) subjects 
 
• 
Safety and tolerability of carfilzomib 
administered once weekly in combination 
with lenalidomide and dexamethasone, as 
defined by the type, incidence, and severity 
of Adverse Events (AEs) and changes from 
baseline in key laboratory analyses, 
including vital signs, and the extent and 
duration of exposure to study drugs 
Secondary 
• 
To evaluate the pharmacokinetics (PK) 
of carfilzomib when administered once 
weekly in a KRd regimen in RRMM and 
NDMM subjects separately. 
• 
To evaluate the clinical activity (efficacy) 
of a once-weekly KRd regimen in RRMM 
and NDMM subjects separately 
• 
Pharmacokinetics (PK) of carfilzomib  
• 
Overall Response Rate (ORR), defined as 
the proportion of subjects who achieve a 
best overall response of stringent complete 
response (sCR), complete response (CR), 
very good partial response (VGPR), or 
partial response (PR) in accordance with 
IMWG-URC (Rajkumar et al. 2011) 
• 
Complete Response Rate (CRR), defined 
as the proportion of subjects who achieve 
a best overall response of sCR or CR in 
accordance with IMWG-URC 
• 
Progression-free Survival (PFS), defined 
as the time from the first day of study 
treatment to the earlier of disease 
progression or death due to any cause 
• 
Duration of Response (DOR), defined as 
the time from the first evidence of 
confirmed PR or better to disease 
progression or death due to any cause 
among subjects who respond 
Exploratory 
• 
To explore the genomic and 
transcriptional biomarkers that might 
predict response and resistance to a 
once-weekly KRd regimen 
• 
To characterize the pharmacodynamics 
(PDn) of proteasome inhibition with a 
once-weekly KRd regimen in RRMM and 
NDMM subjects 
• 
To assess minimal residual disease 
(MRD) status with a once-weekly KRd 
regimen in RRMM and NDMM subjects 
• 
To assess subject convenience and 
satisfaction with a once-weekly KRd 
regimen using subject questionnaire in 
RRMM and NDMM subjects 
• 
Pharmacodynamics (PDn) of proteasome 
inhibition by carfilzomib measured in whole 
blood  
• 
MRD[-] rate, defined as the proportion of 
subjects who are negative for MRD at 
Cycle 8 Day 1  
• 
MRD[-]CR rate, defined as the proportion 
of subjects who are MRD[-] at CR or 
better 
• 
Subject convenience and satisfaction with 
the carfilzomib dosing schedule   
• 
WGS, WES, whole transcriptome 
sequencing, and other nucleic acid and 
protein quantification data and 
immunoglobulin levels in tumor cells 


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2.2 
Hypotheses and/or Estimations 
No formal hypothesis testing is planned for this study.  The number (%) of subjects with 
Dose Limiting Toxicities (DLTs) and AEs at each dose level will be summarized.  Point 
and interval estimates will be provided for specific efficacy summary statistics.  Point 
estimates for overall response rate (ORR), complete response rate (CRR), along with 
their exact 2-sided 95% confidence intervals will be calculated.  Summary statistics for 
DOR and PFS, including 95% confidence intervals for quartiles and probability 
estimates, will be calculated using the Kaplan-Meier method. More details for the 
efficacy analyses are provided in section 9.5. 
 


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3. 
Study Overview 
3.1 
Study Design 
This is an open-label, multicenter, Phase 1b, dose-finding study of carfilzomib 
administered once weekly in combination with lenalidomide and dexamethasone (KRd) 
in 28-day cycles to subjects with multiple myeloma. Subjects may continue to receive 
study treatment for up to 18 cycles or until 1 or more of the following events occurs: 
disease progression; allogeneic stem cell transplant, initiation of non-protocol MM 
therapy (including maintenance KRd therapy beyond cycle 18), withdrawal from the 
study for any reason, study termination by the sponsor, death. Subjects who 
discontinued study therapy (for any reason other than progressive disease, allogeneic 
stem cell transplant, death, or withdrawal of consent) could enter active follow up for 
up to one year. 
The study included dose-evaluation and dose-expansion, and was amended three times.  
The final study schema is shown in Figure 1. 
Figure 1.  Study Schema 
 
 
Approximately 8 dose-limiting toxicity (DLT) evaluable subjects were planned to be 
enrolled into each opened dose-evaluation cohort.  Dose-expansion arms 2 and 3 for 
RRMM and NDMM were planned to enroll approximately 30 subjects each.  The cohort 
safety review committee (CSRC) would review all available safety data and make 
recommendations regarding ongoing enrollment and opening of subsequent 
cohorts during the dose-evaluation components and would also select the KRd 


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regimens to be evaluated in the dose-expansion components. After 3 amendments 
to the protocol, 6 dosing groups were enrolled, as seen in Table 1. 
Table 1.  KRd Dose Level Combinations  
Study treatment 
Cohort 1 
RRMM 
N = 10 
Cohort 2 
RRMM 
N = 12 
Arm 2 
RRMM 
N = 34 
Arm 1 
NDMM 
N = 9 
Cohort 4 b 
NDMM 
N = 9 
Arm 3 
NDMM 
N = 33 
Carfilzomib 
mg/m2, cycle 1 a 
56 
70 
70 
70 
56 
56 
Carfilzomib 
mg/m2, cycles 2+ 
56 
70 
70 
70 
70 
56 
Lenalidomide 
(mg) 
25 
25 
25 
25 
25 
25 
Dexamethasone 
(mg) c 
40 
40 
40 
40 
40 
40 
a All subjects received carfilzomib 20 mg/m2 on Day 1 Cycle 1. 
b Carfilzomib will be given at 56 mg/m2 on Day 8 and 15 of Cycle 1; 70 mg/m2 on Days 1, 8, and 15 of 
Cycle 2 and beyond. 
c IV or oral; Day 22 dexamethasone required only in Cycles 1–8; subjects receiving IV dexamethasone on 
Day 1, 8, 15 may receive dexamethasone orally on Day 22. 
 
3.2 
Sample Size 
Sample sizes are determined to provide preliminary information on safety, clinical 
activity, PDn, and PK.  The study has 2 parts: enrolling approximately 8 DLT 
evaluable subjects in each opened dose-evaluation cohort, and then expanding 
the selected doses by enrolling approximately 30 more subjects. Before opening 
dose-expansion arms, it must be determined that there are not more than  
2 dose-limiting toxicities in 8 DLT-evaluable subjects at the dose selected for 
Dose-expansion. With combined number of subjects in both dose evaluation and 
expansion components, 38 subjects will allow an approximately 86% probability to 
detect an occurrence of an adverse event (AE) with 5% incidence rate.   
Assuming beta (0.5, 0.5) prior distribution for the DLT rate, 95% credible intervals for the 
DLT rate and the posterior probability of DLT rate being larger than 0.33 for each toxicity 
scenario are provided in Table 2.  For example, when 3 out of 8 subjects have DLTs, the 
posterior probability of the DLT rate being >0.33 is 0.62.  
 


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Table 2.  95% Credible Intervals for the Dose-limiting Toxicity Rate and 
Probabilities of Dose-limiting Toxicity Rate Being Larger Than 0.33 
Cohort 
Size 
# DLTs 
Observed 
95% Credible interval for the 
DLT Rate 
8 
0 
0 
0.26 
8 
1 
0.01 
0.45 
8 
2 
0.06 
0.59 
8 
3 
0.12 
0.71 
8 
4 
0.20 
0.80 
8 
5 
0.29 
0.88 
8 
6 
0.41 
0.94 
8 
7 
0.55 
0.99 
8 
8 
0.74 
1 
After the safety evaluation of the first 4 DLT evaluable subjects in each opened 
Cohort, CSRC recommended enrollment of an additional 4 subjects for up to  
8 dose-evaluable subjects in total. Upon the safety evaluation of the opened  
dose-evaluation cohorts, dose-expansion Arm 1 (KRd 70 mg/m2 QW) for NDMM 
and Arm 2 (KRd 70 mg/m2 QW) for RRMM were planned to enroll approximately  
30 subjects each. However, among 9 NDMM subjects enrolled in Arm 1, 2 serious 
adverse events (SAE) were observed and the enrollment stopped. The CSRC 
determined to add a 2-step-up KRd regimen in Cohort 4 NDMM (KRd 56/70 mg/m2 
QW) in the Dose-evaluation component. Following the DLT rules above, the CSRC 
elected to open the second NDMM dose-expansion arm (Arm 3: KRd 56 mg/m2 
QW) where approximately 30 NDMM subjects (upon protocol amendment 3) were 
planned to be enrolled. 
 


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4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Not Applicable. 
4.2 
Subgroups 
No subgroup analyses are planned in this study. 
 
 
 


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5.
Definitions
Baseline
The baseline value is the closest recorded measurement prior to the first dose of study
drug.  If there are multiple valid records on an individual at the same date, then the
record closest to cycle 1 day 1 will be used.
Best overall response by computational assessment 
Best overall response will be derived using the Onyx Response Computational 
Assessment (ORCA) for multiple myeloma disease assessments based on the 
International Myeloma Working Group Uniform Response Criteria (IMWG-URC)  
(Durie et al. 2006, with revisions, Rajkumar, et al. 2011). The detailed algorithm is 
documented in a separate document. 
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 CRF.  The following confirmatory assessments are required for all response 
categories (sCR, CR, VGPR and PR) and PD: 
•
All laboratory-based progressive disease and all responses require two 
consecutive assessments made at any time before initiation of any new therapy. 
Confirmatory lab samples should be separated by at least one calendar day.
•
Progressive disease by non-laboratory-based assessment (ie, plasmacytoma or 
skeletal lesion) does not require confirmatory report.
•
All response categories also require no evidence of progression including new 
bone lesion, if radiographic studies are performed.
•
Confirmation of CR or sCR requires local pathology review of a bone marrow 
biopsy or aspirate (a repeat confirmatory bone marrow sample is not required)
•
Extramedullary plasmacytoma evaluation is required to confirm PR, CR, or sCR 
(if present at baseline) 
Best overall response will be decided in the following order of confirmed responses: 
sCR, CR, VGPR, PR, SD, PD starting from the best to the worst. 
End of Study Date for a Subject 
The end of study date is the date recorded on the End of Study page for an enrolled 
subject.  


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First Dose Date 
The first dose date is the date on which a subject is administered the first dose of any 
study drug. 
Fluorescent in Situ Hybridization (FISH) Risk Group 
Subjects in this study had FISH analysis performed by a central study laboratory and 
local laboratory.   
For central laboratory FISH: Subjects with chromosomal abnormalities (CA) t (4;14) or  
t (14;16) in >=10% of screened plasma cells, and/or deletion 17p in >=20% of screened 
plasma cells are in high risk group. Subjects with other CA or normal cytogenetics are in 
standard risk group. 
For local laboratory FISH (captured on eCRF): Subjects with chromosomal 
abnormalities (CA) t (4; 14) or t (14;16) and/or deletion 17p detected on FISH are in 
high risk group. Subjects with other CA or normal cytogenetics are in standard 
risk group. 
Investigational Product (IP) 
IP for this study refers to Kyprolis® (carfilzomib).  
Informed Consent Date 
The informed consent date is the date on which a subject signs the informed consent for 
this study. 
International Staging System (ISS) Stage at Baseline 
ISS stage at baseline will be calculated using serum beta-2 microglobulin and serum 
albumin value collected at baseline based on the criteria published by the International 
Myeloma Working Group (Greipp 2005). 
ISS Stage I: Serum beta-2 microglobulin < 3.5 mg/L and serum albumin ≥ 3.5 g/dL 
ISS 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 
ISS Stage III: Serum beta-2 microglobulin ≥ 5.5 mg/L 
Revised International Staging System (R-ISS) Stage at Baseline 
R-ISS stage at baseline will be calculated using ISS (serum beta-2 microglobulin and 
serum albumin value collected at baseline, with ISS calculated as above), cytogenetic 


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risk group by FISH (central lab data, local lab data), and LDH, based on the criteria 
published by the International Myeloma Working Group (Palumbo, 2015): 
R-ISS Stage I: Serum beta-2 microglobulin < 3.5 mg/L, serum albumin ≥ 3.5 g/dL and 
standard risk CA by FISH and normal LDH 
R-ISS Stage II: Not R-ISS I or III 
R-ISS Stage III: ISS III and either high risk CA by FISH or greater than normal LDH 
Last Dose Date 
The last dose date is the date on which a subject is administered the final dose of any 
study drug.   
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, lenalidomide, or dexamethasone is 
given for subjects who receive at least one dose of study drug, enrollment date for 
subjects who are enrolled but not treated. 
Study Day 
The number of days from the study day 1 to a date of interest, inclusive: Study day = 
(date of interest – date of study day 1) + 1. 
Unless otherwise specified, the timing of all study-related events, assessments, and 
interventions will be calculated relative to study day 1.  Study day −1 will be the day 
before study day 1, and in general for assessments prior to study day 1, study day is 
defined as: 
Study Day n = (date of interest – date of Study day 1) 


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Subject Incidence Rate 
The subject incidence rate for a given event is defined as the number of subjects with 
one or more reported occurrence of the event divided by the number of subjects who 
had the opportunity to experience the event.   
Treatment-emergent Adverse Event  
Treatment-emergent adverse events are defined as any adverse events starting on or 
after the first dose of any study drug, and up to including 30 days after the last dose 
of any study drug or End of Study date, whichever is earlier. 
 
 


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6. 
Analysis Sets 
6.1 
Safety Analysis Set 
The safety analysis set includes all subjects who received at least one dose of study 
drug. 
6.2 
Response-Evaluable Analysis Set 
The response-evaluable analysis set is defined as subjects who are included in the 
safety analysis set, have a baseline disease assessment and at least 1 post-baseline 
disease assessment, or dropped out due to AE prior to the first post-baseline disease 
assessment. 
6.3 
Pharmacokinetic Analysis Set  
The pharmacokinetic analysis subset includes subjects in the safety analysis set that 
have sufficient carfilzomib exposure and plasma concentration versus time data for the 
estimation of PK parameters by a non-compartmental analysis on Day 8 of Cycle 1. 
6.4 
Pharmacodynamic Analyses Set  
The pharmacodynamic analysis subset includes subjects in the safety analysis set that 
have at least one measurable PDn endpoints. Proteasome activity for the chymotrypsin-
like, trypsin-like and caspase-like activities from whole blood will be reported for the 
collected time points to determine if carfilzomib treatment produces a pharmacodynamic 
reduction in proteasome activity relative to baseline activity levels. 


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7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
A Cohort Safety Review Committee (CSRC) comprised of the lead investigator, selected 
additional investigators, the sponsor’s study medical monitor, and sponsor’s drug safety 
representative will review all available safety data and make recommendations regarding 
ongoing enrollment and opening of subsequent cohorts during the Dose Evaluation 
Component.  The CSRC will also select the KRd regimens to be evaluated in the 
Dose-expansion Component.  
No formal interim analyses with the purpose of stopping the study early for efficacy or 
futility will be conducted for this study. 
7.2 
Primary Analysis 
No primary analysis is planned for this study. 
7.3 
Final Analysis 
The final analysis will occur when last subject completes the last assessment in the 
study (last subject last visit). 
Approximately 6 months will be required to enroll subjects in the RRMM Dose evaluation 
component of the study.  Approximately 9 months will be required to enroll subjects in 
the RRMM dose-expansion component of the study.  Subjects will be followed for up to 
17 months in order to complete primary safety and efficacy evaluation with up to an 
additional 12 months of Active follow-up.  
It will take up to approximately 12 months to enroll NDMM subjects into Dose-evaluation 
Cohort 4, review the safety data, and enroll NDMM subjects into the NDMM  
Dose-expansion Arm 3. Subjects will be followed for up to 17 months on treatment (with 
an allowed interruption of up to 4.5 months for ASCT), and for up 12 months for Active 
Follow-up. 
Based on the assumption, it is estimated that the final analysis will occur approximately 
60 months after the first subject is enrolled. 
In preparation for this analysis, data will be subject to ongoing checks for 
integrity, completeness and accuracy in accordance with the Data Management 
Plan with the expectation that all outstanding data issues are resolved ahead of 
the snapshot.  The data will be locked to prevent further changes, and a snapshot 
of the locked database will be used in the analysis. 


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8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. The 
database will be subject to edit checks outlined in the data management plan (DMP) by 
Amgen Clinical Data Management (CDM) department. Data inconsistencies and 
suspicious values will be reviewed and resolved before the database is locked. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. PK, FISH, MRD and biomarker data will be evaluated by central laboratory 
transferred to Amgen GSO-DM. The data handling and electronic transfer of data are 
described in the DMP.  
8.3 
Handling of Missing and Incomplete Data 
Missing and incomplete data will be identified through programmatic checks and a 
review of the tables and listings created within Biostatistics.  Missing and incomplete 
data will be identified for investigation, and possible resolution, by DM and Global Study 
Management prior to each planned data snapshot and final database lock.   
The handling of dropouts and missing disease status assessments for the efficacy 
variables is described in the description of the analyses.  In general, data will be 
analyzed as retrieved from the study database and no imputation for missing data will be 
performed.  Exceptions to this rule are detailed as below.  
Missing or incomplete dates for adverse events, concomitant medications will be 
imputed as outlined by the algorithms below.   


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Table 3.  Imputation Rules for Partial or Missing Start Dates 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: 
yyyymm 
Partial: 
yyyy 
Missing 
< 1st 
dose 
≥ 1st 
dose 
< 1st 
dose 
yyyymm 
≥ 1st 
dose 
yyyymm 
< 1st 
dose 
yyyy 
≥ 1st 
dose 
yyyy 
Partial: 
yyyymm 
= 1st dose 
yyyymm 
2 
1 
2 
1 
n/a 
1 
1 
≠ 1st dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st dose 
yyyy 
3 
1 
3 
1 
n/a 
1 
1 
≠ 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1 = Impute the date of first dose 
2 = Impute the first of the month 
3 = Impute January 1st of the year 
4 = Impute January 1st of the stop year 
Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date. 
Imputation Rules for Partial or Missing Stop Dates 
1. Initial imputation
•
If the month and year are present, impute the last day of that month
•
If only the year is present, impute December 31 of that year
•
If the stop date is entirely missing, assume the event or medication is ongoing
2. If the stop date imputation leads to a stop date that is after the death date, then 
impute the stop date as the death date.
3. If the stop date imputation leads to a stop date that is before the start date, then 
there is a data error and do not impute the stop date. (ie, set the stop date as 
missing). 


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If a partial or complete stop date is present and the ‘ongoing’ or ‘continuing’ box is 
checked, then it will be assumed that the adverse event or concomitant medication is 
ongoing.  Missing stop dates will not be imputed beyond the subject last contact date or 
data cutoff date. 
Imputation Rules for Partial or Missing Death Dates: 
1. If death year and month are available but day is missing: 
• 
If mmyyyy for last contact date = mmyyyy for death date, set death date to 
the day after the last contact date. 
• 
If mmyyyy for last contact date < mmyyyy for death date, set death date to 
the first day of the death month. 
• 
If mmyyyy for last contact date > mmyyyy for death date, data error and do 
not impute. 
2. If both month and day are missing for death date or a death date is totally 
missing, do not impute. 
The imputed death date will be used in calculation of duration of response, progression-
free survival.  
Imputation Rules for date of initial diagnosis:  
If the day is missing and month and year < month and year of enrollment then impute 15 
for the day. 
If the day is missing and month and year = month and year of enrollment then impute 
day with 15 unless the day of enrollment is <15 then impute date of enrollment. 
If the day and month are missing and year is < year of enrollment then impute July 1st.  
If the day and month are missing and year = year of enrollment then impute July 1st 
unless the day of enrollment is <July 1st then impute January 1st. 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations in each cohort.  
The clinical study team will identify and document the criteria for important protocol 
deviations. 
8.5 
Outliers 
Outlier data will not be excluded unless scientifically justified. 


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PK plasma concentration data will be evaluated for outliers by visual inspection and 
decisions to re-assay individual samples will be made in accordance with standard 
PKDM practices.  
8.6 
Distributional Characteristics 
The investigation of distributional characteristics for the proposed summaries of the data 
is not needed for this study.   
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software SAS version 9.3. or later   


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9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
In general, the data will be presented in the CSR by considering RRMM patient groups 
(Cohort 1, Cohort 2 and Arm 2) and NDMM patient groups (Arm 1, Cohort 4 and Arm 3) 
separately. The data will be presented by each assigned dose cohort and by combined 
dose cohort in RRMM group and NDMM group. The dose cohort grouping is as follows. 
RRMM patient groups: 
1. RRMM 56 mg/m2 (n=10) – Cohort 1 
2. RRMM 70 mg/m2 (n=12) – Cohort 2 
3. RRMM 70 mg/m2 (n=34) – Arm 2 
4. RRMM 70 mg/m2 (n = 46) – Cohort 2 + Arm 2 
NDMM patient groups: 
1. NDMM 70 mg/m2 (n=9) – Arm 1 
2. NDMM 56/70 mg/m2 (n=9) – Cohort 4 (step up dosing) 
3. NDMM 70 mg/m2 (n=18) – Arm 1 + Cohort 4 
4. NDMM 56 mg/m2 (n=33) – Arm 3 
Summary statistics will be provided for selected study variables.  For continuous 
variables, the number of subjects with non-missing data (n), mean, standard deviation, 
median, minimum, and maximum will be presented.  For discrete variables, the 
frequency and percentage distribution will be presented.  Unless otherwise stated, the 
denominator for percentages is the number of subjects in the analysis set of interest for 
the summary.  Graphical methods will be used, as appropriate, to illustrate study 
endpoints. 
Confidence interval, when presented, will be constructed at the 95% level. For binomial 
variable, exact distribution methods will be employed. The distribution of time-to-event 
endpoints will be summarized by Kaplan-Meier method. Quartiles including median will 
be estimated by Kaplan-Meier along with their 95% confidence intervals. 
Individual subject data recorded on the electronic case report forms (eCRFs) and any 
derived data will be presented in dataset tabulations. 
 


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9.2 
Subject Accountability 
The following subject disposition information will be summarized as follows 
• 
Number of enrolled subjects 
• 
Number of subjects in Safety Analysis Set  
• 
Number (%) of subjects in Response Evaluable Analysis Set 
• 
Number (%) of subjects who discontinued treatment 
• 
Number (%) of subjects who discontinued the study 
• 
Primary reason for study discontinuation 
• 
Primary reason for carfilzomib discontinuation 
In addition, the number (%) of subjects who had done the following on-study procedures 
will be reported: stem cell collection, autologous stem cell transplant, allogeneic stem 
cell transplant. 
The percentages are based on the number of subjects in the Safety Analysis Set. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. All IPDs will be summarized by category and sub-category for the Safety 
analysis set.   
9.4 
Demographic and Baseline Characteristics 
9.4.1 
Demographics and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized for the 
Safety analysis Set: 
• 
Age (years) and age categorized (years) as: < 65, 65 - < 75, and ≥ 75; 
• 
Sex (Male, Female); 
• 
Ethnicity (Hispanic or Latino, Non-Hispanic or Latino) 
• 
Race (White and other categories depending on frequency observed) 
• 
ECOG performance status (0, 1, 2)  
• 
Weight (kg) 
• 
Height (cm) 
• 
Body surface area (m2)  
 


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9.4.2 
Medical History 
The number (%) of subjects who experienced a prior disease or disorder will be 
summarized by system organ class and preferred term for the Safety Analysis Set.  
9.4.3 
Disease Characteristics 
The following disease characteristics will be summarized for the Safety Analysis Set: 
• 
Time (months) since initial diagnosis, defined as date of informed consent signed 
minus date of diagnosis 
• 
Type of measurable disease (SPEP and UPEP, SPEP, UPEP, SFLC only) 
• 
Heavy chain and light chain status 
• 
Plasma cell involvement (%) as assessed with bone marrow assessment (< 50%, 
≥ 50%, unknown or missing) 
• 
Cytogenetic risk group determined by central laboratory FISH (standard risk, 
high risk, unknown).  
• 
Cytogenetic risk group determined by local laboratory FISH (standard risk, 
high risk, unknown) 
• 
Baseline beta2 microglobulin (mg/L) (< 3.5, 3.5 - < 5.5, ≥ 5.5 mg/L)  
• 
Baseline albumin (g/dL) (as continuous variable; <3.5, >=3.5 g/dL) 
• 
International Staging System (ISS) stage at diagnosis (I, II, III, unknown) 
• 
ISS stage at baseline (I, II, III, unknown) 
• 
Revised ISS at baseline (I, II, III, unknown): FISH data from central laboratory 
• 
Revised ISS at baseline (I, II, III, unknown): FISH data from local laboratory 
9.4.4 
Prior Cancer Therapies 
The following information related to prior cancer therapy will be summarized for the 
RRMM subjects in the Safety analysis set: 
• 
Number (%) of subjects with at least one systemic anti-myeloma therapy, 
transplant, radiation or multiple myeloma-related surgery, respectively. 
• 
Number of regimens of prior treatment (1, 2, etc.) for multiple myeloma 
• 
Best response to most recent prior regimen 
• 
Refractory status to any prior regimen and to most recent prior regimen 
(bortezomib, lenalidomide, bortezomib and lenalidomide) 
9.5 
Efficacy Analyses 
The primary analysis of efficacy will be based on the Safety Analysis Set. Additionally, 
the response data (ORR, CRR) may also be analyzed based on the Response-
evaluable Analysis Set.   


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9.5.1 
Overall Response Rate and Complete Response Rate 
The number (%) of subjects with a best response of sCR, CR, VGPR, PR, SD, PD or NE 
will be summarized.  
Overall response rate is defined as the proportion of subjects for whom the best overall 
confirmed response is sCR, CR, VGPR, or PR as determined by International Myeloma 
Working Group Uniform Response Criteria (IMWG-URC) per investigator.  The ORR 
along with the associated 95% exact binomial confidence interval (Clopper-Pearson 
method) will be determined.  
The Complete Response rate (CRR), defined as the proportion of subjects with the best 
overall confirmed response of complete response (CR) or better, will be determined 
along with the 95% exact binomial confidence interval.  
Same summary and analysis for ORR will be repeated based on ORCA assessments. 
9.5.2 
Progression-Free Survival 
Progression free survival (PFS) is defined as number of months (one month = 30.4 days) 
between start of treatment and first evidence of documented disease progression or 
death (due to any cause), whichever occurs first.  Disease progression will be 
determined using IMWG-URC and will be determined by the investigator.   
• 
PFS = (Earliest date of disease progression, death, or censoring – Date of 
first dose + 1) / 30.4  
Progression-free survival will be right-censored for subjects who met one of the following 
conditions: 1) no baseline disease assessments, 2) non-protocol systemic anticancer 
treatment started before documentation of PD or death, 3) death or disease progression 
after more than 1 missed disease assessment visit, or 4) alive and does not have 
documentation of PD before a data analysis cutoff date.  These conventions 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).  For such 
subjects, the primary analysis of PFS will be right-censored according to the conventions 
described in Table 4. 
The Kaplan-Meier curves will be used to estimate the distribution of PFS and the median 
and other quartiles in addition to the corresponding two-sided 95% confidence intervals.  
Duration of follow-up for PFS will be summarized according to the Kaplan-Meier 
estimate of potential follow-up also termed “reverse Kaplan-Meier” (Schemper 1996).    
Same summary and analysis for PFS will be repeated based on ORCA assessments. 


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Table 4.  Conventions for Censoring for PFS 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline disease assessments 
Date of first dose 
Censored 
New anticancer therapy started before 
documentation of PD or death 
Date of last disease assessment prior 
to start of new anticancer therapy 
Censored 
Death or PD immediately after more 
than 1 consecutively missed disease 
assessment visit 
Date of last disease assessment visit 
before the first missed visit 
Censored 
Alive and without PD documentation  
Date of last disease assessment 
Censored 
Lost to follow up or withdrawn 
consent 
Date of last disease assessment 
Censored 
Death or PD between planned 
disease assessments 
Date of death or first disease 
assessment showing PD, whichever 
occurs first 
Progressed 
Death before first disease assessment 
Date of death 
Progressed 
9.5.3 
Duration of Response 
Duration of response (DOR) will be calculated for subjects who achieve a PR or better.  
For such subjects, the duration of overall response is defined as the time (months) from 
first documentation of response to disease progression or death due to any cause.  
Dates of progression and censoring will be determined as described for the analysis of 
PFS.   
DOR = (Earliest date of disease progression, death, or censoring - Date of first 
observation of PR or better before confirmation + 1) / 30.4  
Kaplan-Meier methods will be used to estimate the distribution of DOR and the median 
and other quartiles in addition to the corresponding two-sided 95% confidence intervals; 
a figure showing the estimated DOR distribution will be provided.   
9.6 
Safety Analyses 
All safety analyses will be based on the Safety Analysis Set. 
9.6.1 
Adverse Events and Disease-related Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 21.0 or later will be 
used to code all adverse events (AEs) to a system organ class (SOC) and a preferred 
term (PT).  The severity of AEs will be coded according to NCI-CTCAE v 4.03.  


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Treatment emergent adverse events will be summarized based on the number (%) of 
subjects experiencing events by MedDRA SOC and PT.  The denominator for the 
percentage will be based on the number of subjects in the Safety Analysis Set.  
Summaries of the subject incidence of the following TEAEs will be provided by SOC 
and/ or PT:  
• 
All TEAEs  
• 
TEAEs grade 3 or higher 
• 
Fatal TEAEs 
• 
Serious TEAEs 
• 
TEAEs leading to withdrawal of carfilzomib 
• 
Treatment-related TEAEs  
• 
Treatment-related TEAEs grade 3 or higher  
• 
Treatment-related fatal TEAEs 
• 
Treatment-related serious TEAEs 
• 
Treatment-related TEAEs leading to withdrawal of carfilzomib 
Summaries that are displayed by SOC and PTs will be ordered by descending order of 
incidence of SOC and PT within each SOC for the total group. Summaries of TEAEs, 
and SAEs will be tabulated by SOC, PT and grade. Summaries of TEAEs, treatment-
related AEs, and SAEs will also be provided by descending order of incidence of PTs in 
the total group 
All TEAEs will be included in listings by subject. Listings of AEs determined to be DLTs, 
SAEs, AEs leading to discontinuation of study and AEs leading to discontinuation of 
investigational product will be provided. 
A summary of the number of deaths and the cause of death, classified by deaths within 
30 days of last dose of study drug and deaths more than 30 days after the last dose, will 
be provided. 
Subject incidence of adverse events of interest (standardized MedDRA queries (SMQ) 
and/or Amgen MedDRA queries (AMQ)) will also be summarized according to their 
categories, PTs and grade. The adverse events of interest would include 
• 
Acute renal failure (SMQ Narrow search)  
• 
Cardiac arrhythmias (SMQ Narrow search)  
• 
Cardiac failure (SMQ Narrow search)  
• 
Cardiomyopathy (SMQ Narrow search) 


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• 
Dyspnoeas (HLT) - MedDRA Search Strategy HLT   
• 
Embolic and thrombotic events, venous (SMQ Narrow search)  
• 
Haematopoietic erythropenia (SMQ Broad search) 
• 
Haematopoietic leukopenia (SMQ Narrow search)  
• 
Haematopoietic thrombocytopenia (SMQ Narrow search)  
• 
Haemorrhage terms (excl laboratory terms) (SMQ Narrow search)  
• 
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions 
(SMQ Narrow search)  
• 
Hepatitis B virus reactivation (AMQ including PTs: Hepatitis viral, Hepatitis 
acute, Hepatitis B, Acute hepatitis B, Hepatitis B reactivation, Hepatitis B 
DNA assay positive, Hepatitis B DNA increased) 
• 
Hypertension (SMQ Narrow search)  
• 
Infusion reactions – (AMQ Narrow search)  
− 
event on same date of any Carfilzomib dosing 
− 
event on same date of first Carfilzomib dosing 
• 
Interstitial lung disease (SMQ Narrow search)  
• 
Ischaemic heart disease (SMQ Narrow search)  
• 
Liver related investigations, signs and symptoms (SMQ Narrow search)  
• 
Myocardial infarction (SMQ Narrow search) 
• 
Peripheral neuropathy (SMQ Narrow search) 
• 
Progressive multifocal leukoencephalopathy (AMQ Narrow search) 
• 
Pulmonary hypertension (SMQ Narrow search)  
• 
Respiratory failure (SMQ Narrow search) 
• 
Respiratory tract infections (HLGT) 
• 
Reversible posterior leukoencephalopathy syndrome (AMQ Narrow search) 
• 
Torsade de pointes/QT prolongation (SMQ Narrow search)  
• 
Tumour lysis syndrome (SMQ Narrow search)  
 
9.6.2 
Laboratory Test Results 
Actual values and change from baselines for all chemistry and hematology laboratory 
parameters will be summarized descriptively for each scheduled visit based on the 
Safety Analysis Set.  


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Selected laboratory values will also be categorized according to their NCI-CTCAE 
(V4.03) toxicity grade.  The laboratory parameters of interest for these summaries are: 
Hematology 
Serum Chemistry 
Hemoglobin (decrease) 
Alanine transaminase 
(ALT) (increase) 
Albumin (decrease) 
Platelets (decrease) 
Aspartate transaminase 
(AST) (increase) 
Uric Acid (increase) 
White Blood Cell (WBC, 
increase, decrease) 
Alkaline Phosphatase 
(increase) 
Sodium (increase, 
decrease) 
Absolute Neutrophil Count 
(ANC, decrease) 
Total Bilirubin (increase) 
Phosphorus (decrease) 
Absolute Lymphocyte 
Count (increase, decrease) 
Creatinine (increase) 
Potassium (increase, 
decrease) 
 
Calcium (increase, 
decrease) 
Magnesium (increase, 
decrease) 
 
Glucose (increase, 
decrease) 
 
For hypocalcemia and hypercalcemia, serum calcium will be corrected using the 
formula: 
• 
Corrected calcium = Serum calcium + 0.8 * (4 – serum albumin) where serum 
calcium is recorded in mg/dL and serum albumin is recorded in g/dL. 
Shift tables will be presented for the baseline toxicity grade by the worst on-study toxicity 
grade and the toxicity grade at the end of treatment for the chemistry and hematology 
parameters with NCI-CTCAE toxicity grading. 
9.6.3 
Vital Signs 
Actual value and change from baseline for weight and vital sign results including blood 
pressure, pulse, respiratory rate, and temperature will be summarized at each scheduled 
protocol time point. The mean pre- and post-carfilzomib SBP and DBP on C1 – 6, C12 
and C18 will be presented with average change from pre-to post SBP and DBP 
summarized for each date. Any clinically significant values as assessed by the 
investigator will be reported as adverse events. 
 
 


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9.6.4 
Physical Measurements 
The following physical examination will be summarized over time 
• 
ECOG PS 
• 
Weight  
• 
BSA  
 
9.6.5 
Electrocardiogram 
The ECG measurements from this clinical study were performed at Screening and as 
per standard of care for routine safety monitoring, rather than for purposes of 
assessment of potential QTc effect.  No summary of ECG results will be provided. 
9.6.6 
Echocardiogram 
Left ventricular ejection fraction (LVEF) as determined by MUGA Scan or 
Echocardiogram at baseline, during cycle 2 (for dose evaluation subjects), and at End of 
Treatment will be summarized over time.  Changes in LVEF from baseline will be 
presented descriptively. 
9.6.7 
Exposure to Investigational Product 
Extent of exposure to all study treatments (carfilzomib, lenalidomide, and 
dexamethasone) will be summarized for Safety population 
• 
Duration of treatment (weeks) (carfilzomib in combination with lenalidomide and 
dexamethasone and each component) 
o Defined as the duration (in weeks) from the date of the first dose of any study 
drug to the date of the last dose of all study drugs + 1 
o Duration of treatment with carfilzomib / lenalidomide / dexamethasone is defined 
as duration (in weeks) from the date of the first dose of carfilzomib / lenalidomide 
/ dexamethasone to the date of the last dose of carfilzomib / lenalidomide / 
dexamethasone + 1 
• 
Total number of treatment cycles received (carfilzomib in combination with 
lenalidomide and dexamethasone and each component) 
o Defined as the total number of treatment cycles in which at least one dose of any 
study drug is administered. 
o Number of cycles with carfilzomib / lenalidomide / dexamethasone is defined as 
the total number of treatment cycles in which at least one dose of carfilzomib / 
lenalidomide / dexamethasone is administered. 
• 
Number of treatment cycles received (carfilzomib in combination with 
lenalidomide and dexamethasone and each component) prior to stem cell 
transplant (SCT) for subjects who had SCT. 


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• 
Number of treatment cycles received (carfilzomib in combination with 
lenalidomide and dexamethasone and each component) for subjects who did 
not have SCT. 
• 
Number (%) of subjects dosed by cycle (carfilzomib in combination with lenalidomide 
and dexamethasone and each component) 
• 
Number of doses of carfilzomib / lenalidomide /dexamethasone administered 
o Defined as the total number of non-zero doses of carfilzomib / lenalidomide 
/dexamethasone respectively, a subject received during the treatment period of 
the study. 
• 
Cumulative dose received of carfilzomib (mg and mg/m2), lenalidomide (mg) / 
dexamethasone (mg) across all cycles, defined as the cumulative dose of carfilzomib 
/ lenalidomide / dexamethasone, respectively. 
• 
Average dose of carfilzomib (mg and mg/m2), lenalidomide (mg), and 
dexamethasone (mg) per administration, defined as the total dose received divided 
by the number of doses administered  
• 
Relative dose intensity of carfilzomib / lenalidomide / dexamethasone, calculated as 
the ratio of actual dose intensity to planned dose intensity and expressed as a 
percent (Appendix A). 
• 
Number (%) of subjects with doses missed, dose delays, dose changes, and dose 
interruptions for carfilzomib and dose changes and dose delays for lenalidomide and 
dexamethasone, respectively. 
 
9.6.8 
Exposure to Concomitant Medication 
Concomitant medications are defined as medications with start date or end date on or 
after the date of first dose and start date before the date of the last dose + 30 days or 
are ongoing at the time of first dose.  For the purpose of determining if a medication 
should be noted as a concomitant medication, the imputation rules stated in Section 8.3 
will be used.  The number and proportion of subjects receiving concomitant medications 
will be summarized by preferred name as coded by the World Health Organization Drug 
(WHO DRUG) dictionary.  A subject is counted once if he/she reported one or more 
medications.  The summaries will be ordered by descending frequency of preferred 
name in the total group.  
9.7 
Other Analyses 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
PK/PDn analyses will be provided by the Department of Clinical Pharmacology, 
Modeling & Simulation (CPMS). Actual collection times of PK samples will be recorded 
to assess the plasma concentration. The PK parameter estimates for carfilzomib will be 
summarized. Exploratory analyses may be performed to evaluate the relationship 
between the estimated PK parameters and selected safety, biomarker, or clinical effect 


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endpoints. In addition, the population modeling program may be used to fit a nonlinear 
mixed effects model to estimate PK parameters. Details regarding the analyses will be 
provided in a separate analysis plan by CPMS. 
9.7.2 
Analyses of Minimal Residual Disease Negative Rate Endpoints 
The analysis of MRD[-] rate will not be included in the clinical study report (CSR). The 
MRD analyses will be summarized in a separate analysis plan by Clinical Biomarkers & 
Diagnostics group. 
9.7.3 
Analyses of Patient Reported Outcomes and Other Health Related 
Quality of Life Endpoints 
Results from the subject convenience and satisfaction questionnaire will be summarized 
descriptively at Cycle 3 Day 1 and Cycle 18 Day 1 by presenting the number and 
percentage of subjects for each item of the questionnaire The denominator for 
percentage will be based on (1) the number of subjects in the safety analysis set; 
(2) the number of subjects received carfilzomib at the specified timepoint (Cycle 3
Day 1, Cycle 18 Day 1).
9.7.4 
Analyses of Biomarker Endpoints 
Biomarker analyses will be performed by Clinical Biomarkers & Diagnostics group and 
will not be included in CSR.   


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10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses.   
 


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11. 
Literature Citations / References 
Bladé J, 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. 
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. 
Kalbfleisch, J. D. and Prentice, R. L. The Statistical Analysis of Failure Time Data, New 
York: John Wiley & Sons; 1980. 
Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for 
Multiple Myeloma: a report from International Myeloma Working Group, J Clin Oncol,  
33 (26) (2015), pp. 2863–2869 
Rajkumar 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 
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. 
Controlled Clinical Trials 17:343–346, 1996 
 
 
 
 


Product: Carfilzomib 
Protocol Number:  20140241 (CFZ013) 
Date:  15 October 2019 
Page 39 of 42 
 
CONFIDENTIAL            
 
12. 
Appendices 


Product: Carfilzomib 
Protocol Number:  20140241 (CFZ013) 
Date:  15 October 2019 
Page 40 of 42 
CONFIDENTIAL       
Appendix A.  Dose Intensity Calculations 
Dose intensity is calculated for each drug component and expressed as an average 
dose per unit of time. In this study, we choose the time unit to be week. 
1. The formula for Actual Dose Intensity (mg/m2/wk or mg/wk) is defined as:
Actual Dose Intensity (mg/m2/wk or mg/wk) = Cumulative actual dose (mg or mg/m2)
Duration of exposure (wk)
•
Cumulative actual dose (mg or mg/m2) received of carfilzomib and
dexamethasone is defined as the cumulative dose of
carfilzomib/dexamethasone, respectively, a subject received during the
treatment period of the study.
•
Duration of exposure (weeks) is defined as
(last dose date –  fist dose date) + planned interval to next treatment week
7 days
Carfilzomib dosing schedule and planned interval 
Cycle 
Cycle Day of 
Treatment 
Dose (mg/m2) 
Interval (Days) to 
Next Planned 
Treatment Week (or 
Completion) 
1 
Day 1 
20 
7 
Day 8 
56 if Cohort 1; Cohort 4; Arm 3  
70 if Cohort 2; Arm 1; Arm2 
7 
Day 15 
56 if Cohort 1; Cohort 4; Arm 3  
70 if Cohort 2; Arm 1; Arm 2 
14 
2 -18 
Day 1 
56 if Cohort 1; Arm 3   
70 if Cohort 2; Cohort 4; Arm 1; Arm 2 
7 
Day 8 
56 if Cohort 1; Arm 3   
70 if Cohort 2; Cohort 4; Arm 1; Arm 2 
7 
Day 15 
56 if Cohort 1; Arm 3   
70 if Cohort 2; Cohort 4 ; Arm 1; Arm 2 
14 
Dexamethasone dosing schedule and planned interval 
Cycle 
Cycle Day of 
Treatment 
Dose (mg) 
Interval (Days) to Next 
Planned Treatment 
1 - 8 
Day 1 
40 
7 
Day 8 
40 
7 
Day 15 
40 
7 
Day 22 
40 
7 
9 -18 
Day 1 
40 
7 
Day 8 
40 
7 
Day 15 
40 
14 


Product: Carfilzomib 
Protocol Number:  20140241 (CFZ013) 
Date:  15 October 2019 
Page 41 of 42 
 
CONFIDENTIAL            
 
Lenalidomide dosing schedule and planned interval 
Cycle 
Cycle Day of 
Treatment 
Dose (mg) 
 
Interval (Days) to Next 
Planned Treatment 
1 - 18 
Day 1 - 7 
25  
7 
 
Day 8 – 14 
25  
7 
 
Day 15 - 21 
25  
7 
2. The formula for Planned Dose Intensity (mg/m2/wk or mg/wk) is defined as: 
Planned Dose Intensity (mg/m2/wk or mg/wk) = 
Cumulative planned dose (mg/m2 or mg)
Number of protocol specified treatment weeks 
 
• 
Number of protocol specified treatment weeks is the sum of treatment weeks the 
patient completed. It is counted by 4 weeks for a completed or skipped cycle.  For 
the last cycle, use the following rules to count: 
Carfilzomib 
1 week if the last dose is on Day 1;  
2 weeks if the last dose is on Day 8; 
4 weeks if the last dose is on Day 15; 
 
Example:  Patient’s last carfilzomib is on cycle 2 Day 8. The number of protocol 
specified treatment weeks is D=4x1+2=6 weeks. 
Dexamethasone 
1 week if the last dose is on Day 1;  
2 weeks if the last dose is on Day 8; 
3 weeks if the last dose is on Day 15 in Cycle 1 to 8; 
4 weeks if the last dose is on Day 15 after Cycle 8 or Day 22; 
Lenalidomide 
1 week if the last dose is on Day 1-7;  
2 weeks if the last dose is on Day 8-14; 
4 weeks if the last dose is on Day 15- 21; 
 
• 
Cumulative planned dose for each drug is the sum of protocol specified doses 
across the treatment weeks as determined above. Per study treatment regimen on 
protocol: 
Carfilzomib cumulative planned dose: 
For Cohort 1; Arm 3: [20, 56, 56, 0], [56, 56, 56, 0] …… 
For Cohort 2, Arm 1; Arm 2: [20, 70, 70, 70], [70, 70, 70, 0] …… 
For Cohort 4: [20, 56, 56, 0], [70, 70, 70, 0] …… 


Product: Carfilzomib 
Protocol Number:  20140241 (CFZ013) 
Date:  15 October 2019 
Page 42 of 42 
 
CONFIDENTIAL            
 
Dexamethasone cumulative planned dose:  
[40, 40, 40, 40], repeated 7 more times, [40, 40, 40, 0] …… 
Lenalidomide cumulative planned dose:  
[25, 25, 25, 25, 25, 25, 25], [25, 25, 25, 25, 25, 25, 25], [25, 25, 25, 25, 25, 25, 25],  
[0, 0, 0, 0, 0, 0, 0], …… 
3. Relative dose intensity is calculated as actual dose intensity / planned dose intensity 
and expressed as a percent.