Conditions: Relapsed Multiple Myeloma Refractory Multiple Myeloma
Keywords: Carfilzomib Dexamethasone Daratumumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 466
Healthy volunteers: no

Brief summary:
Compare carfizomib, dexamethasone, and daratumumab (KdD) to Carfilzomib and dexamethasone (Kd) in terms of progression free survival (PFS) in participants with multiple myeloma who have relapsed after 1 to 3 prior therapies.

Detailed description:
This is a phase 3 multicenter, open-label, randomized study in participants with relapsed or refractory multiple myeloma (RRMM) who have received 1 to 3 prior therapies.

Participants receive the treatment determined by randomization for a maximum of approximately 5 years, up to 30 days prior to the final analysis data cutoff (DCO) date or until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or death (whichever occurs first). No crossover between the treatment arms is allowed.

This was an open-label study. However, the assessment of response and disease progression for the primary analysis was determined by an Independent Review Committee (IRC) in a blinded manner. Sensitivity analyses of response and disease progression were determined centrally by the sponsor using a validated computer algorithm (Onyx Response Computational Assessment \[ORCA\]) in a blinded manner.

Following progression or discontinuation of study drug(s), participants will have 1 follow-up visit (30 days \[+3} after last dose of all study drug\[s\]). After disease progression, data on survival status and subsequent antimyeloma therapy will be gathered at long-term follow-up (LTFU) visits every 12 weeks (+/-2 weeks) until the Final Analysis DCO.

Arms:
arm 1: Carfilzomib was administered intravenously (IV) at 20 mg/m\^2 in Cycle 1: days 1 and 2; at 56 mg/m\^2 in Cycle 1: days 8, 9, 15 and 16. The 56 mg/m\^2 dosage was continued in Cycles 2+ on days 1, 2, 8, 9, 15 and 16.

Dexamethasone was taken by IV infusion at 20 mg on Cycle 1, days 1 and 2 (in Cycles 2+, days 1 and 2 could be either oral or IV) and either orally or by IV infusion on days 8, 9, 15 and 16 and at 40 mg on day 22 of all 28-day cycles. arm 2: Carfilzomib was administered intravenously (IV) at 20 mg/m\^2 in Cycle 1: days 1 and 2; at 56 mg/m\^2 in Cycle 1: days 8, 9, 15 and 16. The 56 mg/m\^2 dosage was continued in Cycles 2+ on days 1, 2, 8, 9, 15 and 16.

Dexamethasone was taken by IV infusion at 20 mg on Cycle 1, days 1 and 2 (in Cycles 2+, days 1 and 2 could be either oral or IV) and either orally or by IV infusion on days 8, 9, 15 and 16 and at 40 mg on day 22 of all 28-day cycles. The administration of dexamethasone was given on carfilzomib and/or daratumumab IV infusion days.

Daratumumab was administered by IV at 8 mg/kg on Cycle 1: days 1 and 2; at 16 mg/kg on Cycle 1: days 8, 15 and 22, and Cycle 2: days 1, 8, 15, and 22. The 16 mg/kg dosage was continued on Cycles 3-6: days 1 and 15. The 16 mg/kg was further continued on Cycles 7+: day 1 only.

Interventions: intervention 1: Dexamethasone intervention 2: Daratumumab intervention 3: Carfilzomib
Intervention descriptions: intervention 1: Commercially available oral and IV formulas were obtained by investigative sites. Amgen supplied IV or PO dexa for some countries (Poland, Hungry, Romania, Bulgaria, Korea). Dosage modification rules applied based on participant age (participants \> 75 years were given lower doses), dexa-related toxicities, and discontinuation of carfilzomib. intervention 2: Daratumumab was supplied as a concentrated solution for infusion in single-use vials. intervention 3: Carfilzomib for infusion was supplied as a lyophilized, sterile product in single-use vials. The lyophilized product was reconstituted with preservative-free sterile water for injection, the reconstituted solution contained carfilzomib 2 mg/mL. IV injections lasted approximately 30 minutes.

Dose could be modified based on a \>20% change in body weight or toxicity.

Protocol document:
Prot_002.pdf: 
Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 1 of 140 
CONFIDENTIAL 
 
 
Title:  A Randomized, Open-label, Phase 3 Study Comparing Carfilzomib, 
Dexamethasone, and Daratumumab to Carfilzomib and Dexamethasone for the 
Treatment of Patients With Relapsed or Refractory Multiple Myeloma 
CANDOR 
Study of Carfilzomib ANd Daratumumab fOr Relapsed myeloma 
Amgen Protocol Number (carfilzomib) 20160275 
EudraCT number 2016-003554-33 
NCT03158688 
Clinical Study Sponsor: 
Amgen Inc. 
1 Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Tel:  1 (805) 447-1000 
Key Sponsor Contacts: 
 PhD 
Clinical Research Medical Director 
Amgen Inc. 
Tel: 
 
Email:
Date: 
13 December 2016 
Amendment 1: 
15 February 2017 
Amendment 2: 
09 June 2017 
Amendment 3: 
 
19 April 2018 
Amendment 4: 
17 May 2019 
Amendment 5 
02 October 2019 
Amendment 6 
17 March 2021 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US (1-805-447-1000). 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 2 of 140 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Randomized, Open-label, Phase 3 Study 
Comparing Carfilzomib, Dexamethasone, and Daratumumab to Carfilzomib and 
Dexamethasone for the Treatment of Patients With Relapsed or Refractory Multiple 
Myeloma (CANDOR), dated 17 March 2021, and agree to abide by all provisions set 
forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
 
my sub investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 
 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 3 of 140 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Randomized, Open-label, Phase 3 Study Comparing Carfilzomib, Dexamethasone, and 
Daratumumab to Carfilzomib and Dexamethasone for the Treatment of Patients With Relapsed or 
Refractory Multiple Myeloma (CANDOR) 
Study Phase:  3 
Indication:  Relapsed or Refractory Multiple Myeloma 
Primary Objective:  The primary objective is to compare carfilzomib, dexamethasone, and 
daratumumab (KdD) to carfilzomib and dexamethasone (Kd) in terms of progression free survival 
(PFS) in patients with multiple myeloma who have relapsed after 1 to 3 prior therapies. 
Secondary Objective(s):  Key secondary objectives are to compare the following between the 
2 arms: 
 
Overall Response Rate (ORR; defined as the proportion of best overall response of stringent 
complete response [sCR], complete response [CR], very good partial response [VGPR], and 
partial response [PR]) 
 
rate of minimal residual disease negative-complete response (MRD[-]CR) in bone marrow 
aspirates at 12 months ( 4 weeks) as determined by Next-Generation sequencing (NGS) 
 
overall survival (OS) 
Additional secondary objectives are to compare the following between the 2 arms: 
 
safety and tolerability 
 
duration of response (DOR) 
 
time to next treatment  
 
time to progression (TTP) 
 
time to response 
 
persistence of MRD[-]CR 
 
complete response rate (CRR) 
 
MRD[-] rate 
 
quality of life 
Hypothesis:  The KdD regimen will provide significant improvement in PFS over the Kd regimen. 
Primary Endpoint:  PFS defined as time from randomization until disease progression or death 
from any cause.  Response and disease progression determined by a blinded Independent 
Review Committee (IRC). 
Secondary Endpoint(s):  Key secondary endpoints include: 
 
ORR:  defined as the proportion of best overall response of stringent complete response 
(sCR), complete response (CR), very good partial response (VGPR), and partial response 
(PR) by IRC 
 
MRD[-]CR rate, MRD[-]CR defined as achievement of CR by IRC per International Myeloma 
Working Group-Uniform Response Criteria (IMWG-URC) and MRD[-] status as assessed by 
NGS (at a 10-5 level, pending analytical validation) at 12 months  
 
OS 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 4 of 140 
CONFIDENTIAL 
 
 
Additional secondary endpoints: 
 
DOR 
 
time to next treatment 
 
TTP 
 
time to response  
 
sustained MRD[-]CR (defined as the proportion of subjects that maintain MRD[-]CR for 
12 months or more after achieving MRD[-]CR status) 
 
CRR (defined as the proportion of best overall response of sCR or CR) 
 
MRD[-] rate 
 
electronic clinical outcome assessments (eCOAs):  quality of life questionnaire – core 
30 items (QLQ-C30) Global Health Status/Quality of Life (QoL) measured by European 
Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 version 
3 questionnaire  
 
subject incidence of treatment-emergent adverse events 
 
safety laboratory values, left ventricular ejection fraction (LVEF), forced expiratory volume in 
1 second (FEV1)/forced vital capacity (FVC) ratio, and vital signs at each scheduled 
assessment 
Study Design:  This is a phase 3 multicenter, open-label, randomized study in subjects with 
relapsed or refractory multiple myeloma (RRMM) who have received 1 to 3 prior therapies. 
Subjects will be randomized in a 2:1 ratio to 1 of 2 arms: 
 
Arm 1:  KdD 
 
Arm 2:  Kd 
Randomization will be performed using an interactive voice/web response system (IxRS) and 
subjects will be stratified based on the following criteria:  Original International Staging System 
(ISS) stage (variables:  albumin and beta 2 microglobulin; strata:  Stage 1 or 2 vs Stage 3) at 
screening, prior proteasome inhibitor exposure (yes vs no), number of prior lines of therapy 
(1 vs  2), and prior cluster differentiation antigen 38 (CD38) antibody therapy (yes vs no). 
Subjects will receive the study treatment determined by randomization
 or 
until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or death 
(whichever occurs first).  No crossover between the treatment arms will be allowed.  All subjects 
will be assessed for multiple myeloma disease response according to the IMWG-URC using 
central laboratory test results every 28  7 days.  
 
 disease response assessments will be performed every 28  7 days until confirmed 
progressive disease (PD). 
Following progression or discontinuation of study drug(s), subjects will have 1 follow-up visit 
(30 days [ 3] after last dose of all study drug[s]).  After disease progression, data on survival 
status and subsequent antimyeloma therapy will be gathered at 
 
 
.   
Local serology testing for hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B 
core antibody will be performed at the next scheduled visit for all subjects that do not already 
have a known medical history of hepatitis B infection or who have not had testing conducted 
within the previous 12 weeks.  In addition, subjects with a known medical history of hepatitis B 
infection or who test positive for hepatitis B virus (HBV) serologies will be monitored closely for 
signs and symptoms of hepatitis B and will have local HBV deoxyribonucleic acid (DNA) testing 
performed at their next visit and then every 12 weeks ( 2 weeks) or more frequently if 
clinically indicated through follow-up Visit 1.  Subjects in arm 1 (KdD) will continue to be 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 5 of 140 
CONFIDENTIAL 
 
 
monitored and tested for 6 months following the last dose of daratumumab.  A hepatitis 
specialist should be consulted for all subjects who test positive for HBV serology or HBV DNA to 
undergo full assessment and make decisions regarding HBV reactivation treatment and/or 
confirmation whether HBV reactivation is adequately controlled to resume study drugs.  
Subjects who have received Hepatitis B vaccination with only anti-HBs positivity and no clinical 
signs of hepatitis do not require HBV DNA monitoring. 
Sample Size:  Approximately 450 subjects will be enrolled (300 in arm 1 and 150 in arm 2). 
Summary of Subject Eligibility Criteria:   
Key Inclusion Criteria 
 
male or female subjects 18 years of age 
 
relapsed or progressive multiple myeloma after last treatment 
 
received at least 1 but not more than 3 prior lines of therapy for multiple myeloma (induction 
therapy followed by stem cell transplant and consolidation/maintenance therapy will be 
considered as 1 line of therapy; see Appendix E for guidance) 
 
prior therapy with carfilzomib is allowed as long as the patient had at least a PR to most 
recent therapy with carfilzomib, was not removed due to toxicity, did not relapse within 
60 days from discontinuation of carfilzomib, and will have at least a 6-month carfilzomib 
treatment-free interval from last dose received until first study treatment.  (Patients may 
receive maintenance therapy with drugs that are not proteasome inhibitors or 
CD38 antibodies during this 6-month carfilzomib treatment free interval) 
 
prior therapy with anti-CD38 antibodies is allowed as long as the patient had at least a PR to 
most recent therapy with CD38 antibody, was not removed due to toxicity, did not relapse 
within 60 days from intensive treatment (at least every other week) of CD38 antibody therapy, 
and will have at least a 6-month CD38 antibody treatment-free interval from last dose 
received until first study treatment. 
Key Exclusion Criteria 
 
prior participation in a Janssen daratumumab phase 3 study (with exception of subjects in 
control arm that have withdrawn consent from study participation)  
 
known moderate or severe persistent asthma within the past 2 years 
 
known chronic obstructive pulmonary disease (COPD) with a FEV1  50 of predicted 
normal 
 
active congestive heart failure (New York Heart Association [NYHA] Class III to IV), 
symptomatic ischemia, uncontrolled arrhythmias, clinically significant electrocardiogram 
(ECG) abnormalities, screening ECG with corrected QT interval (QTc) of  470 msec, 
pericardial disease, or myocardial infarction within 4 months prior to randomization 
For a full list of eligibility criteria, please refer to Section 4. 
Investigational Product 
Amgen Investigational Product Dosage and Administration: 
Carfilzomib will be administered as an intravenous (IV) infusion.  On days when more than 
1 investigational product is administered, the required order of administration is as follows:  
dexamethasone, pre-infusion medications for daratumumab, carfilzomib, daratumumab, and 
post-infusion medications for daratumumab. 
Carfilzomib will be dosed twice weekly over 30  5 minutes, on days 1, 2, 8, 9, 15, and 16 of each 
28-day cycle.  The administration may be within  2 days for each scheduled dose.  The dose will 
be 20 mg/m2 on cycle 1 days 1 and 2 and 56 mg/m2 beginning on cycle 1 day 8 and thereafter. 
Each subject’s first dose of carfilzomib will be calculated based upon baseline body surface area 
(BSA) using the Mosteller formula.  In subjects with BSA of greater than 2.2 m2, the dose should 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 6 of 140 
CONFIDENTIAL 
 
 
be capped based on a BSA of 2.2 m2.  The dose for each subject should not be revised unless 
the subject experiences a change in body weight of  20 in which case the BSA and dose 
should be recalculated.  The dose can also be modified in response to toxicity following the dose 
modification guideline tables. 
Non-Amgen Investigational Product Dosage and Administration: 
Daratumumab will be administered as an IV infusion.  On days 1 and 2 of cycle 1, daratumumab 
will be administered at 8 mg/kg in 500 mL normal saline each day.  The dose of 16 mg/kg in 
500 mL normal saline will be given once weekly as a single infusion for the remaining doses of 
the first 2 cycles (ie, days 8, 15, and 22 of cycle 1; and days 1, 8, 15, and 22 of cycle 2), then 
every 2 weeks for 4 cycles (cycles 3 to 6), and then every 4 weeks for the remaining cycles or 
until disease progression.  The administration may be within  2 days for each scheduled dose. 
Non-investigational Product 
Non-Amgen Non-investigational Product Dosage and Administration: 
Dexamethasone 40 mg will be taken orally (PO) or by IV infusion weekly.  The IV administration 
of dexamethasone must be given on cycle 1 days 1 and 2.  Dexamethasone IV or PO will be 
given on successive days at 20 mg each treatment day on weeks with carfilzomib and/or 
daratumumab infusions.  All subjects regardless of age will be required to receive 20 mg of 
dexamethasone on days 1 and 2 of cycle 1 (as a preinfusion medication for daratumumab 
infusion) followed by 20 mg of methylprednisolone or equivalent on the third day.  For 
Subjects 75 years of age or subjects whose weekly dexamethasone dose has been reduced to 
20 mg/week, 20 mg of dexamethasone will be given as a preinfusion medication for 
daratumumab infusion, followed by 8 mg of dexamethasone prior to carfilzomib infusion on 
days 9 and 16 of cycle 1.   
Starting with cycle 2, 20 mg dexamethasone must be given on days daratumumab is 
administered (without 8 mg dose on subsequent carfilzomib dosing day), otherwise the 20 mg 
dose can be split across carfilzomib dosing days. 
For days when dexamethasone is given in the absence of other IV infusion (neither carfilzomib 
nor daratumumab is scheduled), it may be given within  2 days for each scheduled dose.  
Dexamethasone will be administered at least 30 minutes (but no more than 4 hours) prior to 
carfilzomib and within 1 to 3 hours from the daratumumab dose. 
When carfilzomib is permanently discontinued, dexamethasone may be omitted on days when 
given in the absence of daratumumab based on their assessment of the subject’s steroid 
tolerance.  
For subjects in arm 1 on cycles 7 without previous infusion-related reaction (IRR), 
dexamethasone premedication may be decreased or omitted, if the subject cannot tolerate 20 mg 
of dexamethasone or equivalent. 
Procedures:  Written informed consent must be obtained from all subjects or legally acceptable 
representatives before any study specific screening procedures are performed.  The following 
procedures will occur per the Schedule of Assessments:  medical history, complete physical 
examination, physical measurements, vital signs, Eastern Cooperative Oncology Group 
performance status (ECOG PS), ECG, echocardiogram (ECHO), pulmonary function tests 
(PFTs), recording of concomitant medications, review of adverse events and serious adverse 
events.  Electronic clinical outcome assessments will no longer be collected after protocol 
Amendment 6.  Imaging studies for bone lesions (all subjects) and soft tissue plasmacytoma 
evaluation (if clinically indicated).  Central laboratory testing will be performed to confirm disease 
and stage including bone marrow with samples for MRD and fluorescence in-situ hybridization 
(FISH).  Additional central laboratory testing will include hematology, serum chemistry, hepatic 
and renal function.  Local laboratory testing will include coagulation factors, pregnancy testing, 
blood typing with indirect antiglobulin test (IAT), HBV serologies, and HBV DNA testing.  Samples 
will also be taken to perform pharmacokinetic (PK), pharmacodynamic (PDn), biomarker studies, 
and anti-daratumumab antibody assessments.  Subjects will be assessed for survival status and 
subsequent antimyeloma therapies will be collected during LTFU. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 7 of 140 
CONFIDENTIAL 
 
 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 11).   
Statistical Considerations: 
The efficacy analyses of PFS and key secondary endpoints will be conducted on the full analysis 
set.  Treatment effects in efficacy endpoints will be evaluated and compared KdD vs Kd.  For 
PFS, response and disease progression will be determined by an IRC in a blinded manner.  In 
addition, response and disease progression outcomes will be determined locally by investigators 
in an unblinded manner and centrally by the sponsor using a validated computer algorithm (Onyx 
Response Computer Algorithm [ORCA]) in a blinded manner.  The primary analysis of PFS will 
be based on IRC assessed outcomes; the timing will be event driven and will happen when 
approximately 188 PFS events are reached.  The PFS outcomes assessed by the investigators 
as well as by ORCA will serve as supportive analyses of PFS. 
The primary comparison of PFS will be tested using a log rank test stratified by the randomization 
stratification factors per IxRS at 1-sided significance level of 0.025.   
If PFS is significant, the key secondary endpoints will be tested by hierarchical testing in the order 
of ORR, MRD[-]CR by NGS, and OS.  Overall response rate and MRD[-]CR will be tested once at 
the time when primary analysis of PFS is significant.  If PFS, ORR, and MRD[-]CR are all 
statistically significant at 0.025 significance level, then OS will be tested multiple times with an 
overall alpha of 0.025. 
 
  
 
 
  Overall response rate and MRD[-]CR will be analyzed using the 
Cochran-Mantel-Haenszel chi-square test controlling for the randomization stratification factors 
per IxRS.  Overall survival will be analyzed using the same method as described for the PFS 
endpoints.  
Safety data, including laboratory test results, vital signs, treatment-emergent adverse events, 
serious adverse event and treatment related events, will be summarized by actual treatment 
received.  Analysis on changes on LVEF and PFTs over time will be conducted. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen, Inc. 
Data Element Standards 
Version(s)/Date(s):  
 
Version 5.0, 20 March 2015 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 8 of 140 
CONFIDENTIAL 
 
 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
Ab  antibody; CD38  cluster differentiation antigen 38; CR  complete response; d  dexamethasone; D  daratumumab; DCO  data cutoff; ISS  International 
Staging System; K  carfilzomib; MRD  minimal residual disease; MRD[-]CR  minimal residual disease negative-complete response; ORR  overall response rate; 
OS  overall survival; PFS  progression-free survival; PI  proteasome inhibitor; RRMM  relapsed or refractory multiple myeloma. 
a For patients with baseline chronic hepatic impairment (mild, moderate), reduce the starting and subsequent doses of carfilzomib by 25 (ie, 15 mg/m2 day 1 and 2 of 
cycle 1 and 42 mg/m2 day 8 cycle 1 and thereafter). 
 
Arm 1:  KdD  
Ka at 20/56 mg/m2  
 
 
 
d 40 mg  
 
 
 
D 16 mg/kg  
Arm 2:  Kd  
 
Ka at 20/56 mg/m2  
 
 
 
d 40 mg 
RRMM 
1-3 prior lines 
N~450 
 
Stratify:  Original 
ISS stage, lines of 
therapy, prior PI 
exposure, prior 
CD38 Ab exposure 
Primary 
Endpoint:  
PFS 
 
Key 
Secondary: 
ORR, MRD, 
OS 
28-day cycles 
0   
  
16    
24 
4   
  
8     
20 
12    
28 
48 
MRD sample: 
Landmark Analysis 
MRD sample: 
Baseline 
MRD sample (if CR): 
Sustained MRD[-]CR 
MRD samples will also be obtained: 
•
When a bone marrow sample is obtained to confirm CR 
•
Samples for MRD analysis are not required after the 
 
months 
N = 300 
N = 150 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 9 of 140 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ADCC 
antibody-dependent cellular cytotoxicity 
ADCP 
antibody-dependent cellular phagocytosis 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
AST 
aspartate aminotransferase 
BSA 
body surface area 
CD38 
cluster differentiation antigen 38 
CDC 
complement dependent cytotoxicity 
CI 
confidence interval 
COPD 
chronic obstructive pulmonary disease 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CRR 
complete response rate 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DCO 
data cutoff 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DTT 
dithiothreitol 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCOA  
electronic clinical outcome assessment  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
End of Study  
defined as the date when the last subject is assessed or receives an 
intervention for evaluation in the study (ie, last subject last visit) 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 10 of 140 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
EORTC  
European Organisation for Research and Treatment of Cancer  
ESC 
European Society of Cardiology 
ESH 
European Society of Hypertension 
FC 
flow cytometry 
FCBP 
females of childbearing potential 
FcR 
Fc receptor 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FEV1 
forced expiratory volume in 1 second 
FISH 
fluorescence in-situ hybridization 
FSH 
follicle stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
gDNA 
genomic DNA 
HBsAg 
hepatitis B surface antigen  
HBV 
hepatitis B virus 
Heart rate 
number of cardiac cycles per unit of time 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRT 
hormonal replacement therapy 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IFE 
immunofixation 
Ig 
immunoglobulin 
IMiD 
immunomodulatory drug 
IMWG-URC 
International Myeloma Working Group-Uniform Response 
Criteria 
INR 
international normalized ratio 
Interactive Voice 
Response (IVR) 
telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information.  
Interactive Web 
Response (IWR) 
web based technology that is linked to a central computer in real 
time as an interface to collect and process information.  
IRB/IEC 
institutional review board/independent ethics committee 


Product:  Carfilzomib 
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Page 11 of 140 
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Abbreviation or Term 
Definition/Explanation 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
ISS 
International Staging System 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
IV 
intravenous 
IxRS 
interactive voice/web response system 
Kd 
20/56 mg/m2 twice weekly carfilzomib and dexamethasone 
KdD 
20/56 mg/m2 twice weekly carfilzomib, dexamethasone, and 
daratumumab 
K-M 
Kaplan-Meier 
KRd 
carfilzomib, lenalidomide, and dexamethasone 
LDH 
lactate dehydrogenase 
LD WBCT 
low-dose whole body computed tomography 
LTFU 
long-term follow-up 
LVEF 
left ventricular ejection fraction 
MDSC 
myeloid-derived suppressor cells 
MoA 
mechanisms of action 
MR 
minimal response 
MRD 
minimal residual disease 
MRD[-]CR 
minimal residual disease negative-complete response; defined as 
achievement of CR (includes sCR) per International Myeloma 
Working Group-Uniform Response Criteria (IMWG-URC) and MRD[-] 
status as assessed by NGS (at a 10-5 level, pending analytical 
validation)  
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NE 
not evaluable 
NGS 
Next-Generation sequencing 
NK 
natural killer 
NT-proBNP 
N-terminal of the prohormone brain natriuretic peptide 
NYHA 
New York Heart Association 
ORCA 
Onyx Response Computer Algorithm 
ORR 
overall response rate 
OS 
overall survival 
PBMCs 
peripheral blood mononuclear cells 
PD 
progressive disease 
PDn 
pharmacodynamics 


Product:  Carfilzomib 
Protocol Number:  20160275 
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Page 12 of 140 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
PET 
positron emission tomography 
PFS 
progression free survival 
PFT 
pulmonary function test 
PJP 
pneumocystis jirovenci pneumonia 
PK 
pharmacokinetic 
PO 
orally 
POEMS 
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, 
and skin changes 
POR 
proof of receipts 
PR 
partial response 
Primary Completion 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the 
protocol or was terminated early 
PR interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG 
PS 
performance status 
PSA 
prostate specific antigen 
QLQ-C30 
quality of life questionnaire – core 30 items 
QoL 
quality of life  
QRS interval 
QRS interval the interval between the Q wave and the S wave in the 
heart's electrical cycle as measured by ECG; represents the time it 
takes for the depolarization of the ventricles 
QTc interval 
QT interval corrected for heart rate using accepted 
methodology 
QT interval 
QT interval is a measure of the time between the start of the Q wave 
and the end of the T wave in the heart's electrical cycle as measured 
by ECG 
RBC 
red blood cell 
R-ISS 
Revised International Staging System 
RRMM 
relapsed or refractory multiple myeloma 
SAP 
statistical analysis plan 
SBECD 
sulfobutylether beta-cyclodextrim sodium 
sCD38 
soluble cluster differentiation antigen 38 
sCR 
stringent complete response 
SD 
stable disease 


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Abbreviation or Term 
Definition/Explanation 
SFLC 
serum free light chain 
SIFE 
serum immunofixation 
 
 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies). 
(ICH Guideline (E6)).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value. 
SPEP 
serum protein electrophoresis 
sWFI 
sterile water for injection 
TCR 
T-cell receptor 
TLS 
tumor lysis syndrome 
TTE 
transthoracic echocardiogram 
UIFE 
urine immunofixation 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
US FDA 
United States Food and Drug Administration’s 
Vd 
bortezomib with dexamethasone 
VGPR 
very good partial response 
 


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TABLE OF CONTENTS 
Protocol Synopsis ......................................................................................................... 3 
Study Schema ................................................................................................................ 8 
Study Glossary .............................................................................................................. 9 
TABLE OF CONTENTS ................................................................................................ 14 
1. 
OBJECTIVES ....................................................................................................... 20 
1.1 
Primary ..................................................................................................... 20 
1.2 
Secondary ................................................................................................. 20 
1.3 
Exploratory ................................................................................................ 20 
2. 
BACKGROUND AND RATIONALE ...................................................................... 21 
2.1 
Multiple Myeloma ...................................................................................... 21 
2.2 
Proteasome Background ........................................................................... 21 
2.3 
Amgen Investigational Product Background .............................................. 21 
2.3.1 
Carfilzomib Background (Nonclinical) ........................................ 21 
2.3.2 
Carfilzomib Background (Clinical) .............................................. 22 
2.4 
Non-Amgen Medicinal Product Background .............................................. 22 
2.4.1 
Daratumumab Background (Non-Amgen 
Investigational Product) ............................................................. 22 
2.4.2 
Daratumumab Mechanism of Action .......................................... 25 
2.4.3 
Dexamethasone (Non-Amgen Non-investigational 
Product) .................................................................................... 26 
2.5 
Rationale ................................................................................................... 27 
2.5.1 
Study Rationale ......................................................................... 27 
2.5.2 
Rationale for Daratumumab Dose ............................................. 28 
2.5.3 
Rationale for the Combination ................................................... 29 
2.5.4 
Rationale for the Carfilzomib Dose Schedule............................. 30 
2.6 
Clinical Hypothesis .................................................................................... 31 
3. 
EXPERIMENTAL PLAN ........................................................................................ 31 
3.1 
Study Design ............................................................................................. 31 
3.2 
Number of Sites ........................................................................................ 33 
3.3 
Number of Subjects ................................................................................... 33 
3.4 
Replacement of Subjects .......................................................................... 33 
3.5 
Estimated Study Duration .......................................................................... 33 
3.5.1 
Study Duration for Subjects ....................................................... 33 
3.5.2 
End of Study .............................................................................. 34 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 34 
4.1 
Inclusion Criteria ....................................................................................... 34 
4.2 
Exclusion Criteria ...................................................................................... 36 
5. 
SUBJECT ENROLLMENT .................................................................................... 38 


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5.1 
Randomization/Treatment Assignment ...................................................... 39 
6. 
TREATMENT PROCEDURES .............................................................................. 40 
6.1 
Classification of Products .......................................................................... 40 
6.2 
Investigational Products ............................................................................ 40 
6.2.1 
Amgen Investigational Product:  Carfilzomib.............................. 40 
6.2.1.1 
Carfilzomib:  Dosage, Administration, and 
Schedule ................................................................. 40 
6.2.1.2 
Carfilzomib:  Dosage Adjustments, Delays, 
Rules for Withholding or Restarting, 
Permanent Discontinuation ..................................... 41 
6.2.1.3 
Carfilzomib:  Dose Reduction Levels ....................... 42 
6.2.1.4 
Carfilzomib:  Guidelines for Hematologic 
Toxicity .................................................................... 43 
6.2.1.5 
Carfilzomib:  Guidelines of 
Nonhematologic Toxicity ......................................... 43 
6.2.2 
Non-Amgen Investigational Product:  Daratumumab ................. 46 
6.2.2.1 
Daratumumab:  Dosage, Administration, 
and Schedule .......................................................... 46 
6.2.2.2 
Daratumumab:  Dosage Adjustments, 
Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ................... 49 
6.2.2.3 
Daratumumab:  Management of 
Infusion-related Reactions ....................................... 51 
6.3 
Non-Amgen Non-investigational Product:  Dexamethasone ...................... 52 
6.3.1 
Dexamethasone:  Dosage, Administration, and 
Schedule ................................................................................... 52 
6.3.2 
Dexamethasone:  Dosage Adjustments, Delays, Rules 
for Withholding or Restarting, Permanent 
Discontinuation .......................................................................... 53 
6.3.2.1 
Dexamethasone:  Dose Reduction Levels ............... 53 
6.3.2.2 
Dexamethasone:  Guidelines for 
Dexamethasone-related Toxicity ............................. 54 
6.4 
Conditions Not Requiring Dose Reduction ................................................ 57 
6.4.1 
Medical Devices ........................................................................ 57 
6.5 
Other Protocol-required Therapies ............................................................ 57 
6.5.1 
Antiviral Prophylaxis .................................................................. 57 
6.5.2 
Thromboprophylaxis .................................................................. 58 
6.5.3 
Tumor Lysis Syndrome Prophylaxis .......................................... 58 
6.5.4 
Proton-pump Inhibitor ................................................................ 58 
6.5.5 
Bone Health Therapy ................................................................. 58 
6.5.6 
Prophylaxis for Pneumocystis Jirovenci ..................................... 58 
6.5.7 
Prophylaxis for Hepatitis B Virus ................................................ 59 
6.5.8 
Other Permitted Therapies ........................................................ 59 
6.6 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 59 


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6.7 
Concomitant Therapy ................................................................................ 59 
6.7.1 
Management of Hepatitis B Virus Reactivation .......................... 60 
6.8 
Product Complaints ................................................................................... 61 
6.9 
Excluded Treatments and/or Procedures During Study Period .................. 61 
6.10 
Contraceptive Requirements ..................................................................... 61 
6.10.1 
Female Subjects ........................................................................ 62 
6.10.2 
Male Subjects ............................................................................ 63 
6.10.3 
Unacceptable Methods of Birth Control for Male and 
Female Subjects ....................................................................... 64 
7. 
STUDY PROCEDURES ....................................................................................... 64 
7.1 
Schedule of Assessments ......................................................................... 64 
7.2 
General Study Procedures ........................................................................ 74 
7.2.1 
Screening Enrollment and/or Randomization ............................. 74 
7.2.2 
Rescreening .............................................................................. 75 
7.2.3 
Treatment Period ....................................................................... 75 
7.2.4 
Follow-up Visits ......................................................................... 76 
7.2.5 
Long-term Follow-up .................................................................. 76 
7.3 
Description of Study Procedures ............................................................... 77 
7.3.1 
Demographics ........................................................................... 77 
7.3.2 
Medical History .......................................................................... 77 
7.3.3 
Multiple Myeloma Frailty Index .................................................. 77 
7.3.4 
Review of Safety Events and Current Concomitant 
Medications ............................................................................... 77 
7.3.5 
Concomitant and Prior Medications ........................................... 78 
7.3.6 
Physical Examination ................................................................ 78 
7.3.7 
Physical Measurements ............................................................ 78 
7.3.8 
ECOG Performance Status ....................................................... 78 
7.3.9 
Echocardiogram ........................................................................ 78 
7.3.10 
Vital Signs ................................................................................. 79 
7.3.11 
Electrocardiogram ..................................................................... 79 
7.3.12 
Pulmonary Function Tests (PFTs) ............................................. 80 
7.3.13 
Survival ..................................................................................... 80 
7.3.14 
Subsequent Antimyeloma Therapies ......................................... 80 
7.3.15 
Laboratory Assessments ........................................................... 80 
7.3.16 
Pregnancy Evaluation ................................................................ 83 
7.3.17 
Blood Typing and IAT ................................................................ 83 
7.3.18 
Pharmacokinetic Samples ......................................................... 84 
..... 84 
..... 84 
.................... 84 
7.3.20 
Antibody Testing Procedures ..................................................... 85 


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7.3.21 
Tumor Response and Multiple Myeloma Disease 
Assessment .............................................................................. 85 
7.3.21.1 
SPEP, UPEP, SFLC, SIFE, and UIFE ..................... 85 
7.3.21.2 
Bone Marrow Sample Evaluation Including 
FISH and MRD[-]CR Assessment ........................... 86 
7.3.21.3 
Bone Lesion Assessment (Skeletal 
Survey, CT, or PET/CT) .......................................... 87 
7.3.21.4 
Extramedullary Plasmacytoma ................................ 87 
7.3.21.5 
Progressive Disease Assessment ........................... 88 
7.4 
Biomarker Development ............................................................................ 88 
7.5 
Pharmacogenetic Studies ......................................................................... 89 
7.6 
Sample Storage and Destruction ............................................................... 90 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 91 
8.1 
Subjects’ Decision to Withdraw ................................................................. 91 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 92 
8.3 
Reasons for Removal From Treatment or Study ....................................... 92 
8.3.1 
Reasons for Removal From Treatment ...................................... 92 
8.3.2 
Reasons for Removal From Study ............................................. 92 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 92 
9.1 
Definition of Safety Events ........................................................................ 92 
9.1.1 
Adverse Events ......................................................................... 92 
9.1.2 
Serious Adverse Events ............................................................ 93 
9.2 
Safety Event Reporting Procedures .......................................................... 94 
9.2.1 
Adverse Events ......................................................................... 94 
9.2.1.1 
Reporting Procedures for Adverse Events 
That Do Not Meet Serious Criteria ........................... 94 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 95 
9.2.1.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 96 
9.2.1.4 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 96 
9.2.1.5 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 96 
9.2.1.6 
Safety Monitoring Plan ............................................ 97 
9.3 
Pregnancy and Lactation Reporting .......................................................... 97 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 98 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 98 
10.1.1 
Study Endpoints ........................................................................ 98 
10.1.1.1 
Primary Endpoint ..................................................... 98 
10.1.1.2 
Secondary Endpoint(s) ............................................ 98 
10.1.1.3 
Exploratory Endpoint(s) ........................................... 99 


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10.1.2 
Analysis Sets ............................................................................. 99 
10.1.2.1 
Full Analysis Set ...................................................... 99 
10.1.2.2 
Safety Analysis Set ................................................. 99 
10.1.2.3 
Per Protocol Analysis Set ...................................... 100 
10.1.3 
Covariates and Subgroups ...................................................... 100 
10.1.4 
Handling of Missing and Incomplete Data ................................ 100 
10.2 
Sample Size Considerations ................................................................... 101 
10.3 
Planned Analyses ................................................................................... 102 
10.3.1 
Data Monitoring Committee (DMC) .......................................... 102 
10.3.2 
Independent Review Committee (IRC) .................................... 102 
10.3.3 
Primary Analysis ...................................................................... 102 
 
 ...................................................................... 102 
 
 .......................................................................... 103 
10.4 
Planned Methods of Analysis .................................................................. 103 
10.4.1 
General Considerations ........................................................... 103 
10.4.2 
Primary Efficacy Endpoint ........................................................ 104 
10.4.3 
Secondary Efficacy Endpoint(s) ............................................... 105 
10.4.4 
Safety Endpoints ..................................................................... 106 
11. 
REGULATORY OBLIGATIONS .......................................................................... 106 
11.1 
Informed Consent .................................................................................... 106 
11.2 
Institutional Review Board/Independent Ethics Committee ...................... 107 
11.3 
Subject Confidentiality ............................................................................. 108 
11.4 
Investigator Signatory Obligations ........................................................... 108 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 109 
12.1 
Protocol Amendments and Study Termination ........................................ 109 
12.2 
Study Documentation and Archive .......................................................... 109 
12.3 
Study Monitoring and Data Collection ..................................................... 110 
12.4 
Investigator Responsibilities for Data Collection ...................................... 111 
12.5 
Language ................................................................................................ 111 
12.6 
Publication Policy .................................................................................... 111 
12.7 
Compensation ......................................................................................... 112 
13. 
REFERENCES ................................................................................................... 113 
14. 
APPENDICES .................................................................................................... 116 
List of Tables 
Table 1.  Response Rates and Progression Free Survival in Recent Relapsed 
Multiple Myeloma Phase 3 Clinical Trials ................................................ 28 
Table 2.  Dose Decrements for Carfilzomib ................................................................... 42 
Table 3.  Dose Modification Guidelines for Thrombocytopenia and 
Neutropenia ............................................................................................ 43 


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Table 4.  Dose Modification Guidelines for Nonhematologic Toxicities .......................... 44 
Table 5.  Daratumumab Infusion Rate ........................................................................... 47 
Table 6.  Accelerated/Shortened Infusion Rate .............................................................. 48 
Table 7.  Daratumumab Administration Schedule .......................................................... 50 
Table 8.  Dose Decrements for Dexamethasone ........................................................... 54 
Table 9.  Treatment Guidelines for Dexamethasone-related Toxicity ............................. 55 
Table 10.  Highly Effective Contraceptive Methods for Female Subjects ....................... 63 
Table 11.  Schedule of Assessments ............................................................................. 66 
Table 12.  Schedule of Disease Assessments ............................................................... 71 
Table 13.  Dosing Schedule - Arm 1 (KdD) .................................................................... 72 
Table 14.  Dosing Schedule - Arm 2 (Kd) ...................................................................... 73 
Table 15.  Laboratory Analyte Listing ............................................................................ 82 
.  
 ....................................................................... 106 
List of Figures 
Figure 1.  Daratumumab Mechanisms of Action ............................................................ 26 
List of Appendices 
 


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1. 
OBJECTIVES 
1.1 
Primary 
The primary objective is to compare carfilzomib, dexamethasone, and daratumumab 
(KdD) to carfilzomib and dexamethasone (Kd) in terms of progression free survival 
(PFS) in patients with multiple myeloma who have relapsed after 1 to 3 prior therapies. 
1.2 
Secondary 
Key secondary objectives are to compare the following between the 2 arms: 
 
Overall Response Rate (ORR; defined as the proportion of best overall response of 
stringent complete response [sCR], complete response [CR], very good partial 
response [VGPR], and partial response [PR]) 
 
rate of minimal residual disease negative-complete response (MRD[-]CR) in bone 
marrow aspirates at 12 months ( 4 weeks) as determined by Next-Generation 
sequencing (NGS) 
 
overall survival (OS) 
Additional secondary objectives are to compare the following between the 2 arms: 
 
safety and tolerability 
 
duration of response (DOR) 
 
time to next treatment  
 
time to progression (TTP) 
 
time to response 
 
persistence of MRD[-]CR 
 
complete response rate (CRR) 
 
MRD[-] rate 
 
quality of life  
1.3 
Exploratory 


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2. 
BACKGROUND AND RATIONALE 
2.1 
Multiple Myeloma 
Multiple myeloma, a clonal neoplastic proliferation of plasma cells, is the second most 
common hematologic malignancy and is responsible for approximately 80000 annual 
deaths worldwide (1 of cancer deaths).  The estimated incidence of multiple myeloma 
in 2012 worldwide was 114000 persons and this represents 0.8 of all cancers.  The 
5 year prevalence of multiple myeloma worldwide was estimated at 229000 persons 
(Ferlay et al, 2015).  Multiple myeloma is a disease of older adults, with a median age at 
diagnosis of 70 years (Howlader et al, 2013). 
2.2 
Proteasome Background 
The proteasome is a multicatalytic proteinase complex that is responsible for 
degradation of a wide variety of protein substrates within normal and transformed 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. 
2.3 
Amgen Investigational Product Background 
2.3.1 
Carfilzomib Background (Nonclinical) 
Carfilzomib is a tetrapeptide epoxyketone based inhibitor of the 20S proteasome.  
Carfilzomib, showed less off target activity when measured against a broad panel of 
proteases including metallo-, aspartyl-, and serine proteases compared to bortezomib; 
bortezomib showed off target inhibitory activity in the nanomolar range against several 


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serine proteases (Arastu-Kapur et al, 2009).  This selectivity may be responsible for the 
reductions in myelosuppression and neuropathy observed in studies comparing 
carfilzomib with bortezomib. 
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 (Suzuki et al, 2011; Kuhn et al, 2007). 
Carfilzomib has also been administered to rats and monkeys for 6 and 9 months, 
respectively (twice weekly 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 (Onyx data 
on file and Carfilzomib Investigator's Brochure [IB]). 
2.3.2 
Carfilzomib Background (Clinical) 
Carfilzomib entered clinical studies in September 2005.  On 20 July 2012, Kyprolis 
(Carfilzomib for Injection) was approved under the United States Food and Drug 
Administration’s (US FDA) accelerated approval program for the treatment of patients 
with multiple myeloma who have received at least 2 prior therapies, including bortezomib 
and an immunomodulatory drug (IMiD), and have demonstrated disease progression on 
or within 60 days of completion of the last therapy.  The initial accelerated approval was 
based on the results of the phase 2 PX-171-003-A1 study in the United States.  
Subsequent full approval in the United States and globally were based on 2 phase 
3 trials:  PX 171-009 ASPIRE and 2011-003 ENDEAVOR.  Following these approvals, 
Kyprolis in combination with either lenalidomide and dexamethasone or dexamethasone 
alone is indicated for treatment of relapsed or refractory multiple myeloma (RRMM).  The 
exact indication wording varies by region.  Additional data is summarized in the IB. 
As of 19 July 2020, an estimated 4361 subjects (3976.4 subject-years) have been 
exposed to carfilzomib in company-sponsored clinical trials since the beginning of the 
development program. 
Refer to Section 4 of the Carfilzomib IB for additional information related to the physical, 
chemical, and pharmaceutical properties and formulation(s). 
2.4 
Non-Amgen Medicinal Product Background 
2.4.1 
Daratumumab Background (Non-Amgen Investigational Product) 
Daratumumab is a first in class human anti-cluster differentiation antigen 38 (CD38) 
immunoglobulin (Ig) G1 (kappa) monoclonal antibody.  CD38 is differentially expressed 


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during B-cell development with greatest expression on terminally differentiated B-cells.  
CD38 is an enzyme that catalyzes the metabolism of cyclic adenine dinucleotide 
phosphate ribose and nicotinic acid to adenine dinucleotide phosphate which functions 
in regulation of intracellular calcium stores.  Various preclinical experiments with multiple 
myeloma cell lines, purified multiple myeloma cells, and mononuclear cell suspensions 
have demonstrated that daratumumab triggers lysis of multiple myeloma cells by a 
variety of mechanisms.  The binding of the antibody to CD38 positions of the Fc receptor 
(FcR) in a way that optimizes interaction with complement resulting in strong 
complement dependent lysis (de Weers et al, 2011). 
Antibody dependent lysis with daratumumab has been demonstrated in complement free 
cell suspensions of multiple myeloma cells and cell lines with peripheral blood 
mononuclear cells (PBMCs) enriched for natural killer (NK) cells using both normal and 
patient PBMCs.  Other mechanisms of action (MoA) including antibody-dependent 
cellular phagocytosis (ADCP) and apoptosis triggered by FcR-crosslinking have been 
demonstrated with daratumumab (van der Veer et al, 2011b).  Analysis from clinical 
trials of daratumumab revealed an immunomodulatory role of daratumumab that leads to 
the induction of clonal T cell expansion and reduction of immune suppressive cell 
populations CD38 myeloid-derived suppressor cells (MDSC), CD38 TReg, and CD38 
BReg cells (Krejcik et al, 2016). 
Clinical activity of daratumumab was first studied in phase 1/2 Gen 501 and 
phase 2 SIRIUS trials.  A recent summary of the pooled results of these trials was 
reported (Usmani et al, 2016).  The patient population was RRMM with 2 or more prior 
lines of therapy, 76 of patients received more than 3 lines of therapy (median 5, 
range 2 to 14 lines).  A total of 148 patients were treated at the 16 mg/kg dose, 86.5 of 
patients were double refractory to both IMiD and proteasome inhibitors.  The ORR was 
31 and DOR 7.6 months with a median PFS of 4 months.  Only 4 of patients 
discontinued therapy due to adverse events.  Most adverse events were due to infusion 
reactions with approximately 50 with reactions to first infusion dropping to 
approximately 10 with second infusion and rare with subsequent infusions.  Of interest, 
patients achieving only stable disease/minimal response (SD/MR) also appeared to 
benefit with a median OS of 18 months compared to 20 months for responders and 
3 months for those with not evaluable/progressive disease (NE/PD).  The highly 
significant activity of daratumumab in RRMM, novel non-overlapping mechanism or 


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toxicity with regard to bortezomib and lenalidomide predict high tolerability and efficacy 
of KdD combination therapy in treatment of relapsed multiple myeloma. 


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2.4.2 
Daratumumab Mechanism of Action 
Daratumumab is a targeted immunotherapy that binds to CD38, a transmembrane 
glycoprotein that is overexpressed in multiple myeloma plasma cells.  Multiple MoA have 
been observed for daratumumab, including complement dependent cytotoxicity (CDC), 
antibody-dependent cellular cytotoxicity (ADCC), induction of apoptosis by Fc gamma 
receptor mediated crosslinking of tumor bound monoclonal antibodies, and ADCP. 
Translational biomarker studies of samples from patients treated in daratumumab 
phase 1 and phase 2 studies (Studies GEN501 and MMY2002, respectively) have 
revealed previously unknown immunomodulatory effects of daratumumab 
(Krejcik et al, 2016).  Detailed analysis by flow cytometry (FC) of changes in circulating 
immune cells demonstrated that daratumumab was able to induce large increases in 
CD8 T numbers.  Next generation T-cell receptor (TCR) sequencing was utilized to 
evaluate changes in T cell clonality.  Interestingly, in patients who responded to 
daratumumab, both the maximal individual increase in a T cell clone, as well as the sum 
of expanded T cell clones, were significantly increased suggesting that T cell expansion 
may have a role in eliminating the myeloma cells.  In order to assess the potential 
mechanism by which daratumumab could lead to these increases in T cell clones, 
additional analysis revealed that there was a rapid and sustained elimination of highly 
immunosuppressive subsets of CD38 Tregs, CD38 MDSCs, and CD38 Bregs in 
patients treated with daratumumab.  The CD38 Tregs identified is a novel population of 
Tregs that are more immunosuppressive than CD38- Tregs.  In addition, it has also been 
shown that daratumumab can modulate the enzymatic activity of CD38 and potentially 
lead to a reduction in immunosuppressive adenosine levels in the tumor 
microenvironment (Horenstein et al, 2013). 
Some of daratumumab’s most differentiating attributes are the depth of response 
achieved in responders and the drug’s multifaceted MoA.  Based upon these new 
findings, it is hypothesized that daratumumab’s deep and durable responses in patients 
with multiple myeloma are induced, in part, by the immunomodulatory activity that 
removes immune suppressive functions of CD38 MDSC, CD38 TReg, and 
CD38 BReg cells and increases T cell clonality.  A figure summarizing daratumumab’s 
novel, converging MoA is presented in Figure 1. 


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Figure 1.  Daratumumab Mechanisms of Action 
 
ADCC  antibody dependent cellular cytotoxicity; ADCP  antibody dependent cellular phagocytosis;  
ADPR  adenosine diphosphate ribose; AMP  adenosine monophosphate; Ca2  calcium ion;  
cADPR  cyclic adenosine diphosphoribose; CD38  cluster differentiation antigen 38; CD8  cluster of 
differentiation 8; CDC  complement-dependent cytotoxicity; DARA  daratumumab; MM  multiple 
myeloma; MDSC  myeloid-derived suppressor cell; NAADP  nicotinic acid adenine dinucleotide 
phosphate; NAD  nicotinamide adenine dinucleotide; NK  natural killer. 
Previously reported to kill tumor cells by immune-mediated mechanisms, such as ADCC, 
ADCP, and CDC, as well as by programmed cell death via cross linking of the antibody 
on the cell surface, it is now known that daratumumab also induces immunomodulatory 
effects via several different pathways that contribute to killing of CD38 immune cells that 
modulate T cell activity, namely MDSC, TReg, and BReg.  This is a novel mechanism 
previously unreported that is hypothesized to drive development of multiple opportunities 
for daratumumab beyond CD38 myeloma and other heme malignancies. 
2.4.3 
Dexamethasone (Non-Amgen Non-investigational Product) 
Dexamethasone is commercially available.  Details regarding the description, supply, 
and storage instructions for dexamethasone are found in the prescribing information.  
Sites are advised to refer to the prescribing information for information that is specific to 
the brand or formulation of the drug product in use. 


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2.5 
Rationale 
2.5.1 
Study Rationale 
Relapsed or refractory multiple myeloma treatment has evolved rapidly in recent years.  
ASPIRE was the first phase 3 randomized study demonstrating that a triplet using 
non-conventional chemotherapy agents had significant improvement in outcomes when 
compared with a duplet.  In this study, KRd reduced the risk of progression by 31 when 
compared to lenalidomide and dexamethasone (hazard ratio [HR]  0.69, P  0.0001; 
Stewart et al, 2015) which translated in a median PFS of 26.3 months in the KRd arm 
with consistent benefit in subgroup analyses.  These positive results were despite 
limiting carfilzomib treatment to the first 18 cycles of therapy.  Soon after, the concept of 
superior outcomes with novel agent-based triplets as treatment of early relapsed multiple 
myeloma (1 to 3 prior lines) was confirmed with other combinations (Table 1).  More 
recently, interim data from 2 phase 3 trials with daratumumab has shown improvement 
of outcomes when added to either bortezomib and dexamethasone or lenalidomide and 
dexamethasone backbones.  Compared to lenalidomide and dexamethasone for 
patients with RRMM with a median of 1 prior line of therapy, the addition of 
daratumumab reduced the risk of progression by 63 (HR  0.37, P  0.0001; 
Dimopoulos et al, 2016).  Compared to bortezomib and dexamethasone, the addition of 
daratumumab reduced the risk of progression by 61 in patients with RRMM with a 
median of 2 prior lines of therapy (HR  0.39, P  0.0001; Palumbo et al, 2016). 
Among the phase 3 studies in relapsed multiple myeloma, the results achieved with 
carfilzomib and daratumumab based combinations suggest that these 2 agents are likely 
the most potent in their respective classes.  They both have demonstrated high rates of 
overall responses and significant increment of CRRs (Table 1).  Moreover, pre-clinical 
and clinical studies combining daratumumab to proteasome inhibitors have 
demonstrated synergy (Palumbo et al, 2016; van der Veer et al, 2011a).  Therefore, it is 
expected that the combination of both agents, carfilzomib and daratumumab, would 
provide a highly efficacious treatment option for patients with relapsed disease. 
A number of ongoing phase 3 studies in newly diagnosed transplant ineligible patients 
are evaluating lenalidomide-based triplets with planned treatment to continue until 
progression (NCT01335399, NCT01850524, NCT02252172, and NCT02579863).  
Moreover, a recent meta-analysis has demonstrated OS advantage on the use of 
lenalidomide maintenance after autologous stem cell transplant (McCarthy et al, 2016).  
This information points to an increase in the number of subjects that have been exposed 


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to lenalidomide in first line.  Developing lenalidomide-sparing options is expected to 
address a significant unmet need in the near future for the treatment of relapsed 
myeloma. 
Table 1.  Response Rates and Progression Free Survival in Recent Relapsed 
Multiple Myeloma Phase 3 Clinical Trials 
Trial 
Arm 
ORR () 
CR () 
PFS (mo) 
ENDEAVOR 
Kd 
77 
13 
18.7 
Vd 
63 
6 
9.4 
ASPIRE 
KRd 
87 
31.8 
26.3 
 
Rd 
67 
9 
17.6 
CASTOR 
DVd 
83 
19 
NR 
 
Vd 
63 
9 
7.3 
POLLUX 
DRd 
93 
43 
NR 
 
Rd 
76 
19 
18.4 
ELOQUENT-II  
Elotuzumab Rd  
79 
4 
19.4 
 
Rd 
66 
7 
14.9 
TOURMALINE-II 
Ixazomib Rd 
78 
11.7 
20.6 
 
Rd 
71.5 
6.6 
14.7 
CR  complete response; d  dexamethasone; D  daratumumab; K  carfilzomib; mo  month; NR  not 
reached; ORR  overall response rate; PFS  median progression-free survival; R  lenalidomide; 
V  bortezomib. 
2.5.2 
Rationale for Daratumumab Dose 
Dosing of daratumumab in subjects with multiple myeloma is recommended at 16 mg/kg 
(weekly for 8 weeks, then every 2 weeks for 16 weeks, then every 4 weeks thereafter) 
administered via intravenous (IV) until disease progression or unacceptable toxicity.  The 
dose selection was based on an acceptable safety profile, maximal clinical activity, and 
PKs consistent with saturation of the target.  The data supporting the selection of a 
16 mg/kg dose for the treatment of multiple myeloma are as follows: 
 
Safety:  Clinical safety data demonstrated that daratumumab is well-tolerated, with 
clinically manageable side effects, highlighted by the fact that no subject treated with 
16 mg/kg daratumumab monotherapy discontinued treatment as a result of a 
daratumumab related adverse event. 
 
For doses above 4 mg/kg, there was no dose dependent toxicity pattern 
observed. 


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 
Clinical efficacy:  Clinical response data derived from Study GEN501 and 
Study MMY2002 show robust activity among subjects treated at 16 mg/kg with ORRs 
of 36 and 29, respectively. 
 
The response rates were consistently and significantly higher and deeper at the 
16 mg/kg dose level as compared to various schedules at the 8 mg/kg dose 
level. 
 
Pharmacokinetics:  Daratumumab exhibits target-mediated drug disposition.  
Daratumumab binds to CD38 receptors in the body and the complex with 
daratumumab is rapidly cleared.  As the dose is increased or after repeated 
administration, CD38 becomes saturated, and the impact of target binding clearance 
is minimized and PK data can indicate target saturation. 
 
Population PK and exposure-response analyses suggested that 16 mg/kg is the 
lowest tested dose at which the majority (approximately 80) of subjects 
achieved serum concentrations above the model-predicted 99 target saturation 
threshold and 90 of the maximum effect on ORR threshold. 
 
Lowering the dose would likely result in reduced efficacy, whereas increasing the 
dose may not provide further improvement of the benefit-risk profile. 
 
The initial weekly dosing schedule rapidly established efficacious concentrations.  
The every 2 week and every 4 week dosing frequencies were sufficient to 
produce serum concentration levels that maintained target saturation; thus 
reducing the risk of disease progression. 
2.5.3 
Rationale for the Combination 
The rationale for combining daratumumab with a proteasome inhibitor is supported by 
the results obtained in the CASTOR study as described above.  This study was 
conducted with bortezomib, a reversible inhibitor of the proteasome which was also 
evaluated head-to-head against carfilzomib and dexamethasone in the ENDEAVOR 
study with a similar patient population.  The results of this comparison suggest superior 
outcomes with carfilzomib with a 47 reduction in the risk of progression or death 
(HR  0.53, P  0.0001; Dimopoulos et al, 2016) and are the basis for the labeled dose 
in RRMM.  Given the orthogonal MoA of daratumumab, the addition to the carfilzomib 
and dexamethasone regimen is hypothesized to be highly efficacious and possibly result 
in a longer duration of PFS compared to the experimental arm in the CASTOR study.  
An ongoing phase 1b study is evaluating the safety of the addition of daratumumab to 
carfilzomib and dexamethasone (NCT01998971).  As of 30 June 2016, 20 subjects have 
been treated with KdD in the ongoing Study MMY1001.  The most frequently reported 
grade 3 or 4 adverse events were laboratory-related and included thrombocytopenia 
(35), neutropenia (25), and anemia (15).  Cardiac disorders were reported in 
4 subjects and were grade 1 and 2 tachycardia (2 subjects), atrial fibrillation (1 subject), 
and cardiac failure (1 subject).  No grade  3 cardiac disorder adverse events were 


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reported.  The subject with grade 2 cardiac failure recovered from the event and 
continued on investigational product, receiving a reduced dose of carfilzomib.  Based on 
these preliminary data, the combination of KdD is well tolerated with a safety profile that 
is consistent with the known safety profile of daratumumab or Kd. 
For the combination of these 2 agents, the initial daratumumab infusion and any 
subsequent infusions that would otherwise require a large volume (eg, 1 liter); will be 
divided in 2 days to minimize the risk of volume overload given that new or worsening 
cardiac failure has occurred following the administration of carfilzomib. 
2.5.4 
Rationale for the Carfilzomib Dose Schedule 
The dose schedule in the KdD arm is based on the objective of evaluating the effect of 
the addition of daratumumab to a well characterized carfilzomib dexamethasone 
regimen.  The safety and efficacy of 20/56 mg/m2 twice-a-week carfilzomib combined 
with dexamethasone has been defined in a randomized phase 3 trial (ENDEAVOR; 
Dimopoulos et al, 2016).  In ENDEAVOR, Kd was compared to bortezomib with 
dexamethasone (Vd) in a similar patient population proposed in this phase 3 trial 
(Study 20160275).  The carfilzomib arm proved superior at the first interim analysis for 
efficacy reducing the risk of progression or death by 47 (median PFS [Kd vs Vd]:  
18.7 months vs 9.4 months).  The median follow up for the Kd arm was 11.9 months at 
the time of the first interim analysis.  A pre-planned interim analysis for OS demonstrated 
a 21 reduction in the risk of death (median OS [Kd vs Vd] 47.6 vs 40 months).  The 
median number of weeks of carfilzomib received per subject was 48.0 in the Kd group 
(Dimopoulos et al, 2017).  At the time of this analysis, there were 212 subjects who have 
received over 1 year of therapy, 89 with more than 2 years, and 31 with more than 
3 years.  The incidence of grade 3 treatment-emergent adverse events has decreased 
over the years, from 74.1 in the first 12 months, to 52.8 between 12 and 24 months, 
44.9 between 24 and 36 months, and 29.0 in subjects with more than 36 months.  
Similarly, the rate of serious adverse events shows a decrease from 47.9 in the first 
12 months, 32.5 between 12 to 24 months, 24.7 between 24 to 36 months, and 
3.2 in subjects exposed more than 36 months (data on file).  The data to-date are 
supportive of at least 3 years exposure of carfilzomib and low-dose dexamethasone as 
done in the ENDEAVOR trial.   
Daratumumab has been successfully combined with a range of anti-myeloma therapies, 
including recently released data on successful combination with a proteasome inhibitor 
in the CASTOR study in a similar patient population.  An ongoing phase 1b study 


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evaluating the addition of daratumumab to several standards of care includes an arm of 
carfilzomib dosed at 20/70 mg/m2 weekly in combination with daratumumab.  As of 
30 June 2016, there have been 20 subjects treated with KdD in this study with the 
observed adverse events were consistent with the known individual safety profiles for 
carfilzomib and daratumumab.  The safety profile of carfilzomib dosed at 
20/70 mg/m2 weekly in combination with dexamethasone and daratumumab is 
consistent with the known safety profiles of carfilzomib and daratumumab independently. 
Carfilzomib PKs with the 20/70 mg/m2 weekly dose showed higher Cmax (maximum 
concentration) than that with the 20/56 mg/m2 twice-a-week dose (2390 ng/mL vs 
2079 ng/mL, respectively).  Although the area under the curve is higher with 
20/56 mg/m2 twice a week (1896 nghr/mL vs 1030 nghr/mL per week), it is unlikely that 
these parameters would be modified by the addition of daratumumab.  This assumption 
is based on the short half-life of carfilzomib ( 1 hour) leading to no accumulation.  
Additionally, no drug-drug interaction is expected due to the orthogonal MoA of these 
agents and their different metabolism and elimination routes. 
Given these data, this study will evaluate the 20/56 mg/m2 twice-a-week dose schedule 
for carfilzomib in combination with daratumumab and low-dose dexamethasone in this 
phase 3 study to develop a highly efficacious regimen for RRMM patients. 
2.6 
Clinical Hypothesis 
The KdD regimen will provide significant improvement in PFS over the Kd regimen. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 3 multicenter, open-label, randomized study in subjects with RRMM who 
have received 1 to 3 prior therapies. 
Subjects will be randomized in a 2:1 ratio to 1 of 2 arms: 
 
Arm 1:  KdD using 20/56 mg/m2 carfilzomib and 16 mg/kg daratumumab 
 
Arm 2:  Kd using 20/56 mg/m2 carfilzomib 
Randomization will be performed using an interactive voice/web response system (IxRS) 
and subjects will be stratified based on the following criteria: 
1. 
Original International Staging System (ISS) stage (variables:  albumin and beta 
2 microglobulin; strata:  Stage 1 or 2 vs Stage 3) at screening 
2. 
Prior proteasome inhibitor exposure (yes vs no) 
3. 
Number of prior lines of therapy (1 vs  2) 


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4. 
Prior CD38 antibody therapy (yes vs no) 
Subjects will receive the study treatment determined by randomization 
 
 
, or until confirmed disease progression, unacceptable toxicity, withdrawal of 
consent, or death (whichever occurs first).  No crossover between the treatment arms 
will be allowed.  All subjects will be assessed for multiple myeloma disease response 
according to the International Myeloma Working Group-Uniform Response Criteria 
(IMWG-URC) (Appendix M) using central laboratory test results every 28  7 days.  
, disease response assessments will be 
performed every 28  7 days until confirmed PD irrespective of cycle duration including 
dose delays or treatment discontinuation.  
 
.   
Following progression or discontinuation of study drug(s), subjects will have 1 follow-up 
visit 30 days (3) after last dose of all study drug(s).  After disease progression, data 
on survival status and subsequent antimyeloma therapy will be gathered at 
 
. 
Local serology testing for hepatitis B testing (hepatitis B surface antigen [HBsAg], 
hepatitis B surface antibody [anti-HBs], and hepatitis B core antibody [anti-HBc]) will be 
performed at the next scheduled visit for all subjects that do not already have a known 
medical history of hepatitis B infection or who have not had testing conducted within the 
previous 12 weeks.  In addition, subjects with a known medical history of hepatitis B 
infection or who test positive for hepatitis B virus (HBV) serologies will be monitored 
closely for signs and symptoms of hepatitis B and will have local HBV DNA testing 
performed at their next visit and then every 12 weeks ( 2 weeks) or more frequently if 
clinically indicated through follow-up visit 1.  Subjects in arm 1 (KdD) will continue to be 
monitored and tested for 6 months following the last dose of daratumumab.  A hepatitis 
specialist should be consulted for all subjects who test positive for HBV serology or HBV 
DNA to undergo full assessment and make decisions regarding HBV reactivation 
treatment and/or confirmation whether HBV reactivation is adequately controlled 
to resume study drugs.  Subjects who have received Hepatitis B vaccination with only 
anti-HBs positivity and no clinical signs of hepatitis do not require HBV DNA monitoring.  
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 


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The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 120 sites in North America, Australia, Europe, and Asia will participate in 
this global study.  During the conduct of the study, additional sites may be added as 
necessary. 
Sites that do not enroll subjects within 5 months of site initiation may be closed. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects.”  Approximately 
450 subjects will be enrolled (300 in arm 1 and 150 in arm 2).  Amgen may choose to 
increase sample size upon observation of slower than expected PFS event rate. 
Please refer to Section 10.2 for sample size considerations. 
3.4 
Replacement of Subjects 
Subjects who are enrolled and then withdrawn (or removed from treatment or the study) 
will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
Subject accrual is estimated as 11 months. 
Subjects may be treated until disease progression, but not longer than up to 
 
.  There is a 21-day screening window and a 
follow-up visit 30 (3) days after the last dose of all study drug(s).   
For subjects who discontinue treatment before disease progression, follow-up 
visits will be conducted for disease response assessments every 28  7 days until 
PD (
) or locally per Schedule of 
Assessments (
).  After disease 
progression, 
 
 
.  Subjects in arm 1 (KdD) with a known history of HBV 
infection or with positive serology testing will continue to be monitored and tested 
for HBV reactivation for a maximum of 6 months following the last study dose of 
daratumumab. 
Total study duration for an individual subject is estimated to be approximately 5 years. 


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3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early.  Primary completion 
is anticipated to occur when approximately 188 PFS events occur which is expected to 
be 27 months after the first subject is enrolled. 
End of Study:  The end of study date is defined as the date when the last subject in 
arm 1, with a known history of HBV infection or who tested positive for HBV 
serology, is assessed or receives an intervention for evaluation of HBV reactivation or 
when the last patient on the study has an assessment or intervention for the final 
data collection, whatever occurs later.  End of study is anticipated to occur 
approximately 
.  At the end of study, all 
data will be reported. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening). 
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1). 
4.1 
Inclusion Criteria 
101 
Relapsed or progressive multiple myeloma after last treatment 
102 
Males or females  18 years of age  
103 
Measurable disease with at least 1 of the following assessed within 21 days prior 
to randomization: 
 
IgG multiple myeloma:  serum monoclonal paraprotein (M-protein) level 
 1.0 g/dL, 
 
IgA, IgD, IgE multiple myeloma:  serum M-protein level  0.5 g/dL, 
 
urine M-protein  200 mg/24 hours,  
 
in subjects without measurable serum or urine M-protein, serum free light 
chain (SFLC)  100 mg/L (involved light chain) and an abnormal serum 
kappa lambda ratio 
104 
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 
0 to 2 (see Appendix D) 
105 
Patients must have at least PR to at least 1 line of prior therapy 


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106 
Received at least 1 but not more than 3 prior lines of therapy for multiple 
myeloma (induction therapy followed by stem cell transplant and 
consolidation/maintenance therapy will be considered as 1 line of therapy, 
see Appendix E for guidance) 
107 
Prior therapy with carfilzomib is allowed as long as the patient had at least a PR 
to most recent therapy with carfilzomib, was not removed due to toxicity, did not 
relapse within 60 days from discontinuation of carfilzomib, and will have at least a 
6-month carfilzomib treatment-free interval from last dose received until first 
study treatment.  (Patients may receive maintenance therapy with drugs that are 
not proteasome inhibitors or CD38 antibodies during this 6-month carfilzomib 
treatment free interval)  
108 
Prior therapy with anti-CD38 antibodies is allowed as long as the patient had at 
least a PR to most recent therapy with CD38 antibody, was not removed due to 
toxicity, did not relapse within 60 days from intensive treatment (at least every 
other week) of CD38 antibody therapy, and will have at least a 6-month CD38 
antibody treatment-free interval from last dose received until first study treatment. 
109 
Left ventricular ejection fraction  40 as assessed by transthoracic 
echocardiogram (TTE) 
110 
Adequate hepatic function within 21 days prior to randomization: 
 
bilirubin  1.5 times the upper limit of normal (ULN) 
 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
 2.5 times the ULN 
111 
Absolute neutrophil count (ANC)  1 x 109/L within 21 days prior to 
randomization.  Screening ANC should be independent of granulocyte- and 
granulocyte macrophage-colony stimulating factor support for at least 1 week 
and of pegylated granulocyte stimulating factor for  2 weeks. 
112 
Hemoglobin  80 g/L within 21 days prior to randomization.  Patients should not 
have received red blood cell (RBC) transfusions for at least 7 days prior to 
obtaining the screening hemoglobin. 
113 
Platelet count  75 x 109/L ( 50 x 109/L if myeloma involvement in the bone 
marrow is  50) within 21 days prior to randomization.  Patients should not 
have received platelet transfusions for at least 7 days prior to obtaining the 
screening platelet count. 
114 
Calculated or measured creatinine clearance (CrCl) of  20 mL/min within 
21 days prior to randomization based on standard formula such as the Cockcroft 
and Gault.  (Subjects on dialysis are excluded) 
115 
Females of childbearing potential (FCBP) must have a negative serum 
pregnancy test within 15 days prior to first dose of study drug and a negative 
urine pregnancy test within the 24 hours prior to first dose 
116 
FCBP must agree to use highly effective method(s) of contraception, during the 
study and for 30 days following the last dose of carfilzomib administration or 
3 months following the last dose of daratumumab administration, whichever is 


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later for subjects in the KdD arm; and 30 days following the last dose of 
carfilzomib administration for the Kd arm.  
117 
Male subjects who are sexually active with an FCBP must agree to use condoms 
(unless they have had a vasectomy with medical confirmation of surgical 
success) during carfilzomib and/or daratumumab treatment and for additional 
90 days following the last carfilzomib and/or daratumumab administration. 
118 
Male subjects must agree to not donate sperm, during treatment and for an 
additional 90 days following the last carfilzomib and/or daratumumab 
administration 
119 
Subject has provided informed consent/assent prior to initiation of any study 
specific activities/procedures. 
4.2 
Exclusion Criteria 
201 
Waldenström macroglobulinemia 
202 
Multiple myeloma of IgM subtype 
203 
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal 
protein, and skin changes)  
204 
Plasma cell leukemia ( 2.0 x 109/L circulating plasma cells by standard 
differential) 
205 
Myelodysplastic syndrome 
206 
History of other malignancy within the past 5 years except: 
 
Adequately treated carcinoma in situ of the cervix without evidence of 
disease 
 
Prostate cancer with a Gleason score  6 with undetectable prostate specific 
antigen (PSA) over 12 months 
 
Ductal breast carcinoma in situ with full surgical resection (ie, negative 
margins) and without evidence of disease 
 
Treated medullary or papillary thyroid cancer 
 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in 
situ 
 
Similar neoplastic conditions with an expectation of  95 5-year 
disease-free survival  
 
Malignancy treated with curative intent and with no known active disease 
present for  3 years before randomization and felt to be at low risk for 
recurrence by the treating physician 
207 
Primary amyloidosis (patients with multiple myeloma with asymptomatic 
deposition of amyloid plaques found on biopsy would be eligible if all other 
criteria are met) 


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208 
Immunotherapy with potential anti-myeloma activity within 21 days prior to 
randomization 
209 
Chemotherapy with approved or investigational anticancer therapeutic within 
21 days prior to randomization 
210 
Glucocorticoid therapy within 14 days prior to randomization that exceeds a 
cumulative dose of 160 mg of dexamethasone or equivalent dose of other 
corticosteroids 
211 
Focal radiation therapy within 7 days prior to randomization.  Radiation therapy to 
an extended field involving a significant volume of bone marrow within 21 days 
prior to randomization (ie, prior radiation must have been to less than 30 of the 
bone marrow) 
212 
Major surgery (except kyphoplasty) within 28 days prior to randomization 
213 
Contraindication to dexamethasone 
214 
Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize 
carfilzomib) 
215 
Contraindication to use daratumumab or any of its components:  allergies, 
hypersensitivity, or intolerance to mannitol, monoclonal antibodies or human 
proteins or excipients (refer to Daratumumab’s IB), or known sensitivity to 
mammalian-derived products. 
216 
Prior participation in a Janssen daratumumab phase 3 study (with exception of 
subjects in control arm that have withdrawn consent from study participation) 
217 
Contraindication to any of the required concomitant drugs or supportive 
treatments, including hypersensitivity to antiviral drugs 
218 
Intolerance to hydration due to preexisting pulmonary or cardiac impairment 
219 
Active congestive heart failure (New York Heart Association [NYHA] Class III to 
IV), symptomatic ischemia, uncontrolled arrhythmias, clinically significant 
electrocardiogram (ECG) abnormalities, screening ECG with corrected QT 
interval (QTc) of  470 msec, pericardial disease, or myocardial infarction within 
4 months prior to randomization 
220 
Infiltrative pulmonary disease, known pulmonary hypertension 
221 
Active infection within 14 days prior to randomization requiring systemic 
antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal 
agents.  Such infection must be fully resolved prior to initiating study treatment. 
222 
Pleural effusions requiring thoracentesis within 14 days prior to randomization 
223 
Ascites requiring paracentesis within 14 days prior to randomization 
224 
Uncontrolled hypertension, defined as an average systolic blood pressure 
 159 mmHg or diastolic  99 mmHg despite optimal treatment (measured 
following European Society of Hypertension/European Society of Cardiology 
[ESH/ESC] 2013 guidelines; Appendix F) 


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225 
Known chronic obstructive pulmonary disease (COPD) with a forced expiratory 
volume in 1 second (FEV1)  50 of predicted normal.   
226 
Subjects with confirmed FEV1  50 of predicted. 
227 
Known moderate or severe persistent asthma within the past 2 years 
(see Appendix G), or currently has uncontrolled asthma of any classification or at 
time of screening has an FEV1 of  50.  (Note that subjects who currently have 
controlled intermittent asthma or controlled mild persistent asthma are allowed in 
the study). 
228 
Known cirrhosis 
229 
Known human immunodeficiency virus (HIV) infection, hepatitis C infection 
(subjects with hepatitis C that achieve a sustained virologic response following 
antiviral therapy are allowed), or hepatitis B infection (subjects with HBsAg or 
core antibody that achieve sustained virologic response with antiviral therapy 
directed at hepatitis B are allowed) 
230 
Currently receiving treatment in another investigational device or drug study, or 
less than 28 days since ending treatment on another investigational device or 
drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
231 
Pregnant or breastfeeding women, or women who are planning to become 
pregnant or breastfeed during treatment and for an additional 30 days after 
discontinuing treatment. 
232 
Ongoing graft-versus-host disease 
233 
Autologous stem cell transplant less than 90 days prior to randomization 
234 
Vaccination with live attenuated vaccines within 4 weeks prior to randomization 
235 
Subject likely to not be available to complete all protocol required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessment [COAs]) to the best of the subject and investigator’s 
knowledge. 
236 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion 
237 
Subjects with grade 3 or worse neuropathy within 14 days prior to randomization 
238 
Allogeneic stem cell transplant less than 100 days prior to randomization  
239 
Patients on any immunosuppressive therapy for graft versus host disease, even 
if it has resolved 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 


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committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects or legally acceptable representatives must personally sign and date the 
IRB/IEC approved ICF before commencement of study-specific activities/procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (up to 21 days before 
cycle 1 day 1) will receive a unique subject identification number before any 
study-related activities/procedures are performed.  The subject identification number will 
be assigned by the IxRS.  This number will be used to identify the subject throughout the 
clinical study and must be used on all study documentation related to that subject. 
Subjects who are determined not eligible after screening must be screen-failed in the 
IxRS and the reason for the screen-failure provided.  Subjects who are determined to be 
not eligible after screening may be rescreened once at the discretion of the investigator.  
Subjects who are determined not eligible after re-screening must be screen-failed in the 
IxRS and the reason for the screen-failure provided. 
Subjects rescreening within 21 days of the signing of the original informed consent only 
need to repeat the assessment(s) that did not originally meet the eligibility criteria; all 
other initial screening assessments do not need to be repeated.  Subjects rescreening 
greater than 21 days from the signing of the original informed consent must be 
re-consented and repeat all screening procedures. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
Subjects may only be randomized once into this study. 
5.1 
Randomization/Treatment Assignment 
Approximately 450 subjects will be randomized in a 2:1 ratio to 1 of 2 arms (as described 
in Section 3.1). 
Randomization will be performed using an IxRS and subjects will be stratified based on 
the following criteria: 
1. Original ISS stage (Stage 1 or 2 vs Stage 3) at screening 


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2. Prior proteasome inhibitor exposure (yes vs no) 
3. Number of prior lines of therapy (1 vs  2) 
4. Prior CD38 antibody therapy (yes vs no) 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF.  Subjects must receive their first dose of study treatment within 3 days 
of randomization. 
A randomization number will be assigned to each subject by IxRS and appear on the 
IxRS randomization confirmation document.  The randomization number is different than 
the subject identification number and will not be utilized by the site as a subject identifier. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Products 
The Amgen investigational product used in this study includes:  carfilzomib. 
The non-Amgen investigational product used in this study includes:  daratumumab. 
The non-Amgen non-investigational product used in this study includes:  
dexamethasone. 
6.2 
Investigational Products 
6.2.1 
Amgen Investigational Product:  Carfilzomib 
Carfilzomib will be provided by Amgen Inc. 
Carfilzomib is supplied as a sterile, lyophilized, white to off-white powder, ready for 
reconstitution.  It is supplied for single use in 50 mL Type 1 glass vials containing 60 mg 
of carfilzomib drug product with an elastomeric stopper and flip-off lid.  Upon 
reconstitution with 
 mL of preservative-free sterile water for injection (sWFI), the 
reconstituted solution contains 2 mg/mL carfilzomib, 
 mg/mL sulfobutylether 
beta-cyclodextrim sodium (SBECD), and 
 mg/mL citrate buffer, at pH 
 to 
 
Carfilzomib is supplied in labelled cartons containing 4 single use vials per carton.  
Carfilzomib must be stored between C to C and remain protected from light. 
6.2.1.1 
Carfilzomib:  Dosage, Administration, and Schedule 
Carfilzomib will be administered as an IV infusion.  On days when more than 
1 investigational product is administered, the required order of administration is as 
follows:  dexamethasone, pre-infusion medications for daratumumab, carfilzomib, 
daratumumab, and post-infusion medications for daratumumab.  Subjects in arm 1 do 
not require prehydration, however, prehydration can be administered at investigator’s 


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discretion on cycle 1 day 9 and cycle 1 day 16.  Mechanical infusion pumps are 
recommended, but gravity-dependent infusions are permitted if the 30-minute infusion 
duration can be reliably maintained.  For patients with baseline chronic hepatic 
impairment (mild, moderate), reduce the starting and subsequent doses of carfilzomib by 
25 (ie, 15 mg/m2 day 1 and 2 of cycle 1 and 42 mg/m2 day 8 cycle 1 and thereafter).  In 
case of resolution of hepatic abnormalities, dose escalation may be considered. 
Carfilzomib will be dosed twice weekly over 30  5 minutes, on days 1, 2, 8, 9, 15, and 
16 of each 28-day cycle.  The administration may be within  2 days for each scheduled 
dose.  The dose will be 20 mg/m2 on cycle 1 days 1 and 2 and 56 mg/m2 beginning on 
cycle 1 day 8 and thereafter.  See Table 13 and Table 14 to review the arm 1 and 
arm 2 dosing schedules, respectively. 
Each subject’s first dose of carfilzomib will be calculated based upon baseline body 
surface area (BSA) using the Mosteller formula.  In subjects with BSA of greater than 
2.2 m2, the dose should be capped based on a BSA of 2.2 m2.  The dose for each 
subject should not be revised unless the subject experiences a change in body weight of 
 20 in which case the BSA and dose should be recalculated.  The dose can also be 
modified in response to toxicity following the dose modification guideline tables. 
The planned dose (mg/m2), dose (mg), start date/time, stop date/time, reason for change 
in planned dose, reason for dose change/withheld, reason for dose delay, reason for 
dose interruption and package lot number of carfilzomib is to be recorded on each 
subject's electronic case report form (eCRF). 
6.2.1.1.1 
Intravenous Prehydration 
Subjects in arm 2 will receive IV prehydration prior to each carfilzomib infusion during 
cycle 1.  For subjects in arm 1, no prehydration for carfilzomib will be required on days of 
daratumumab administration. 
Prehydration will consist of 250 mL normal saline or other appropriate IV fluid. 
Thereafter, carfilzomib prehydration should only be administered if the subject’s 
condition and/or risk factors require it.  The total volume of prehydration and the reason 
for prehydration after cycle 1 will be recorded. 
6.2.1.2 
Carfilzomib:  Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation  
Carfilzomib may be discontinued, temporarily delayed, or dosage temporarily reduced, in 
the event of a treatment-related toxicity that, in the opinion of the investigator, warrants 


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the discontinuation, temporary delay or dose reduction, as indicated in Table 3 and 
Table 4.  The subject will be considered on protocol treatment while receiving either 
carfilzomib or daratumumab (ie, if either carfilzomib or daratumumab are discontinued or 
interrupted, the subject is still considered on treatment if still taking the other 
investigational product).   
If day 1 of a cycle is delayed, all subsequent doses within the cycle and also day 1 of 
subsequent cycles should be adjusted accordingly to maintain the 28-day cycle duration.  
However, if a within-cycle dose is delayed, then the dates of the subsequent within-cycle 
doses should not be adjusted.  For within-cycle doses, if administration does not 
commence within the allowable window of the scheduled administration date, then the 
dose will be considered a missed dose.  Administration may resume at the next planned 
dosing date.  A missed dose will not be made up. 
Carfilzomib must be discontinued permanently if a delay of more than 6 weeks is 
required due to unresolved toxicity. 
6.2.1.3 
Carfilzomib:  Dose Reduction Levels 
Dose reduction levels of carfilzomib for toxicity management of individual subjects are 
provided in Table 2.  Subjects that require a dose level reduction and tolerate the 
reduced dose for 1 full cycle, may at the discretion of the treating physician increase the 
dose to a prior dose starting with the next cycle except when the dose reduction is due 
to:  pulmonary hypertension, pulmonary toxicity, grade 3 or worse cardiac failure, and 
drug-induced hepatotoxicity. 
Table 2.  Dose Decrements for Carfilzomib 
Dosea, b 
(mg/m2) 
First Dose 
Reduction 
Dose -1 
(mg/m2) 
Second Dose 
Reduction 
Dose -2 
(mg/m2) 
Third Dose 
Reduction 
Dose -3 
(mg/m2) 
Fourth Dose 
Reduction 
Dose -4 
(mg/m2) 
56 
45 
36 
27 
20 
CxDx  cycle X day X 
a If dose reduction of carfilzomib is required on C1D1 or C1D2, the investigator should contact the medical 
monitor to discuss the situation, before any additional doses of carfilzomib are administered. 
b For patients with baseline chronic hepatic impairment (mild, moderate), reduce the starting and subsequent 
doses of carfilzomib by 25 (ie, 15 mg/m2 day 1 and 2 of cycle 1 and 42 mg/m2 day 8 cycle 1 and 
thereafter). 


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6.2.1.4 
Carfilzomib:  Guidelines for Hematologic Toxicity 
Guidelines for carfilzomib dose modification in the event of thrombocytopenia and 
neutropenia are summarized in Table 3. 
Table 3.  Dose Modification Guidelines for Thrombocytopenia and Neutropenia 
Hematologic toxicity 
Recommended Action 
Thrombocytopenia 
When platelets fall to 
 30 x 109/L and for each 
subsequent drop to 
 30 x 109/L 
If platelets 10 to 30 x 109/L 
without evidence of 
bleeding 
 Hold 
 restart at previous dose 
when platelets  30 x 109/L 
If evidence of bleeding or 
platelets  10 x 109/L 
 hold 
 restart at 1 dose decrement 
when platelets  30 x 109/L 
Neutropenia 
When ANC falls to 
 0.75 x 109/L and for each 
subsequent drop to 
 0.75 x 109/L  
If ANC 0.5 to 0.75 x 109/L 
 continue at full dose 
If ANC  0.5 x 109/L 
 hold dose 
 resume at 1 dose 
decrement when  
ANC  0.5 x 109/L 
ANC  absolute neutrophil count. 
6.2.1.5 
Carfilzomib:  Guidelines of Nonhematologic Toxicity 
Guidelines for dose modification in the event of nonhematologic toxicities are 
summarized in Table 4. 


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Table 4.  Dose Modification Guidelines for Nonhematologic Toxicities 
Symptom/Sign/Investigation 
Recommended Action 
Renal Dysfunctiona: 
CrCl  15 mL/min  
Full dose 
CrCl  15 mL/min (NCI-CTCAE grade 4) 
Hold dose and monitor renal 
function.  If attributable to 
carfilzomib, resume when renal 
function has recovered to within 
25 of baseline; restart at 1 dose 
level reduction.  If not 
attributable to carfilzomib, 
dosing may be resumed at the 
discretion of the investigator.  If 
dialysis required, use the maximal 
dose of 20 mg/m2 and administer 
carfilzomib after dialysis. 
Chronic dialysis stable for  30 days 
Dose may be re-escalated up to full 
dose as clinically tolerated 
Hepatic Dysfunction and Related Investigations 
Mild to moderate liver dysfunction: 
defined as 2 consecutive values, at least 28 days 
apart, of: 
 (1) total bilirubin ( 33 direct)  1x ULN to  3x ULN 
 
OR 
 (2) an elevation of AST and/or ALT with normal 
bilirubin 
25 dose reduction. 
Dose may be re-escalated if liver 
function tests return to normal and 
drug-induced hepatotoxicity is 
excluded. 
 
Grade 3 elevation in ALT and/or AST ( 5x ULN) 
 
Hold carfilzomib until resolution to 
baseline. 
Monitor any abnormality weekly.  
Resume carfilzomib with a 25 
dose reduction if drug-induced 
hepatotoxicity is excluded. 
Grade 3 elevation in total bilirubin 
Hold carfilzomib until resolution to 
baseline.  Monitor total bilirubin and 
direct bilirubin weekly. 
Upon resolution of total bilirubin to 
normal, resume carfilzomib dosing 
with a 25 dose reduction if 
drug-induced hepatotoxicity is 
excluded. 
Drug-induced hepatotoxicity (attributable to carfilzomib) 
Discontinue carfilzomib 
Other Nonhematologic Toxicities 
Tumor lysis syndrome:  3 or more of the following: 
 increase in creatinine of  50 from baseline 
 increase in uric acid of  50 from baseline 
 increase in phosphate of  50 from baseline 
 increase in potassium of  30 from baseline 
 decrease in calcium from baseline OR 
 increase in LDH of  2-fold from baseline 
Hold carfilzomib until all 
abnormalities in serum chemistries 
have resolved; resume at full dose. 
Page 1 of 3 
Footnotes defined on the next page of the table 


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Table 4.  Dose Modification Guidelines for Nonhematologic Toxicities 
Symptom/Sign/Investigation 
Recommended Action 
Congestive heart failure 
 
Any subject with congestive heart failure, whether or not drug 
related, must have the dose held until resolution or return to 
baseline.  Appropriate medical management should be initiated.   
If no resolution after 4 weeks, carfilzomib will be permanently 
discontinued.  
 Grade 3 
Once congestive heart failure resolves or returns to baseline, 
resume at full dose. 
Grade 3 
Once congestive heart failure resolves or returns to baseline, 
treatment may continue at 1 dose level reduction.   
Infection (grade 3 or 4) 
Hold carfilzomib.  Once infection is controlled and the subject is 
without infection-related symptoms, and if ANC  1.0 x 109/L, 
resume at full dose.  If ANC  1.0 x 109/L, follow hematologic 
toxicities dose reduction guidelines. 
Hepatitis B Virus 
Reactivation 
Hold carfilzomib until infection is adequately controlled (see 
Section 6.7.1).   
Neuropathy (grade 2 with 
emergent pain, or grade 3) 
Hold carfilzomib until resolved to  grade 2 without pain; then 
resume at 1 dose decrement. 
Neuropathy (grade 4) 
Permanently discontinue carfilzomib. 
Dyspnea (grade  2) 
Hold carfilzomib until resolution to grade 1 or baseline, then 
resume at 1 dose decrement.  Investigate cause and record 
findings.  If caused by another adverse event listed in this table, 
follow recommendations for that adverse event. 
Hypertension (SBP  140 and/or DBP  90, measured per Appendix F) 
 Grade 3 
Continue at same dose if initiation of appropriate treatment 
controls hypertension (see Appendix F for guidance) 
Grade 3 
Hold carfilzomib until resolution to normal or baseline.  Initiate 
appropriate anti-hypertensive therapy prior to resuming 
carfilzomib at 1 dose decrement. 
Pulmonary toxicity: 
Non-infectious interstitial 
lung disease, acute 
respiratory failure, ARDS 
( grade 3) 
Hold carfilzomib until resolution to grade 1 or baseline and 
restart at 1 dose decrement. 
Pulmonary hypertension 
(grade  3) 
Hold carfilzomib until resolution to grade 1 or baseline and 
restart at 1 dose decrement 
Posterior reversible 
encephalopathy syndrome: 
Headaches, altered mental 
status, seizures, visual loss, 
and hypertension 
If PRES is suspected, hold carfilzomib.  Consider evaluation 
with neuroradiological imaging, specifically MRI, for onset of 
visual or neurological symptoms suggestive of PRES.  If PRES 
is confirmed, permanently discontinue carfilzomib.  If the 
diagnosis of PRES is excluded, carfilzomib administration may 
resume at same dose, if clinically appropriate.   
Page 2 of 3 
Footnotes defined on the next page of the table 


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Table 4.  Dose Modification Guidelines for Nonhematologic Toxicities 
Symptom/Sign/Investigation 
Recommended Action 
Progressive Multifocal 
Leukoencephalopathy 
Patients should be monitored for any new or worsening 
neurologic, cognitive, or behavioral signs or symptoms that 
may be suggestive of PML as part of the differential 
diagnosis of CNS disorders. 
If PML is suspected, withhold administration of carfilzomib; 
patients should be promptly referred to a specialist and 
appropriate diagnostic testing should be initiated.  
Discontinue carfilzomib if PML diagnosis is confirmed.  If 
the diagnosis is excluded, carfilzomib can be restarted at 
the same dose. 
Thrombotic 
microangiopathy: 
Fever, microangiopathic 
hemolytic anemia, renal 
failure, thrombocytopenia, 
neurological manifestations 
If the diagnosis is suspected, hold carfilzomib and manage per 
standard of care including plasma exchange as clinically 
appropriate.  If TMA is confirmed, permanently discontinue 
carfilzomib.  If the diagnosis is excluded, carfilzomib can be 
restarted at the same dose. 
Venous thrombosis  
( grade 3) 
Hold carfilzomib and adjust anticoagulation regimen; resume at 
full dose once anticoagulation has been optimized per treating 
investigator’s discretion. 
Any other drug-related 
nonhematologic toxicity 
 grade 3b 
For carfilzomib attribution, hold dose.  Resume at 1 dose 
decrement when toxicity has resolved to grade 1 or less or to 
baseline grade. 
Page 3 of 3 
ALT  alanine aminotransferase; ANC  absolute neutrophil count; ARDS  acute respiratory distress 
syndrome; AST  aspartate aminotransferase; CNS  central nervous system; CrCl  creatinine 
clearance; DBP  diastolic blood pressure; LDH  lactate dehydrogenase; MRI  magnetic resonance 
imaging; NCI-CTCAE  National Cancer Institute-Common Terminology Criteria for Adverse Events; PML 
 Progressive Multifocal Leukoencephalopathy; 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 daratumumab (D), carfilzomib (K), dexamethasone (d), or the 
combination of KdD to the extent possible.  If both carfilzomib and daratumumab are considered likely to 
be involved, then recommended actions for both should be instituted. 
6.2.2 
Non-Amgen Investigational Product:  Daratumumab 
6.2.2.1 
Daratumumab:  Dosage, Administration, and Schedule 
Daratumumab will be administered as an IV infusion.  On days when more than 
1 investigational products are administered, the required administration is as follows:  
dexamethasone, other pre-infusion medications for daratumumab, carfilzomib, 
daratumumab, and post-infusion medications for daratumumab. 
 
On days 1 and 2 of cycle 1, daratumumab will be administered at 8 mg/kg in 
500 mL normal saline each day.   
o If the subject’s first 2 infusions of 8 mg/kg daratumumab are well-tolerated 
(defined as an absence of infusion-related reaction [IRR]  grade 1), the first 
infusion of 16 mg/kg in 500 mL normal saline will be given once weekly as a 


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single infusion for the remaining doses of the first 2 cycles, ie, days 8, 15, and 
22 of cycle 1; and days 1, 8, 15, and 22 of cycle 2, then every 2 weeks for 
4 cycles (cycles 3 to 6), and then every 4 weeks for the remaining cycles or 
until disease progression.   
o If the 8 mg/kg infusions are not well-tolerated (defined as IRR  grade 1), the 
dilution will be in 1000 mL of normal saline until the subject completes an 
infusion without  grade 1 IRR.  For any infusions that would require a large 
volume (eg, 1000 mL); the daratumumab dose may be divided in 2 days.  
The administration may be within  2 days for each scheduled dose.  See Table 13 to 
review the arm 1 dosing schedule. 
Each subject’s dose will be calculated based on the subject’s weight rounded to the 
nearest kilogram.  Dosing calculations do not need to be changed for weight changes 
that are  10 from baseline.  The pharmacist will calculate the required volume and 
number of vials needed.  The daratumumab infusion rates are provided in Table 5 and 
Table 6. 
The planned dose (mg/kg), dose (mg), start date/time, stop date/time, reason for change 
in planned dose, reason for dose change/withheld, reason for dose delay, reason for 
dose interruption and package lot number of daratumumab is to be recorded on each 
subject's eCRF. 
Table 5.  Daratumumab Infusion Rate 
C1D1 and C1D2 (8 mg/kg) 
C1D8 (16 mg/kg) 
Subsequent Infusions 
Time (minutes) 
mL/hr 
Time (minutes) 
mL/hr 
Time (minutes) 
mL/hr 
0 – 60 
50 
0 – 60 
50a 
0 - 60 
100b 
61 – 120 
100 
61 – 120 
100 
61 - 120 
150 
121 – 180 
150 
121 - 180 
150 
121 - 180 
200 
181 – 240 
200 
181 - 240 
200 
181- 
200 
 
500 mL 
 
500 mLa 
 
500 mL 
CxDx  cycle X day X; IRR  infusion-related reaction. 
a If the subject’s first 2 infusions of 8 mg/kg daratumumab are well-tolerated (defined as an absence of 
IRR  grade 1), the first infusion of 16 mg/kg daratumumab will be administered at an initial rate of 
50 mL/hour and increased by 50-mL/hour increments at 60-minute intervals, as tolerated, to a maximum 
rate of 200 mL/hour.  If the 8 mg/kg infusions are not well-tolerated (defined as IRR  grade 1), the dose 
may be split in 2 days (on 500 mL each day). 
b Modified rates should only be used if at least 1 16 mg/kg infusions of daratumumab was well-tolerated as 
defined by an absence of grade 1 infusion-related reactions during a final infusion rate of  100 mL/hr. 
 
The duration of infusion may be shortened starting in cycle 2 onwards to a 
90-minute infusion for subjects without a history of an infusion related reaction 
after the third dose of daratumumab.  


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The 90-minute daratumumab accelerated infusions (Barr et al, 2017) can be 
administered at an initial rate of 20 of the total dose over 30 minutes, followed by 
the remaining 80 of the total dose over 60 minutes (90-minute total infusion 
time). 
 
Rapid infusion will be given in a total volume of 500 mL 
 
This allows for a rate of 200 mL/hour for the first 30 minutes and a rate of 
400 mL/hour for the final 60 minutes. 
 
If a subject experiences any grade infusion related reaction, the subject will 
not be eligible to receive additional rapid infusions until he/she has 
received standard infusion daratumumab without any grade 
hypersensitivity reaction. 
Table 6.  Accelerated/Shortened Infusion Rate 
Accelerated/Shortened 
Infusion 
Dilution 
Volume 
Initial 
Infusion Rate  
(first 
30 minutes) 
Subsequent 
Infusion Rate 
(last 60 minutes) 
Maximum 
Infusion Rate 
500 mL 
200 mL/hour 
400 mL/hour 
400 mL/hour 
Rapid infusion will be given in a total volume of 500 mL.  This allows for a rate of 200 mL/hour or the 
first 30 minutes and a rate of 400 mL/hour for the final 60 minutes.  If a subject experiences any 
grade infusion related reaction, he/she is not eligible to receive additional rapid infusions until they 
have received standard infusion daratumumab without any grade hypersensitivity reaction. 
Source: Barr et al, 2017. 
See Section 7.3.10 for details on vital sign monitoring during daratumumab and other 
infusions. 
6.2.2.1.1 
Pre-infusion Medications for Daratumumab 
On daratumumab infusion days, subjects will receive the following medications 1 to 
3 hours before daratumumab infusion (and prior to carfilzomib infusion): 
1. paracetamol 650 to 1000 mg orally (PO) or IV, and 
2. antihistamine (diphenhydramine 25 to 50 mg or equivalent, PO or IV), and 
3. leukotriene inhibitor (montelukast 10 mg PO or equivalent) should be given. 
Dexamethasone is also required pre-infusion, as well as 1 day after daratumumab 
infusion.  Refer to Section 6.3.1 for additional information on dexamethasone dosing. 


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6.2.2.1.2 
Post-infusion Medications for Daratumumab 
Any post-infusion medication will be administered after the infusion has completed. 
For the prevention of delayed IRR, all subjects will receive long- or intermediate-acting 
corticosteroid (see Section 6.2.2.1.1).  
In the absence of infusion-related adverse events after the first 3 infusions, post-infusion 
corticosteroids should be administered per investigator discretion. 
For subjects with a higher risk of respiratory complications (eg, subjects with mild 
asthma or subjects with COPD who have an FEV1  80 at screening or developed 
FEV1  80 during the study without any medical history) the following post-infusion 
medications must be administered: 
 
antihistamine (diphenhydramine or equivalent)  
 
leukotriene inhibitor (montelukast or equivalent) 
 
short-acting 2 adrenergic receptor agonist such as salbutamol aerosol  
 
control medications for lung disease (eg, inhaled corticosteroids  long-acting 
2 adrenergic receptor agonists for subjects with asthma; long-acting bronchodilators 
such as tiotropium or salmeterol  inhaled corticosteroids for subjects with COPD) 
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights 
after an infusion.  If subjects are hospitalized, then their spirometry test (FEV1) should 
be performed and documented before discharge.  If these subjects are not hospitalized, 
then a follow-up telephone call should be made to monitor their condition within 48 hours 
after all infusions.  If the subject has not experienced a significant medical event but is 
hospitalized overnight only for observation, the hospitalization should not be reported as 
a serious adverse event.  Investigators may prescribe bronchodilators, 
H1-antihistamines, and corticosteroids that are deemed necessary to provide adequate 
supportive care in the event a bronchospasm occurs after subjects are released from the 
hospital/clinic.  If an at-risk subject experiences no major IRRs, then these post-infusion 
medications may be waived after 4 doses at the investigator’s discretion. 
Any post-infusion medication will be administered after the infusion has completed. 
6.2.2.2 
Daratumumab:  Dosage Adjustments, Delays, Rules for Withholding 
or Restarting, Permanent Discontinuation 
Individual dose modification of daratumumab is not permitted, but dose delay is the 
primary method for managing daratumumab-related toxicities. 
During a cycle, a daratumumab dose must be held if any of the following criteria below 
are met, to allow for recovery from toxicity.  The criteria for a dose delay are: 


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 
grade 4 hematologic toxicity, except for grade 4 lymphopenia 
 
grade 3 thrombocytopenia with bleeding 
 
febrile neutropenia 
 
neutropenia with infection, of any grade 
 
grade 3 or higher non-hematologic toxicities with the following exceptions:  
 
grade 3 nausea that responds to antiemetic treatment within 7 days 
 
grade 3 vomiting that responds to antiemetic treatment within 7 days 
 
grade 3 diarrhea that responds to antidiarrheal treatment within 7 days 
 
grade 3 fatigue that was present at baseline or that lasts for  7 days after the 
last administration of daratumumab 
 
grade 3 asthenia that was present at baseline or that lasts for  7 days after the 
last administration of daratumumab 
Administration of daratumumab may be restarted upon recovery from toxicity to 
grade 2 or baseline, with the exception that grade 2 laryngeal edema or grade 
2 bronchospasm must be fully recovered. 
If daratumumab administration does not commence within the prespecified window 
(Table 7) of the scheduled administration date, then the dose will be considered a 
missed dose.  Administration may resume at the next planned dosing date.  A missed 
dose will not be made up. 
Table 7.  Daratumumab Administration Schedule 
Cycles 
Frequency 
Dose Held 
Dosing Re-start 
1 and 2 
Weekly (q1wk) 
 3 days 
next planned weekly dosing date 
3 to 6 
Biweekly (q2wks) 
 7 days 
next planned biweekly dosing date 
7 
Every 4 weeks 
(q4wks) 
 14 days 
next planned every 4 weeks dosing 
date 
Doses of daratumumab may be delayed up to 4 weeks (cycles 1 to 6) or up to 8 weeks 
(cycle 7 and beyond).  If day 1 of a cycle is delayed, day 1 of subsequent cycles should 
be adjusted accordingly to maintain the 28-day cycle duration.  However, if a within-cycle 
dose is delayed, then the dates of the subsequent within-cycle doses should not be 
adjusted.  Any adverse event deemed to be related to daratumumab that requires a 
dose hold of more than 4 weeks (cycles 1 to 6) or more than 8 weeks (cycle 7 and 
beyond) will result in permanent discontinuation of daratumumab.  If a dose delay 
occurs, then PK and PDn assessments should be performed on the actual 
administration day of daratumumab, not on the original scheduled administration day. 


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Daratumumab 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 on 
protocol treatment while receiving either carfilzomib or daratumumab (ie, if either 
carfilzomib or daratumumab are discontinued or interrupted, the subject is still 
considered on treatment if still taking the other investigational product).  
For subjects who are diagnosed with HBV reactivation while on daratumumab treatment, 
study treatment should be interrupted until the infection is adequately controlled (See 
Section 6.7.1). 
6.2.2.3 
Daratumumab:  Management of Infusion-related Reactions 
Subjects should be carefully observed during daratumumab infusions.  Trained study 
staff at the clinic should be prepared to intervene in case of any infusion reactions 
occurring, and resources necessary for resuscitation (eg, agents such as epinephrine 
and aerosolized bronchodilator, also medical equipment such as oxygen tanks, 
tracheostomy equipment, and a defibrillator) must be available at the bedside.  Attention 
to staffing should be considered when multiple subjects will be dosed at the same time. 
If an IRR develops, then the infusion should be temporarily interrupted.  Subjects who 
experience adverse events during the infusion must be treated according to the 
investigator’s judgment and best clinical practice.  Subjects should be treated with 
acetaminophen, antihistamine, or corticosteroids, as needed.  Intravenous saline may be 
indicated.  For bronchospasm, urticaria, or dyspnea, subjects may require 
antihistamines, oxygen, corticosteroids, or bronchodilators.  For hypotension, subjects 
may require vasopressors.  In the event of a life-threatening IRR (which may include 
pulmonary or cardiac events) or anaphylactic reaction, daratumumab should be 
discontinued and no additional daratumumab should be administered to the subject. 
Infusion-related Reactions of Grade 1 or Grade 2 
If the investigator assesses a grade 1 to 2 IRR adverse event to be related to 
administration of study drug, then the daratumumab administration should be paused.  
When the subject's condition is stable, daratumumab administration may be restarted at 
the investigator's discretion. 
If the subject experiences a grade 2 or higher event of laryngeal edema, or a grade 2 or 
higher event of bronchospasm that does not respond to systemic therapy and does not 
resolve within 6 hours from onset, then the subject must be withdrawn from 
daratumumab treatment. 


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Infusion-related Reactions of Grade 3 or Higher 
For IRR adverse events (other than laryngeal edema or bronchospasm) that are 
grade 3, the daratumumab administration must be stopped and the subject must be 
observed carefully until resolution of the adverse event or until the intensity of the event 
decreases to grade 1, at which point the daratumumab administration may be restarted 
at the investigator’s discretion.  If the intensity of the adverse event returns to 
grade 3 after restart of the daratumumab administration, then the subject must be 
withdrawn from daratumumab treatment. 
For IRR adverse events that are grade 4, the daratumumab administration must be 
stopped and the subject withdrawn from daratumumab treatment. 
Recurrent Infusion-related Reactions 
If a grade 3 IRR (or grade 2 or higher event of laryngeal edema, or a grade 2 or higher 
event of bronchospasm) recurs during or within 24 hours after a subsequent 
daratumumab administration, the daratumumab treatment must be discontinued. 
6.3 
Non-Amgen Non-investigational Product:  Dexamethasone 
6.3.1 
Dexamethasone:  Dosage, Administration, and Schedule 
Dexamethasone, a non-Amgen non-investigational product, will also be used in this 
study.  On days when more than 1 investigational product is administered, the required 
order of administration is as follows:  dexamethasone, pre-infusion medications for 
daratumumab, carfilzomib, daratumumab, and post-infusion medications for 
daratumumab. 
Dexamethasone 40 mg will be taken orally or by IV infusion weekly.  Dexamethasone 
must be given intravenously on cycle 1 days 1 and 2.  See Table 13 and Table 14 to 
review the arm 1 and arm 2, dosing schedules, respectively.  Dexamethasone IV or PO 
will be given on successive days, at 20 mg each treatment day on weeks with 
carfilzomib and/or daratumumab infusions.  All subjects, regardless of age, will be 
required to receive 20 mg of dexamethasone on days 1 and 2 of cycle 1 (as 
a preinfusion medication for daratumumab infusion) followed by 20 mg of 
methylprednisolone or equivalent on the third day (see Appendix N for corticosteroid 
dose equivalents).   
For days when dexamethasone is given in the absence of other IV infusion (neither 
carfilzomib nor daratumumab is scheduled), it may be given within  2 days for each 


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scheduled dose.  Dexamethasone will be administered at least 30 minutes (but no more 
than 4 hours) prior to carfilzomib and within 1 to 3 hours from the daratumumab dose. 
Additional details regarding dexamethasone is provided in the Investigational Product 
Information Manual. 
6.3.2 
Dexamethasone:  Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent Discontinuation 
All dexamethasone administrations must be within the 2 days of the scheduled 
administration; however, it must be given on days carfilzomib and/or daratumumab will 
be administered. 
The dose, date, and time are to be recorded on each subject’s eCRF.  The reason for 
dose change of dexamethasone is also to be recorded on each subject’s eCRF. 
For conditions that do not require dexamethasone dose reduction, refer to Section 6.4. 
For subjects  75 years of age or subjects whose weekly dexamethasone dose has 
been reduced to 20 mg/week, 20 mg of dexamethasone will be given as a preinfusion 
medication for daratumumab infusion, followed by 8 mg of dexamethasone prior to 
carfilzomib infusion on days 9 and 16 of cycle 1.  Starting with cycle 2, 20 mg 
dexamethasone must be given on days daratumumab is administered (without 8 mg 
dose on subsequent carfilzomib dosing day), otherwise the 20-mg dose can be split 
across carfilzomib dosing days (eg, 12/8, 10/10, etc, as shown in Table 13 and 
Table 14). 
When carfilzomib is permanently discontinued, investigators may at their discretion omit 
dexamethasone on days when given in the absence of daratumumab based on their 
assessment of the subject’s steroid tolerance. 
Subjects in arm 1 on cycles 7 without previous IRR, may decrease or omit 
dexamethasone premedication, if the subject cannot tolerate 20 mg of dexamethasone 
or equivalent.   
6.3.2.1 
Dexamethasone:  Dose Reduction Levels 
Three dose reduction levels are defined for dexamethasone based on the age of 
subjects, as shown in Table 8.  Dose reductions are permanent, dose must not be 
increased following a dose reduction.   


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Table 8.  Dose Decrements for Dexamethasone 
Subject Age 
Nominal Dose 
(mg) 
Reduced Weekly Dexamethasone Doses 
(mg) 
 
Dose -1 
Dose -2 
Dose -3 
 75 years 
40 
20 
12a 
8b 
 75 years 
20 
12a 
8 
- 
a If the dose needs to be divided over 2 days, administer 8 mg on the first day and 4 mg on the second day. 
b The third dose reduction is for subjects 75 years old or younger with steroid intolerance. 
6.3.2.2 
Dexamethasone:  Guidelines for Dexamethasone-related Toxicity 
Dexamethasone will be permanently discontinued after 3 dose reductions in subjects 
who are  75 years in the event of additional dexamethasone-related toxicities.  
Dexamethasone will be permanently discontinued after 2 dose reductions in 
subjects who are  75 years in the event of additional dexamethasone-related 
toxicities.  At the investigator’s discretion, dexamethasone may be tapered prior to 
complete discontinuation according to institutional practice.  The subject may continue 
on treatment with the other protocol-specified drug(s). 
Guidelines for dexamethasone-related toxicities are summarized in Table 9. 


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Table 9.  Treatment Guidelines for Dexamethasone-related Toxicity 
Symptom 
Findings 
Recommended Action 
Cardiovascular Edema  grade 3 (anasarca 
or limiting function and 
unresponsive to therapy) 
 
Diuretics as needed, and restart 
dexamethasone at 1 dose decrement; if 
edema persists despite above measures, 
decrease dose by another dose decrement. 
 
Discontinue dexamethasone permanently if 
symptoms persist despite second reduction. 
Gastrointestinal 
Toxicity 
Dyspepsia, gastric or 
duodenal ulcer, or gastritis 
grade 1 or 2 (requiring 
medical management) 
 
Continue dexamethasone at same dose and 
treat with therapeutic doses of histamine 
2 (H2) blockers, or proton pump inhibitor. 
 
Consider adding sucralfate or other 
antiulcer treatment as clinically indicated. 
 
If symptoms persist despite above 
measures, decrease dexamethasone dose 
by 1 dose level. 
Dyspepsia, gastric or 
duodenal ulcer, or gastritis 
 grade 3 (requiring 
hospitalization or surgery) 
 
Hold dexamethasone until symptoms return 
to baseline.  
 
Restart dexamethasone at 1 dose 
decrement along with concurrent therapy 
with H2 blockers, sucralfate, or omeprazole. 
 
If symptoms persist despite above 
measures, discontinue dexamethasone 
permanently. 
Acute pancreatitis 
 
Discontinue dexamethasone permanently. 
Page 1 of 2 


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Table 9.  Treatment Guidelines for Dexamethasone-related Toxicity 
Symptom 
Findings 
Recommended Action 
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. 
Metabolism and 
Nutrition 
Disorders 
Hyperglycemia  
grade 3 (fasting glucose 
 250 mg/dL) 
 
Treat with insulin or other hypoglycemic 
agents as needed until glucose is 
 grade 2 ( 250 mg/dL) then resume 
dexamethasone. 
 
If uncontrolled despite above measures, 
decrease dose by 1 dose decrement 
until  grade 2 ( 250 mg/dL). 
All Other 
Other toxicity  grade 3 felt 
related to dexamethasone 
 
Hold dexamethasone dose.  Resume at 
1 dose decrement when toxicity has 
resolved to  grade 2. 
 
If toxicity recurs, hold dexamethasone 
dose until toxicity has resolved to 
 grade 2 and resume dexamethasone 
dose by another dose decrement. 
 
If toxicity recurs despite 2 dose 
decrements, discontinue 
dexamethasone permanently. 
Page 2 of 2 


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6.4 
Conditions Not Requiring Dose Reduction 
Carfilzomib, daratumumab, and dexamethasone do not need to be held in the following 
cases: 
 
grade 3 nausea, vomiting, or diarrhea (that responds within 7 days to adequate 
treatment of antiemetics and/or antidiarrheal agents) 
 
grade 3 dexamethasone-related hyperglycemia 
 
isolated grade 3 -glutamyl transferase elevation 
 
grade 3 fatigue (unless persisting for  7 days) 
 
alopecia 
 
hypogammaglobulinemia 
6.4.1 
Medical Devices 
No investigational medical devices will be used in the conduct of this study. 
Other non-investigational medical devices may be used in the conduct of this 
study as part of standard care. 
Non-Amgen non-investigational medical devices (eg, syringes, sterile needles), 
that are commercially available are not usually provided or reimbursed by Amgen 
(except, for example, if required by local regulation).  The investigator will be 
responsible for obtaining supplies of these devices. 
6.5 
Other Protocol-required Therapies 
All other protocol-required therapies listed below are commercially available and will not 
be provided or reimbursed by Amgen (except if required by local regulation).  The 
Investigator will be responsible for obtaining supplies of these protocol-required 
therapies. 
6.5.1 
Antiviral Prophylaxis 
An antiviral is required concomitant medication for the duration of treatment with 
carfilzomib.  Acyclovir (eg, 400 mg PO 3 times a day, or 800 mg PO 2 times a day or per 
institutional standards), famcyclovir (eg, 125 mg PO given 3 days, twice a day or per 
institutional standards), or valacyclovir (eg, 500 mg PO, twice a day or per institutional 
standards), dose adjustments for renal function where appropriate, initiated within 
1 week of the first dose should continue for the duration of treatment with carfilzomib 
and/or daratumumab. 


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6.5.2 
Thromboprophylaxis 
An anticoagulant (eg, enteric-coated aspirin at standard prophylactic dose or other 
anticoagulant or antiplatelet medication such as clopidogrel bisulfate, low molecular 
weight heparin, or warfarin), is a suggested concomitant medication in subjects based 
on an individual benefit/risk assessment (Li et al, 2016). 
6.5.3 
Tumor Lysis Syndrome Prophylaxis 
An approved uric acid-lowering agent (eg, allopurinol) in subjects at high risk for tumor 
lysis syndrome (TLS) due to high tumor burden may be prescribed at the investigator’s 
discretion, according to the package insert. 
Subjects should be well hydrated to reduce the risk of TLS and decline in renal function; 
refer to the current Carfilzomib IB for safety guidance regarding TLS. 
6.5.4 
Proton-pump Inhibitor 
Proton-pump inhibitor (omeprazole or equivalent) is required while on dexamethasone. 
6.5.5 
Bone Health Therapy 
Concomitant bone health therapy is strongly recommended for all subjects with evidence 
of lytic destruction of bone or with osteopenia (Terpos et al, 2013; Gralow et al; 2013).  
Commercially available therapies are preferred when available, and should be used 
according to the manufacturer’s recommendations, as described in the prescribing 
information, for subjects with osteolytic or osteopenic myelomatous bone disease.  
Subjects who are using bisphosphonate or monoclonal antibody therapy when they 
enter the study should continue the same treatment.  Subjects with evidence of lytic 
destruction of bone or with osteopenia who are not using a bisphosphonate or 
monoclonal antibody at the time of randomization should start a bisphosphonate or other 
bone health medications that have proven efficacy such as monoclonal antibodies as 
soon as possible during cycle 1 or 2 of treatment.  Investigators should not start 
bisphosphonate or monoclonal antibody therapy during the study, unless it has been 
agreed with the sponsor that there is no sign of disease progression. 
6.5.6 
Prophylaxis for Pneumocystis Jirovenci 
Pneumocystis jirovenci pneumonia (PJP) prophylaxis should be considered, as per 
institutional guidelines while on dexamethasone. 


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6.5.7 
Prophylaxis for Hepatitis B Virus 
Hepatitis B virus reactivation prophylaxis should be considered for subjects at risk (ie, 
subjects who test positive on serology or have a prior history of HBV infection) as per 
institutional standards. 
6.5.8 
Other Permitted Therapies 
The following medications and supportive therapies are examples of support therapies 
that may be used during the study: 
 
antivirals 
 
hyperglycemia medical management 
 
prevention of constipation (eg, adequate hydration, high-fiber diet, and stool 
softeners, if needed) 
 
prophylactic antiemetics, with the exception of corticosteroids 
 
colony stimulating factors, erythropoietin, and transfusion of platelets and RBCs 
 
loperamide is recommended for the treatment of diarrhea, starting at the time of the 
first watery stool.  The loperamide dose and regimen is according to institutional 
guidelines.  Prophylactic loperamide is not recommended. 
 
adequate hydration is recommended for prevention of myeloma-related kidney 
disease 
 
intravenous immunoglobulins may be given at the discretion of the investigator 
according to local guidelines, eg, where low serum IgG concentrations may result in 
recurrent upper respiratory tract infections  
6.6 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Table 4 (carfilzomib), Section 6.2.2.2 (daratumumab), and Table 9 
(dexamethasone) for stopping and rechallenging requirements when subjects have 
abnormal hepatic laboratory values (ie, alkaline phosphatase, AST, ALT, total bilirubin) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis. 
For subjects who are diagnosed with HBV reactivation while on daratumumab treatment, 
study treatment should be interrupted until the infection is adequately controlled (see 
Section 6.7.1).  
6.7 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.9.  Concomitant therapies are to be collected from informed consent, 
through 30 days following the last dose of all study drug(s). 


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For concomitant therapies being taken for the disease under study (eg, pre/post-infusion 
medications), collect therapy name, indication, dose, unit, frequency, route, start dates, 
and enter in the subject’s eCRF. 
For all other concomitant therapies (eg, those listed in Section 6.4.1), collect therapy 
name, indication, dose, unit, frequency, route, start and stop dates, and enter in the 
subject’s eCRF. 
It is recommended to follow the Eighth Joint National Committee 2014 evidence-based 
guideline for the management of high blood pressure in adults (James et al, 2014 and 
Appendix H).  For elderly subjects, it is recommended to implement the 2013 ESH and 
ESC guidelines (Mancia et al, 2013 and Appendix I). 
Any patient presenting at screening with a blood pressure outside parameter is 
suggested to have consultation with the institution’s hypertension service for treatment 
recommendation. 
6.7.1 
Management of Hepatitis B Virus Reactivation 
Local hepatitis B testing (HBsAg, anti-HBs, and anti-HBc) will be performed at the next 
scheduled visit for all subjects that do not already have a known medical history of 
hepatitis B infection or who have not had testing conducted within the previous 
12 weeks.   
Subjects with evidence of positive HBV serology or who have a known history of HBV 
infection should have consultation with a specialist in HBV and be monitored for 
clinical signs of HBV reactivation with HBV DNA testing every 12 weeks ( 2 weeks) 
or more frequently as clinically indicated during and for 30 days following the last 
dose of all study drug(s) (follow-up visit 1).  Thereafter, subjects in arm 1 (KdD) will 
continue to be monitored and have HBV DNA testing for a maximum of 6 months 
following last dose of daratumumab.  Subjects that have received Hepatitis B vaccination 
with only anti-HBs positivity and no clinical signs of hepatitis do not require HBV DNA 
testing and monitoring.  
Any subject who becomes HBV DNA positive or develops reactivation of HBV will have 
study treatment interrupted and a hepatitis specialist should be consulted to 
undergo full assessment and make decisions regarding HBV reactivation 
treatment and/or confirmation whether HBV reactivation is adequately controlled 
to resume study drugs.  In consultation with the investigator, the hepatitis 
specialist may consider and advise resumption of study treatment in subjects whose 


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HBV reactivation is controlled and where the benefits of study treatment outweigh the 
risks.  After cessation of study therapy for any reason, any ongoing monitoring, testing, 
and anti-viral treatment should be under the guidance of a specialist in HBV. 
6.8 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  
This includes any drug(s), device(s) or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) includes investigational product.   
 
carfilzomib 
 
daratumumab 
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported. 
6.9 
Excluded Treatments and/or Procedures During Study Period 
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 corticosteroids for nonmalignant conditions (eg, asthma, inflammatory bowel 
disease) equivalent to a dexamethasone dose  4.0 mg/day or prednisone  20 mg/day 
are not permitted.  Corticosteroids given short-term (up to 2 weeks) for non-malignant 
conditions are permitted provided that the cumulative dose is less than 40 mg per week 
dexamethasone equivalent.  Medical monitor should be contacted in the event that 
short-term corticosteroid use is required greater than 2 weeks or at cumulative dose of 
more than 40 mg dexamethasone equivalent. 
Vaccination with live attenuated vaccines is not permitted at any time while the 
subject is receiving study treatment.  Plasmapheresis is not permitted at any time 
while the subject is receiving study treatment.  For subjects requiring plasmapheresis 
while on study treatment, every attempt should be made to document disease status by 
IMWG criteria first.  Study treatment must be discontinued, and the subject will enter 
LTFU. 
6.10 
Contraceptive Requirements 
Female of Childbearing Potential 


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A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Female in the following categories are not considered of child bearing potential: 
1. Premenopausal female with 1 of the following: 
a.  Documented hysterectomy 
b.  Documented bilateral salpingectomy 
c.  Documented bilateral oophorectomy 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject medical records, 2) subject medical examination, or 3) subject 
medical history interview. 
2. Premenarchal female 
3. Postmenopausal female 
a. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
b. Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study.  Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
6.10.1 
Female Subjects 
Females of childbearing potential should be advised to avoid becoming pregnant while 
being treated with carfilzomib.  Given that carfilzomib was clastogenic in the in vitro 
chromosomal aberration test in peripheral blood lymphocytes, as a precaution, FCBP 
and/or their male partners should use highly effective contraception methods or abstain 
from sexual activity during treatment and for 30 days after treatment with carfilzomib and 
for 3 months after cessation of daratumumab treatment. 
Female subjects of childbearing potential must agree to use 1 highly effective method of 
contraception (as described in Table 10).  It cannot be excluded that the efficacy of oral 
contraceptives may be reduced during carfilzomib treatment.  In addition, due to an 
increased risk of venous thromboembolic events associated with carfilzomib, females 
should avoid the use of hormonal contraceptives that are associated with a risk of 
thrombosis during treatment with carfilzomib.  Female subjects of childbearing potential 


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who are using oral contraceptives or a hormonal method of contraception that is 
associated with a risk of thrombosis should switch to an alternative non-hormonal 
method of highly effective contraception. 
Table 10.  Highly Effective Contraceptive Methods for Female Subjects 
Failure rate of  1 per year when used consistently and correctly 
 
Combined (estrogen and progestogen) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal [vaginal ring], or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable) 
 
Intrauterine device (IUD) 
 
Intrauterine hormonal-releasing system (IUS) 
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female subject 
of childbearing potential and that the vasectomized partner has received medical 
assessment of the surgical success) 
 
Sexual abstinence:  Defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments.  The reliability of sexual abstinence must 
be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the subject. 
If a female subject is suspected of being pregnant, the protocol-required therapies must 
be stopped immediately and may not be resumed until absence of pregnancy has been 
medically confirmed. 
Lactation 
It is not known if carfilzomib is transferred into breast milk.  If the subject is breastfeeding 
and wishes to be in this study, they will be required to discontinue nursing during study 
treatment and for an additional 30 days after stopping carfilzomib. 
There is no information regarding the presence of daratumumab in human milk, the 
effects on the breastfed infant, or the effects on milk production.  Human IgG is known to 
be present in human milk. 
The developmental and health benefits of breast-feeding should be considered along 
with the mother’s clinical need for daratumumab and any potential adverse effects on the 
breast-fed child from daratumumab or from the underlying maternal condition. 
6.10.2 
Male Subjects 
If the male’s sole sexual partner is of non-childbearing potential or has had a bilateral 
tubal ligation/occlusion, he is not required to use additional forms of contraception during 
the study.  The definition of non-childbearing potential is provided above. 


Product:  Carfilzomib 
Protocol Number:  20160275 
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Male subjects with a partner of childbearing potential must agree to not father a child 
during treatment of carfilzomib and/or daratumumab and for an additional 90 days after 
the last dose of carfilzomib and/or daratumumab. 
Contraceptive options for male subjects include: 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with protocol-required therapies).  The reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject, or 
 
Use of a condom during treatment of carfilzomib and/or daratumumab and for an 
additional 90 days after the last dose of carfilzomib and/or daratumumab. 
The female partner is to use an acceptable method of effective contraception such as:  
hormonal, intrauterine device (IUD), intrauterine hormonal-releasing system (IUS), 
female barrier method (diaphragm, cervical cap, contraceptive sponge [a female condom 
is not an option because there is a risk of tearing when both partners use a condom]).  
Male subjects must not donate sperm during treatment of carfilzomib and/or 
daratumumab and for an additional 90 days after the last dose of carfilzomib and/or 
daratumumab. 
Male subjects with a pregnant partner must practice sexual abstinence or wear a 
condom to prevent exposure of the unborn child to carfilzomib through semen. 
6.10.3 
Unacceptable Methods of Birth Control for Male and Female 
Subjects 
Birth control methods that are considered unacceptable in clinical trials include:  periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method. 
Male and female subjects of childbearing potential must receive pregnancy prevention 
counseling and be advised of the risk to fetus if they become pregnant or father a child 
during treatment of carfilzomib and/or daratumumab and for 90 days after the last dose 
of carfilzomib and/or daratumumab. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and for an increased length of time.  In addition, male subjects 
may also be required alter the duration and/or methods of contraception.  The 
investigator must discuss these topics with subjects.  
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 


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For Schedule of Assessments, please refer to Table 11 and Table 12.  For the dosing 
schedule of investigational products and other protocol-required therapies in arm 1 and 
arm 2, please refer to Table 13 and Table 14, respectively. 
Note that assessment cycles and dosing cycles both work to a 28-day cycle, but are 
independent (Table 12).  
, disease 
assessments should be obtained every 28 days from cycle 1 day 1, regardless of cycle 
duration including dose delays.  
 
. 
 


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Date:  17 March 2021 
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Table 11.  Schedule of Assessments 
Assessment 
Screening 
Assessment Cycle Days 
Follow-upa 
LTFU 
Notes 
1 
2 
8 
9 
15 
16 
22 
Visit 1 
General Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history  
X 
 
 
 
 
 
 
 
 
 
Includes multiple myeloma history 
Multiple myeloma frailty index 
X 
 
 
 
 
 
 
 
 
 
 
Review of AEs/SAEs 
Continually 
 
Refer to Section 9.2.1.3 for AEs/SAEs that 
occur  30 days after last dose of all study 
drug(s). 
Concomitant medications 
Continually 
 
 
Complete physical 
examination 
X 
 
 
 
 
 
 
 
X 
 
 
Physical measurements 
(weight, BSA) 
X 
X 
 
 
 
 
 
 
 
 
BSA should be calculated per Mosteller 
formula and utilized to calculate required 
study drug doses.  Weight can be measured 
again in case of substantial weight gain/loss. 
Physical measurement 
(height) 
X 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
X 
 
 
12-lead ECG with QTc interval 
X 
 
 
 
 
 
 
 
 
 
And as clinically indicated. 
 ECG:  cycle 1 
 
 
 
X 
 
 
 
 
 
 
 
 ECG:  cycle 2 
 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
 
Checked prior to administration of study 
drug(s) (K or D) in all cycles.  Additional 
measurements described in Section 7.3.10. 
day 22 (arm 1 only):  cycles 1 and 2 only. 
Page 1 of 5 
(X)  Parentheses indicate that the particular test is situational at that time point, as specified in the respective notes. 
Footnotes defined on the last page of the table. 


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Protocol Number:  20160275 
Date:  17 March 2021 
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Table 11.  Schedule of Assessments 
Assessment 
Screening 
Assessment Cycle Days 
Follow-upa 
LTFU 
Notes 
1 
2 
8 
9 
15 
16 
22 
Visit 1 
General Assessments (continued) 
ECHO 
X 
(X) 
 
 
 
 
 
 
 
 
Screening ECHO may be done within 30 days 
prior to randomization, if performed as a part 
of standard of care. 
Monitored every 6 months ( 2 weeks) from 
C1D1 (not to be assessed within 4 days of 
daratumumab infusion). 
Pulmonary function tests 
(PFTs) 
X 
(X) 
 
 
 
 
 
 
 
 
Screening PFT measurements may be done 
within 30 days prior to randomization, if 
performed as a part of standard of care. 
Monitored every 6 months ( 2 weeks) from 
C1D1 (not to be assessed within 4 days of 
daratumumab infusion). 
Survival 
 
 
 
 
 
 
 
 
 
X 
Every 12 weeks ( 2 weeks) after last 
follow-up visit. 
Subsequent Antimyeloma 
Therapies 
 
 
 
 
 
 
 
 
X 
X 
Data on subsequent antimyeloma therapy will 
be collected regardless of whether the subject 
has progressed (see Section 7.3.14). 
Laboratory Assessments 
Hematology:  Screen/cycle 1 
X 
X 
 
X 
 
X 
 
X 
 
 
Screening:  Subjects must fast for at least 
9 hours. 
Lab results must be evaluated for potential 
dose modification assessment prior to dosing.  
Further details in Section 7.3.15. 
Hematology:  cycles 2 
 
X 
 
 
 
 
 
 
X 
 
Chemistry:  Screen/cycle 1 
X 
X 
 
X 
 
X 
 
X 
 
 
Chemistry:  cycles 2 
 
X 
 
 
 
 
 
 
X 
 
Page 2 of 5 
(X)  Parentheses indicate that the particular test is situational at that time point, as specified in the respective notes. 
Footnotes defined on the last page of the table. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
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Table 11.  Schedule of Assessments 
Assessment 
Screening 
Assessment Cycle Days 
Follow-upa 
LTFU 
Notes 
1 
2 
8 
9 
15 
16 
22 
Visit 1 
Laboratory Assessments (continued) 
Coagulation tests 
X 
 
 
 
 
 
 
 
 
 
 
Quantitative immunoglobulins 
X 
 
 
 
 
 
 
 
 
 
Repeated only in case of clinical need, such as 
recurrent infections. 
Beta 2 microglobulin  
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (FCBP) 
X 
X 
 
 
 
 
 
 
 
 
More frequent pregnancy tests may be conducted if 
required per local regulations. 
Blood typing and IAT: 
arm 1 subjects only 
X 
 
 
 
 
 
 
 
 
 
A card with the results should be provided and 
subject should carry it throughout the treatment 
period and for at least 6 months after treatment ends  
Anti-daratumumab antibodies: 
Cycles:  1, 7, 12 
 
 
(X) 
 
 
 
 
 
 
 
 
Arm 1 only.  Scheduled samples are taken from PK 
sample. 
Page 3 of 5 
(X)  Parentheses indicate that the particular test is situational at that time point, as specified in the respective notes. 
Footnotes defined on the last page of the table. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
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Table 11.  Schedule of Assessments 
Assessment 
Screening 
Assessment Cycle Days 
Follow-
upa 
LTFU 
Notes 
1 
2 
8 
9 
15 
16 
22 
Visit 1 
Laboratory Assessments (continued) 
HBV testing 
 
At the next scheduled site visit and 
every 12 weeks  2 weeks or more 
frequently as clinically indicated through 
follow-up visit 1.   
  
(X) 
Situational testing 
and monitoring will 
continue for 
subjects in arm 1 for 
a maximum of 
6 months following 
the last dose of 
daratumumab.   
Local hepatitis B testing (HBsAg, anti-HBs, and 
anti-HBc) will be performed at the next scheduled 
visit for all subjects that do not already have a 
known medical history of hepatitis B infection or 
who have not had testing conducted within the 
previous 12 weeks. 
See Sections 6.7.1 and 7.3.15 for additional 
information. 
 
Page 4 of 5 
(X)  Parentheses indicate that the particular test is situational at that time point, as specified in the respective notes. 
Footnotes defined on the last page of the table. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
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Table 11.  Schedule of Assessments 
Assessment 
Screening 
Assessment Cycle Days 
Follow-upa 
LTFU 
Notes 
1 
2 
8 
9 
15 
16 
22 
Visit 1 
Optional Assessments (consent must be obtained) 
Pharmacogenetic analysis 
(saliva sample):  cycle 1 
 
X 
 
 
 
 
 
 
 
 
Sample obtained prior to dosing on 
C1D1. 
Pharmacogenetic analysis 
(bone marrow aspirate):  cycle 
1 and follow-up visit 1 
 
X 
 
 
 
 
 
 
(X) 
 
One bone marrow aspirate sample 
(obtained prior to dosing on C1D1) 
can be used for FISH, MRD, and 
pharmacogenetic analyses.   
Follow-up sample collected only from 
subjects who achieve a CR or better 
while on study. 
Biomarker assessment 
(plasma):  Screen/cycle 1  
X 
 
 
 
 
(X) 
 
 
 
 
Screening samples to be obtained 
prior to dosing on C1D1. 
Samples to be obtained on C1D15, 
C3D1, C6D1, C13D1, and follow-up.  
Also collected from consenting 
subjects who achieve a CR. 
Biomarker assessment 
(plasma):  cycles 3, 6, 13, and 
follow-up visit 1 
 
(X) 
 
 
 
 
 
 
X 
 
Biomarker assessment (serum):  
Screen/cycle 1 
X 
 
 
 
 
(X) 
 
 
 
 
Screening samples to be obtained 
prior to dosing on C1D1. 
Samples to be obtained on C1D15, 
C3D1, C6D1, and follow-up. 
Biomarker assessment (serum):  
cycles 3, 6, and follow-up visit 1 
 
(X) 
 
 
 
 
 
 
X 
 
Page 5 of 5 
(X)  Parentheses indicate that the particular test is situational at that time point, as specified in the respective notes. 
AE  adverse event; ADA  anti-drug antibody; BSA  body surface area; CR  complete response; CxDx  cycle X day X; D  daratumumab; 
ECG  electrocardiogram; ECHO  echocardiogram; ECOG  Eastern Cooperative Oncology Group; FCBP  female patients of childbearing potential;  
FISH  fluorescence in-situ hybridization; HBV  hepatitis B virus; IAT  indirect antiglobulin test; K  carfilzomib; LTFU  long-term follow-up; LVEF  left ventricular 
ejection fraction; MRD  minimal residual disease; PD  progressive disease;
PFT  pulmonary function test; PK  pharmacokinetics; 
QTc  corrected QT (interval); SAE  serious adverse event. 
a Follow-up occurs:  30 days ( 3) after the last administration of all study drug(s). 


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Table 12.  Schedule of Disease Assessments 
Assessment 
Screening 
Every 28 Calendar Daysa 
(Starting From C1D1) 
If Clinically 
Indicated 
To Confirm 
PD 
Notes 
Disease Assessments 
Bone marrow sample for FISH and 
MRD[-]: 
X 
(X) 
 
 
See Section 7.3.21.2 for additional timing 
details regarding FISH and MRD[-] 
assessments.  Samples for MRD analysis 
are not required 
 
 
Bone lesion assessment 
X 
 
X 
X 
Within 30 days prior to randomization; will 
be repeated if worsening clinical symptoms 
suggest PD, or as clinically indicated. 
Plasmacytoma evaluation 
(X) 
(X) 
X 
X 
Will be done at screening only if clinically 
suspected.  Screening evaluation may be 
done within 30 days prior to randomization, 
if performed as a part of standard of care.   
Assessment will be performed locally every 
28 days (for physical exam) or every 
12 weeks (for radiological exam). 
SPEP/UPEP/immunofixation 
X 
X 
 
 
Screening values may be used if within 
14 days prior to C1D1.  Post C1D1, UPEP 
and urine immunofixation will be measured 
every disease assessment. 
SFLC 
X 
X 
 
 
(X)  Parentheses indicate that the particular test is situational at that time point, as specified in the respective notes. 
CxDx  Cycle X day X; DCO  data cutoff; FISH  fluorescence in-situ hybridization; MRD  minimal residual disease; OS  overall survival; PD  progressive 
disease; PR  partial response; SFLC  serum free light chain; SPEP  serum protein electrophoresis; UPEP  urine protein electrophoresis. 
a 
, disease assessment should be performed every 28  7 days until PD regardless of cycle duration including dose 
delays.  Subjects who discontinue treatment prior to PD, but remain on study are required to complete the following assessments every 28  7 days until PD.  
 
. 


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Table 13.  Dosing Schedule - Arm 1 (KdD) 
Investigational Products and Other 
Protocol-required Therapies 
Dosing Cycle Day 
Notes 
1 
2 
8 
9 
15 
16 
22 
IV predose and postdose hydration (for carfilzomib as needed) 
 
Cycle 1  
X 
X 
X 
X 
X 
X 
 
Not required for days when daratumumab is administered 
Dexamethasone IV or PO (40 mg/week) 
 
All cycles 
20 
20 
20 
20 
20 
20 
40 
Dexamethasone 40 mg will be taken weekly (20 mg each day when taken on 
successive days). 
Cycle 1:  All subjects, regardless of age, will receive 20 mg C1D1 and C1D2, 
followed by 20 mg methylprednisolone on C1D3. 
Dexamethasone IV or PO (20 mg/week) – for subjects 75 years of age  
 
Cycle 1 
20 
20 
20 
8 
20 
8 
20 
Cycle 1:  All subjects will receive 20 mg C1D1 and C1D2, followed by 20 mg 
methylprednisolone on C1D3.  20 mg will be given as a preinfusion medication for 
daratumumab infusion, followed by 8 mg of dexamethasone prior to carfilzomib 
infusion on C1D9 and C1D16. 
Cycle 2:  20 mg must be given as a preinfusion medication for daratumumab 
infusion (without 8 mg dose on subsequent carfilzomib dosing day), otherwise the 
20 mg dose can be split across carfilzomib dosing days (eg, 12/8, 10/10, etc). 
 
Cycle 2 
20 
- 
20 
- 
20 
- 
20 
 
Cycles 3 to 6 
20 
- 
12 
8 
20 
- 
20 
 
Cycles 7 
20 
- 
12 
8 
12 
8 
20 
Carfilzomib IV 
 
Cycle 1 
20 
20 
56 
56 
56 
56 
 
The dosea will be 20 mg/m2 on C1D1 and C1D2 and 56 mg/m2 beginning on C1D8 
and thereafter. 
 
Cycle 2 
56 
56 
56 
56 
56 
56 
 
Daratumumab IV 
 
Cycle 1 
8 
8 
16 
 
16 
 
16 
For pre/post-infusion medication guidance, see Sections 6.2.2.1.1 and 6.2.2.1.2. 
C1D1 and C1D2:  8 mg/kg in 500 mL NS will be administered each day.  Thereafter, 
daratumumab will be given 16 mg/kg per dose diluted in 500 mL NS.  Daratumumab 
infusions begin after carfilzomib infusions are completed. 
 
Cycle 2 
16 
 
16 
 
16 
 
16 
 
Cycles 3 to 6 
16 
 
 
 
16 
 
 
 
Cycles 7 
16 
 
 
 
 
 
 
CxDx  cycle X day X; IV  intravenous; KdD  carfilzomib, dexamethasone, and daratumumab; NS  normal saline; PO  by mouth. 
a For patients with baseline chronic hepatic impairment (mild, moderate), reduce the starting and subsequent doses of carfilzomib by 25 (ie, 15 mg/m2 day 1 and 2 of 
cycle 1 and 42 mg/m2 day 8 cycle 1 and thereafter). 


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Date:  17 March 2021 
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Table 14.  Dosing Schedule - Arm 2 (Kd) 
Investigational Products and Other 
Protocol-required Therapies 
Dosing Cycle Day 
Notes 
1 
2 
8 
9 
15 
16 
22 
IV predose and postdose hydration (for carfilzomib as needed) 
 
Cycle 1  
X 
X 
X 
X 
X 
X 
 
See Section 6.2.1.1.1 for details. 
Dexamethasone IV or PO 
 
All cycles 
20 
20 
20 
20 
20 
20 
40 
When multiple doses are required within the same week, split the dose amongst 
the days for a total of 40 mg/weekly. 
The dexamethasone dose must be given as IV on C1D1 and C1D2. 
Dexamethasone IV or PO – for subjects 75 years of age 
 
All cycles 
12 
8 
12 
8 
12 
8 
20 
When multiple doses are required within the same week, split the dose amongst 
the days for a total of 20 mg/week (eg, 12/8, 10/10, etc). 
The dexamethasone dose must be given as IV on C1D1 and C1D2. 
Carfilzomib IV 
 
Cycle 1 
20 
20 
56 
56 
56 
56 
 
The dosea will be 20 mg/m2 on C1D1 and C1D2 and 56 mg/m2 beginning on C1D8 
and thereafter. 
 
Cycle 2 
56 
56 
56 
56 
56 
56 
 
CxDx  cycle X day X; IV  intravenous; Kd  carfilzomib and dexamethasone; PO  by mouth. 
a For patients with baseline chronic hepatic impairment (mild, moderate), reduce the starting and subsequent doses of carfilzomib by 25 (ie, 15 mg/m2 day 1 and 2 of 
cycle 1 and 42 mg/m2 day 8 cycle 1 and thereafter). 


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Date:  17 March 2021 
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7.2 
General Study Procedures 
The procedures performed and timing of each study visit are outlined in the Schedule of 
Assessments (Table 11 and Table 12).  Details regarding each type of procedure are 
provided in subsequent subsections.  Procedures that are part of routine care are not 
considered study-specific procedures and may be used at screening to determine 
eligibility. 
Refer to the applicable supplemental central laboratory, IxRS, and study manuals for 
detailed collection and handling procedures. 
7.2.1 
Screening Enrollment and/or Randomization 
The following procedures are to be completed during the screening period at time points 
designated in the Schedule of Assessments (Table 11 and Table 12).  Details of these 
procedures can be found in Section 7.3. 
 
Confirmation that the ICF has been signed prior to any study-specific screening 
procedures being performed 
 
Screening and randomization in IVR/IWR system, as applicable 
 
Demographic data (including sex, age, race, and ethnicity) 
 
Medical/surgical history (including multiple myeloma history) 
 
Multiple myeloma frailty index 
 
Adverse event reporting (any adverse events that occur following subject signing 
consent must be reported) 
 
Concomitant medications 
 
Physical examination, including examination of cardiovascular and respiratory 
systems, abdominal exam, and general neurologic exam 
 
Physical measurements:  height, weight, and BSA (Mosteller Formula) 
 
ECOG performance status 
 
12-lead ECG with QTc interval 
 
Vital signs 
 
Echocardiogram (ECHO) 
 
Pulmonary function tests (PFTs) 
 
Laboratory assessments:  hematology, serum chemistries, coagulation tests, 
quantitative immunoglobulins, 2 microglobulin, pregnancy test (FCBP), blood typing 
and indirect antiglobulin test (IAT) 
 
Disease assessments:  serum protein electrophoresis (SPEP)/urine protein 
electrophoresis (UPEP)/immunofixation (IFE), SFLC, bone marrow sample and 
aspirate for FISH and MRD[-], plasmacytoma evaluation (if clinically indicated), bone 
lesion assessment 


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7.2.2 
Rescreening 
Subjects who are determined not eligible after screening must be screen-failed in the 
IxRS and the reason for the screen-failure provided.  Subjects who are determined to be 
not eligible after screening may be rescreened once at the discretion of the investigator.  
Subjects who are determined not eligible for randomization after rescreening must be 
screen-failed in the IxRS and the reason for the screen-failure provided.   
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
Subjects rescreening within 21 days of the signing of the original informed consent only 
need to repeat the assessment(s) that did not originally meet the eligibility criteria; all 
other initial screening assessments do not need to be repeated.  Subjects rescreening 
greater than 21 days from the signing of the original informed consent must be 
re-consented and repeat all screening procedures. 
In cases of technical failure, central laboratory samples can be retested during 
screening and subject will not be considered a screen failure. 
7.2.3 
Treatment Period 
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Table 11 and Table 12).  Details of these 
procedures can be found in Section 7.3. 
Administration of protocol-required therapies is to occur after all other protocol-required 
assessments in each visit: 
 
Adverse event/serious adverse event reporting 
 
Concomitant medications 
 
Physical measurements:  weight and BSA (Mosteller Formula)  
 
ECG 
 
Vital signs 
 
ECHO 
 
PFTs 
 
Laboratory assessments:  hematology, serum chemistries, pregnancy test (FCBP), 
HBV serologies and HBV DNA testing (see Section 6.7.1) 
 
Disease assessments (every 28  7 days):  SPEP/UPEP/IFE, SFLC 
 
MRD assessments (see Section 7.3.21.2 for time points):  bone marrow aspirate 


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 
Disease assessments (to confirm PD or as clinically indicated):  plasmacytoma 
evaluation, bone lesion assessment 
 
Additional assessments:  carfilzomib PK 
 
Additional assessments (arm 1 only):  daratumumab PK, anti-daratumumab 
antibodies 
 
Optional assessments (additional consent must be obtained):  carfilzomib PDn 
 
Optional assessments (additional consent must be obtained):  pharmacogenetics 
samples (saliva sample and/or bone marrow aspirate) 
 
Optional assessments (additional consent must be obtained):  biomarker samples 
(plasma and serum) 
7.2.4 
Follow-up Visits 
The following procedures will be completed during the follow-up visit (30 days [ 3] after 
last dose of all study drug(s) as listed in the Schedule of Assessments (Table 11).  
Details of these procedures can be found in Section 7.3. 
 
Adverse event/serious adverse event reporting  
 
Concomitant medications  
 
Physical examination as per standard of care 
 
ECOG PS 
 
Vital signs 
 
Laboratory assessments:  hematology, chemistry, and HBV DNA testing  
 
Subjects with a known history of HBV infection or who test positive for HBV 
serologies may require additional testing (see Sections 6.7.1 and 7.3.15) 
 
Subsequent antimyeloma therapy 
 
Optional assessments (consent must be obtained):  pharmacogenetics sample (bone 
marrow aspirate) and biomarker assessment (plasma and serum) 
, subjects who discontinue treatment 
prior to PD, but remain on study are required to complete the following assessments 
every 28  7 days until PD as listed in Table 12 (these visits may overlap with follow-up 
visits that are scheduled based on last dose of all study drug[s]): 
 
Disease assessments:  SPEP/UPEP/IFE, SFLC (analyzed by central laboratory) 
 
 
7.2.5 
Long-term Follow-up 
Survival information and information on subsequent antimyeloma therapies will be 
collected during LTFU as listed in the Schedule of Assessments (Table 11) via a phone 


Product:  Carfilzomib 
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call to subject every 12 weeks ( 2 weeks).  Details of these procedures can be found in 
Section 7.3. 
Arm 1 (KdD) subjects with evidence of positive HBV serology or with a known 
medical history of HBV infection will be monitored for clinical signs and local HBV 
DNA testing for a maximum of 6 months following the last dose of daratumumab (see 
Section 7.3.15). 
7.3 
Description of Study Procedures 
7.3.1 
Demographics 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on biomarker variability 
and PKs of the protocol-required therapies. 
7.3.2 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started within 30 days prior to informed consent.  Medical history will include information 
on the subject’s concurrent medical conditions.  Record all findings on the medical 
history CRF.  Cardiovascular risk factors which include family history of cardiovascular 
disease and smoking history will also be required. 
In addition to the medical history above, multiple myeloma history must date back to the 
original diagnosis.  For subjects who are being referred to the research site, critical 
referral information will constitute multiple myeloma information from source notes.  Prior 
lines of multiple myeloma treatment are defined as a planned course of therapy.  
Therefore, during initial treatment, the induction  autologous stem cell 
transplant  consolidation and maintenance would be considered 1 line of therapy 
(see Appendix E for additional guidance on lines of therapy). 
7.3.3 
Multiple Myeloma Frailty Index 
Subjects  65 years of age will have their frailty score assessed at screening only using 
the Multiple Myeloma Frailty Score (Appendix O; Palumbo et al, 2015). 
7.3.4 
Review of Safety Events and Current Concomitant Medications 
All adverse events, serious adverse events, and changes in concomitant medications 
must be recorded on the subject’s eCRF from informed consent to 30 days following the 
last dose of all study drug(s).  All adverse events are followed until resolution or 
stabilization. 


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Date:  17 March 2021 
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Additional information will be collected for selected cardiopulmonary adverse events 
(including dyspnea, ischemic heart disease or cardiac failure) which will include results 
of work up performed as clinically indicated and/or investigator assessment of etiology. 
7.3.5 
Concomitant and Prior Medications 
All concomitant medications must be recorded in the designated eCRF from informed 
consent to 30 days following the last dose of all study drug(s).  Prior medications are to 
be included if taken 30 days prior to informed consent.  All prior medications that 
continue after the informed consent are to be recorded as concomitant medications. 
For prior therapies, collect therapy name, indication, dose, unit, frequency, route, start 
date and stop date. 
7.3.6 
Physical Examination 
A complete physical examination is to include examination of cardiovascular and 
respiratory systems, abdominal examination, and general neurologic examination.  
Clinically significant abnormal physical examination findings identified prior to the signing 
of informed consent should be reported as part of medical history, not as adverse 
events. 
7.3.7 
Physical Measurements 
Weight (in kilograms) and height (in centimeters) will be measured (height will be 
measured only at the screening physical examination).  Body surface area will be 
determined using the Mosteller Formula (Mosteller, 1987):   
BSA (m²)  ([Height(cm) x Weight(kg)]/3600) ½ 
7.3.8 
ECOG Performance Status 
The subject’s performance status will be assessed using the ECOG performance scale 
(see Appendix D) at intervals identified in the Schedule of Assessments (Table 11). 
7.3.9 
Echocardiogram 
All subjects will have a baseline transthoracic ECHO (TTE) during screening, including 
assessments of systolic and diastolic left ventricular function and right ventricular 
function.  Screening ECHO may be done within 30 days prior to randomization, if 
performed as a part of standard of care.  Echocardiograms are to be repeated 
approximately every 6 months ( 2 weeks) from cycle 1 day 1, until end of treatment, or 
if clinically indicated.  Routine ECHO (every 6 months) should not be assessed within 
4 days after daratumumab infusion.  However, ECHO should be performed within 
72 hours of cardiac failure event initiation, regardless of the timing in relation to infusion.   


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7.3.10 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Vital sign measurements are performed prior to 
administration of study drug(s) in all cycles. 
Subjects must be in a rested and calm state for at least 5 minutes before blood pressure 
assessments are conducted.  The position selected for a subject should be the same 
that is used throughout the study and documented in the medical record and on the vital 
sign CRF.  Take at least 2 blood pressure measurements spaced 1 to 2 minutes apart 
and additional measurements if the first 2 are quite different (Appendix F).  Record the 
average blood pressure on the vital sign CRF. 
The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the vital signs CRF. 
Record all measurements on the vital signs CRF. 
Additional Vital Sign Measurements 
In cycles 1 and 6, an additional blood pressure measurement post-carfilzomib infusion 
will be collected (within 30 minutes of the end of infusion). 
Vital signs are to be monitored extensively on cycle 1 day 1 for the first infusion of 
daratumumab, as described below: 
 
before the start of daratumumab infusion; 
 
at 0.5, 1, 1.5, 2, and 3.5 hours after the start of the infusion; 
 
at end of infusion; and 
 
0.5 and 1 hour after the end of infusion 
For all other daratumumab infusion days, vital signs are also to be measured at the end 
of the infusion. 
7.3.11 
Electrocardiogram 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible. 
The ECG must include the following measurements:  heart rate, QRS, QT, QTc, and PR 
intervals. 


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The primary investigator will review all ECGs.  Once signed, the original ECG tracing will 
be retained with the subject’s source documents.  At the request of the sponsor, a copy 
of the original ECG will be made available to Amgen. 
Electrocardiograms will be required in all subjects at screening.  ECG monitoring is 
required on cycle 1 day 8 and cycle 2 day 1 at the end of the carfilzomib infusion, and as 
clinically indicated. 
7.3.12 
Pulmonary Function Tests (PFTs) 
Pulmonary function tests include spirometry to measure FEV1, FEV1, FEV1/FVC, 
FVC, diffusing capacity of the lungs for carbon monoxide (DLCO) assessment.  
Screening PFT measurements may be done within 30 days prior to randomization, if 
performed as a part of standard of care.  All subjects will have PFTs assessed 
approximately every 6 months ( 2 weeks) from cycle 1 day 1, until end of treatment with 
carfilzomib, or if clinically indicated.  Serial measurements should be performed with the 
same equipment and comparable procedure.  Avoid performing this assessment within 
4 days after daratumumab infusion.   
7.3.13 
Survival 
All subjects will be followed by telephone contact or other method approximately every 
12 weeks ( 2 weeks) after the last follow-up visit until the subject has withdrawn 
consent for further participation, is lost to follow-up, has died, 
 or 
the study is closed, whichever is earliest.  Vital status must be obtained for all subjects 
within the limits of local law.  This includes subjects who may have discontinued study 
visits with or without withdrawing consent and should include interrogation of public 
databases, if necessary.  If deceased, the date and reported cause of death should be 
obtained. 
7.3.14 
Subsequent Antimyeloma Therapies 
All subjects will be followed by telephone contact or other method to collect subsequent 
antimyeloma therapies approximately every 12 weeks ( 2 weeks) after the last 
follow-up visit until the subject has withdrawn consent for further participation, is lost to 
follow-up, has died, 
 or the study is closed, whichever is earliest.   
7.3.15 
Laboratory Assessments 
Laboratory tests including hematology and serum chemistries during scheduled visits will 
be performed at a central laboratory 
, and 
at the local laboratory thereafter.  In the absence of central laboratory values, all 


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local laboratory values must be recorded in the eCRF.  Subjects must fast for at 
least 9 hours before screening hematology and serum chemistries.  If central laboratory 
results for lactate dehydrogenase (LDH), bilirubin, AST, and potassium are not 
reported/available at screening, local laboratory results may be utilized if completed 
within the screening window.  Screening coagulation tests will be done at local 
laboratories.  Post-enrollment, laboratory samples may be collected and analyzed by 
local laboratories if immediate results are necessary for management of 
treatment-emergent adverse events or dosing determination.  Evaluation of lab results 
for dose determination as required per Schedule of Assessments must be documented 
prior to dosing in each cycle.  Any local lab values that lead to dose modification 
decisions must be recorded in the eCRF.  Any local laboratory results that fulfill  grade 
3 values per Common Terminology Criteria for Adverse Events (CTCAE) must be 
recorded in the eCRF. 
For cycle 1 day 1, hematology and serum chemistry panel from screening may be used 
if within 14 days of day 1.  For subsequent visits in cycle 1, hematology and chemistry 
may be completed up to 72 hours prior to scheduled dose weekly for cycle 1.  Starting in 
cycle 2, only day 1 is required. 
Subjects who do not have a prior medical history of hepatitis B or who have not had 
testing conducted within the previous 12 weeks, will be tested locally for HBsAg, 
anti-HBs, and anti-HBc at their next visit.  In addition, subjects with a clinical history of 
hepatitis B infection or who test positive for HBV serologies will be monitored closely for 
signs and symptoms of hepatitis B and will have local HBV DNA testing performed at 
their next visit and then every 12 weeks ( 2 weeks) or more frequently if clinically 
indicated through follow-up visit 1.  Subjects in arm1 (KdD) will continue to be monitored 
and tested for 6 months following the last dose of daratumumab. 
Table 15 below outlines the specific analytes that will be assessed during the study. 


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Table 15.  Laboratory Analyte Listing 
Central/Local 
Laboratory: 
Chemistrya 
Central/Local 
Laboratory: 
Hematologya 
Central Laboratory:  
Disease Assessmentsb 
Central Laboratory: 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Albumin 
Calcium 
Adjusted calcium 
Glucose 
BUN or Urea 
Creatinine 
Total bilirubin 
Direct bilirubin 
Alk phosphatase 
AST (SGOT) 
ALT (SGPT) 
Magnesium 
Phosphorous 
Screening only: 
NT-proBNP 
LDH 
Uric acid 
Amylase 
Lipase 
Fasting lipid panel: 
 
Total cholesterol 
 
HDL 
 
LDL 
 
Triglycerides 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC 
Differential 
Neutrophils 
Bands/stabs 
Segs 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Plasma cell count: 
 plasma cell percent 
Screening only: 
HbA1c 
MRD assessment by 
NGS (bone marrow 
aspirate) 
FISH (bone marrow 
aspirate) 
SPEP 
Serum Immunofixation 
UPEP 
Urine immunofixation 
SFLC 
Quantitative 
immunoglobulins 
(serum): 
 IgA, IgD, IgE, IgG, 
IgM 
2-microglobulin 
(serum) 
Exploratory serum 
biomarker 
Exploratory plasma 
biomarker 
 
 
 
DIRA 
Pharmacokinetics 
 
Local Laboratory:  
Coagulation 
Local Laboratory: 
Other Labs 
PT/INR 
PTT 
Serum pregnancy 
Urine pregnancy 
Blood typing with 
indirect antiglobulin 
test 
Hepatitis B serologies 
(HBsAg, anti-HBs, and 
anti-HBc)c 
HBV DNA testingd 
ALT  alanine aminotransferase; AST  aspartate aminotransferase; BUN  blood urea nitrogen; 
DCO  data cutoff; DIRA  daratumumab immunofixation electrophoresis reflex assay; 
FISH  fluorescence in-situ hybridization; HbA1c  hemoglobin A1c; anti-HBc  hepatitis B core antibody; 
anti-HBs  hepatitis B surface antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; HDL 
 high-density lipoproteins; INR  international normalized ratio; LDH  lactate dehydrogenase; LDL  low-
density lipoproteins; MRD  minimal residual disease; NGS  next generation sequencing; 
NT-proBNP  N-terminal of the prohormone brain natriuretic peptide; OS  overall survival; 
PT  prothrombin time; PTT  partial prothrombin time; RBC  red blood cells; Segs  segmented 
neutrophils; SFLC  serum free light chain; SGOT  serum glutamic oxaloacetic transaminase; 
SGPT  serum glutamate-pyruvate transaminase; SPEP  serum protein electrophoresis; UPEP  urine 
protein electrophoresis; WBC  white blood cells. 
a Laboratory tests (including hematology and serum chemistries) will be performed at a central 
laboratory 
, laboratory 
tests will be performed at a local laboratory. 
b Disease assessments will be performed at the central laboratory 
 
 
 
c Hepatitis B serology testing is only required for subjects who do not have a known medical history of HBV 
or who have not had testing conducted within the previous 12 weeks. 
d Serial testing for HBV DNA is only required for subjects who have a known medical history of HBV or who 
test positive for HBV serologies. 


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7.3.16 
Pregnancy Evaluation 
For FCBP, a serum pregnancy test that is confirmed negative within 15 days prior to first 
dose of study drug and a negative urine pregnancy test within the 24 hours prior to first 
dose is required for eligibility determination and is to be performed at the local 
laboratory.  In addition to the pregnancy test conducted for eligibility, a urine or serum 
pregnancy test must be locally confirmed negative on day 1 of each cycle prior to 
dosing.  More frequent pregnancy tests may be conducted if required per local 
regulations. 
7.3.17 
Blood Typing and IAT 
Blood type, Rh, and IAT should be done before the first dose of daratumumab.  Subject 
RBC phenotyping (standard or extended) is an alternative option to the IAT test, if locally 
required.  Either method must be completed prior to first daratumumab infusion. 
Daratumumab interferes with the IAT, which is a routine pre-transfusion test performed 
to identify a patient’s antibodies to minor antigens so that suitable donor blood can be 
given for transfusion.  Daratumumab does not interfere with ABO/RhD typing.  CD38 is 
expressed at very low levels on erythrocytes.  Daratumumab binds to the CD38 on 
erythrocytes, which results in a positive IAT (Indirect Coombs Test).  This positive result 
masks the detection of antibodies to minor antigens and may prevent or delay blood 
banks from issuing donor blood for transfusion.  This effect occurs during daratumumab 
treatment and for up to 6 months after treatment ends.  Subjects will receive a patient 
identification wallet card for the study that includes the blood profile (ABO, Rh, and IAT 
or phenotyping) determined before the first infusion of daratumumab along with 
information on the IAT interference for healthcare providers/blood banks.  Subjects are 
to carry this card throughout the treatment period and for at least 6 months after 
treatment ends.  Blood banks can eliminate the daratumumab IAT interference with IAT 
by treating reagent RBCs with dithiothreitol (DTT; Chapuy et al, 2015). 
Possible methods for blood banks to provide safe RBCs for transfusion to subjects 
receiving daratumumab include: 
 
Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) 
or genotypically matched units 
 
Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs 
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion 
is needed emergently as per local blood bank practice. 


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Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically 
significant hemolysis has been observed in daratumumab studies.  For additional details, 
refer to the Daratumumab IB. 
7.3.18 
Pharmacokinetic Samples 


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7.3.20 
Antibody Testing Procedures 
Serum from venous blood samples collected from all subjects in arm 1 will be assessed 
for the generation of antibodies to daratumumab (immunogenicity) on day 1 of cycles 1, 
7, and 12 according to Table 11.  Serum samples will be screened for antibodies binding 
to daratumumab and serum titer will also be determined from confirmed positive 
samples using validated immunoassay methods.  Other immunogenicity analyses (eg, 
assessment of neutralizing capabilities) may be performed to further characterize the 
immune responses that are generated.  Daratumumab concentration will be evaluated at 
all immunogenicity time points to ensure appropriate interpretation of immunogenicity 
data.  When both daratumumab serum concentration and immunogenicity analyses are 
specified, they will be performed on aliquots from the same blood draw and no additional 
sampling is required.  Procedures for sample collection, preparation, identification, 
storage, and shipment will be provided in the Laboratory Manual or equivalent 
document. 
7.3.21 
Tumor Response and Multiple Myeloma Disease Assessment 
, disease assessments will be based on 
central laboratory data obtained every 28  7 days until confirmed PD (Section 7.3.21.5) 
irrespective of cycle duration including dose delays and treatment discontinuation.  For 
subjects who do not progress during treatment, disease assessments will continue to be 
measured (by the central laboratory) until PD 
 
 
.  Locally obtained disease 
assessment values will not be recorded in the eCRF. 
Disease response and progression assessments include:  SPEP, UPEP, SFLC, serum 
and urine immunofixation (SIFE, UIFE, respectively) (Section 7.3.21.1), bone marrow 
sample evaluation (Section 7.3.21.2), serum calcium, bone lesion evaluation 
(Section 7.3.21.3), and plasmacytoma evaluation (Section 7.3.21.4). 
7.3.21.1 
SPEP, UPEP, SFLC, SIFE, and UIFE 
, serum protein electrophoresis, UPEP, 
SIFE, UIFE, and SFLC will all be conducted at the central laboratory every 28  7 days 
(starting from cycle 1 day 1) irrespective of cycle duration including dose delays and 
treatment discontinuation.  Blood will be obtained for SFLC, SPEP, and SIFE.  
Twenty-4 hour urine samples will be obtained for UPEP and UIFE.  Results for SPEP, 
UPEP, or SFLC must be available at screening and before randomization.  Serum 


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protein electrophoresis (SPEP), UPEP, and SFLC will be repeated on cycle 1 day 
1 (unless screening values are within 14 days of cycle 1 day 1).  Post cycle 1 day 1, 
UPEP and UIFE will be measured every disease assessment as well as SPEP.  
 
 
. 
Subjects will be evaluated for disease response and progression according to the IMWG 
response criteria in Appendix M.  Disease status categories include CR, VGPR, PR, SD, 
and PD.  
, investigator evaluation of 
disease response is to be based solely on the central laboratory results, not on local 
laboratory results for laboratory-based parameters. 
The following confirmation assessments are required for all response categories (sCR, 
CR, VGPR, PR, and MR; refer to definitions in Appendix M): 
 
All response categories require 2 consecutive assessments made at any time before 
initiation of any new therapy 
 
All categories also require no known evidence of progression including new bone 
lesions if radiographic studies were performed   
 
Confirmation of CR or sCR requires bone marrow assessment (aspirate or biopsy) 
 
Extramedullary plasmacytoma evaluation (if present at screening) 
For subjects with light chain multiple myeloma, both serum and urine IFE test and SFLC 
assay will be performed every disease assessment.   
7.3.21.2 
Bone Marrow Sample Evaluation Including FISH and MRD[-]CR 
Assessment 
A baseline bone marrow sample (aspirate slides and/or biopsy) will be collected prior to 
first dose and will be used to confirm the diagnosis and quantify the percent () of 
myeloma cell involvement.  Biopsy or aspirate slides obtained as standard of care may 
be used as baseline if taken within 45 days prior to randomization and are sent to the 
central laboratory for processing.  The priority of bone marrow aspirate testing at 
screening (prior to dosing at cycle 1 day 1) is MRD NGS, FISH, cytomorphology, 
pharmacogenetics, and biomarker bone marrow aspirate.  All other bone marrow 
aspirate assessments include MRD NGS, cytomorphology, and pharmacogenetics. 
Additional bone marrow aspirate will be obtained as clinically indicated to confirm a 
response of CR.  In addition, a bone marrow aspirate will be obtained for MRD 
assessment at all of the following time points: 
 
at a fixed, landmark analysis at 12 months ( 4 weeks) 


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 
12 months calculated from baseline (cycle 1 day 1) 
 
this sample is collected from subjects who have not had confirmed disease 
progression 
 
if subject reached CR prior to the 12 month landmark and the CR sample was 
taken within 4 months, no additional sample is required, unless clinically 
indicated 
 
when a subject reaches CR and did not have a bone marrow aspirate sample taken 
for MRD analysis within the past 4 months, unless there is a clinical reason to repeat 
the assessment 
 
this sample may be collected/saved at the same time when the cytomorphology 
sample is collected for the confirmation of CR (per IMWG-URC criteria described 
in protocol Appendix M) 
 
at 24 months ( 4 weeks) for all subjects that have reached a CR (at any time prior to 
the 24 month timepoint) and have not had an MRD assessment within the past  
4 months, unless there is a clinical reason to repeat the assessment 
 
24 months is calculated from baseline (cycle 1 day 1) 
 
this sample is collected from all subjects who reached CR at any time prior to the 
24 month timepoint and are still receiving treatment or have not progressed and 
still attend site for disease assessment visits 
Samples for MRD analysis are not collected from subjects who have PD confirmed or 
have withdrawn consent related to this study assessment.  Samples for MRD analysis 
are not required 
. 
7.3.21.3 
Bone Lesion Assessment (Skeletal Survey, CT, or PET/CT) 
Skeletal survey will include lateral radiograph of the skull, anteroposterior and lateral 
views of the spine, and anteroposterior views of the pelvis, ribs, femora, and humeri.  
Low-dose whole body computed tomography (LD WBCT) or 
fluorodeoxyglucose-positron emission tomography/computed tomography 
(FDG-PET/CT) may be used in place of skeletal survey.  Bone lesion assessment (all 
subjects) will be conducted at screening (may be within 30 days prior to randomization) 
and will be repeated if worsening clinical symptoms suggest PD, or as clinically 
indicated.  The same method of assessment used at baseline will be used throughout 
the study.  These imaging studies will be read locally. 
7.3.21.4 
Extramedullary Plasmacytoma 
Extramedullary plasmacytoma evaluation will be conducted at screening only if a lesion 
is suspected clinically.  The evaluation may be done within 30 days prior to 
randomization, if performed as a part of standard of care.  If an extramedullary 
plasmacytoma is detected, evaluation will be repeated during treatment only to confirm a 
response of PR or better, or to confirm PD or as clinically indicated.  Assessment of 


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measurable sites of extramedullary disease will be performed and evaluated locally 
every 28 days (for physical examination) for subjects with a history of plasmacytomas or 
as clinically indicated during treatment for other subjects until confirmed CR or confirmed 
disease progression.  If assessment can only be performed radiologically, then 
evaluation of extramedullary plasmacytomas may be done every 12 weeks.  The same 
technique (which may include clinical evaluation by palpation, ultrasound, CT scan, 
magnetic resonance imaging (MRI), or PET/CT should be employed for each 
measurement of plasmacytoma dimensions as clinically appropriate (refer to 
Appendix M).  Bidimensional lesion measurements must be performed and recorded in 
the designated eCRF.   
7.3.21.5 
Progressive Disease Assessment 
, progressive disease (including PD due 
to development of hypercalcemia attributed solely to recurrence/progression of multiple 
myeloma) must be based on central laboratory evaluation.  Confirmation of PD (using 
2 consecutive assessments) will be required only when it is determined by central 
laboratory evaluations and not if identified via imaging as per IMWG-URC criteria, if 
progression is defined by such laboratory evaluations.  Local laboratory evaluation will 
not be accepted.  The assessments outlined in Appendix M are required for PD.  
Subjects will be considered to have progressive disease if they meet the criteria for 
progression by a variable that was not considered measurable at baseline; however, for 
patients who had a measurable serum or urine M-spike at baseline, progression cannot 
be defined by increases in SFLC alone (Kumar et al, 2016).  
 
 
. 
7.4 
Biomarker Development 
Minimal residual disease in bone marrow is a mandatory biomarker measurement in this 
study.  Minimal residual disease will be measured by a NGS based assay.  Bone marrow 
aspirates will be collected prior to first dose from each screened, consenting subject and 
at 12 months ( 2 weeks).  The bone marrow aspirates will be processed and stored 
according to a protocol that is provided to the central laboratory.  The samples will be 
analyzed centrally by the NGS-based MRD assay.  See Section 7.3.21.2 for details on 
priority of samples for bone marrow aspirate testing. 
Whole blood will be collected from participating subjects at screening, cycle 1 day 15, 
cycle 3 day 1, cycle 6 day 1, and at follow-up to explore the relationship between 


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serum- and plasma-based biomarkers and subject response to treatment.  Plasma 
collected at study start, cycle 13 day 1, at follow-up, and upon achievement of CR, will 
be used for isolation and analysis of circulating tumor DNA (ctDNA).  ctDNA will be 
analyzed by DNA-sequencing for the determination of biomarkers, including but not 
limited to, disease progression, treatment resistance, and patient-specific DNA 
mutations associated with MRD.  Serum collected at study start will be analyzed by 
enzyme-linked immunosorbent assay (ELISA) for the determination of biomarkers 
including, but not limited to, soluble CD38 (sCD38) protein. 
7.5 
Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of multiple myeloma 
and/or to identify subjects who may have positive or negative response to 
protocol-required therapies.  Saliva samples (collected predose on cycle 1 day 1, 
specifically for this optional test) and bone marrow aspirates (collected predose on 
cycle 1 day 1 and the first follow-up visit, as part of required protocol assessments) are 
collected for this part of the study.  For subjects who consent to this/these 
analysis/analyses, DNA may be extracted. 
Bone marrow aspirate collected will be subjected to CD138 enrichment to isolate 
malignant plasma cells and these malignant cells will then be used for both RNA- and 
DNA-sequencing to identify genomic alterations that may be associated with prognosis 
or prediction of drug response (see Section 7.3.21.2 for details on priority of samples for 
bone marrow aspirate testing).  Saliva will be used to isolate genomic DNA (gDNA) for 
use in DNA sequencing, to assist in the identification of tumor-specific mutations in the 
bone marrow. 


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7.6 
Sample Storage and Destruction  
Any blood, biomarker, PK, or PDn samples collected according to the Schedule of 
Assessments (Table 11) can be analyzed for any of the tests outlined in the protocol and 
for any tests necessary to minimize risks to study subjects.  This includes testing to 
ensure analytical methods produce reliable and valid data throughout the course of the 
study.  This can also include, but is not limited to, investigation of unexpected results, 
incurred sample reanalysis, and analyses for method transfer and comparability. 
All samples and associated results will be coded with a unique identification number 
prior to being shipped from the site for analysis or storage.  Samples will be tracked 
using a unique identifier that is assigned to the samples for the study.  Test results are 
stored in a secure database to ensure confidentiality.   
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand 
multiple myeloma, the dose response and/or prediction of response to carfilzomib or 
other protocol-specified therapy, and characterize aspects of the molecule 
(eg, MoA/target, metabolites).  Results from these analyses are to be documented and 
maintained, but are not necessarily reported as part of this study.  Samples can be 
retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker, or other exploratory 
studies are not placed in the subject’s medical record and are not to be made available 
to the subject, members of the family, the personal physician, or other third parties, 
except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject identification number so that any 
remaining blood, urine, saliva, or bone marrow samples and any other components from 
the cells can be located and destroyed.  Samples will be destroyed once all 
protocol-defined procedures are completed.  However, information collected from 
samples prior to the request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 


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appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product, device or other protocol-required therapies and must 
discuss with the subject the options for continuation of the Schedule of Assessments 
(Table 11) including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
as applicable.  Subjects who have discontinued investigational product and/or protocol 
required therapies or procedures should not be automatically removed from the study.  
Whenever safe and feasible it is imperative that subjects remain on-study to ensure 
safety surveillance and/or collection of outcome data.  The investigator must document 
the level of follow-up that is agreed to by the subject.    
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   


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8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.3 
Reasons for Removal From Treatment or Study  
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
subject request 
 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy) 
 
death 
 
lost to follow-up 
 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
 
disease progression  
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor 
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Adverse Events 
An adverse event 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 adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   


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The definition of adverse events 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 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 adverse event.   
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the highest grade (grade 1 to 4) on the Events 
eCRF.  Record a grade 5 adverse event as a separate event with a 1 day duration. 
For situations when an adverse event or serious adverse event is due to multiple 
myeloma report all known signs and symptoms.  Death due to disease progression in 
the absence of signs and symptoms should be reported as the primary tumor type 
(eg, multiple myeloma).  
Note:  The term “disease progression” should not be used to describe the 
disease-related event or adverse event.   
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study. 
9.1.2 
Serious Adverse Events 
A serious adverse event is defined as an adverse event 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 
(exceptions:  hospitalized due to long infusion time of study drugs or if hospitalized 
overnight only for observation as described in Section 6.2.2.1.2) 
 
results in persistent or significant disability/incapacity 
 
congenital anomaly/birth defect 
 
other medically important serious event 


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An adverse event 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 serious adverse event 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. 
9.2 
Safety Event Reporting Procedures  
9.2.1 
Adverse Events 
9.2.1.1 
Reporting Procedures for Adverse Events That Do Not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after signing of ICF through 30 days 
after the last dose of study treatment or the follow-up visit (whichever is later) are 
reported using the Event CRF.  All adverse events of HBV reactivation for 
arm 1 subjects with evidence of positive HBV serology or known medical history 
of HBV infection are required to be reported through end of study. 
The investigator must assign the following adverse event attributes: 
 
adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
 
dates of onset and resolution (if resolved), 
 
severity (and/or toxicity per protocol), 
 
assessment of relatedness to investigational product(s) or other protocol-required 
therapies, and 
 
action taken. 
The adverse event grading scale used will be the Amgen adverse event standard 
grading score; Common Terminology Criteria for Adverse Events (CTCAE).  The grading 
scale used in this study is described in Appendix A. 
The investigator must assess whether the adverse event is possibly related to the 
investigational product(s).  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 
the investigational product(s)? 
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, protocol-required 


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therapies, use of medical device(s) and/or procedure (including any screening 
procedure(s)).  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 a study 
activity (eg, administration of investigational product, protocol-required therapies, use of 
medical device(s)), and/or procedure”?  
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.1.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after the subject signing of the 
informed consent through end of study are recorded in the subject’s medical record and 
are submitted to Amgen.  All serious adverse events must be submitted to Amgen within 
24 hours following the investigator’s knowledge of the event via the Event CRF.   
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event Contingency Report Form within 24 hours of the investigator’s 
awareness of the event.  See Appendix B for a sample of the electronic Serious 
Adverse Event Contingency Report Form.  For EDC studies where the first notification of 
a Serious Adverse Event is reported to Amgen via the eSerious Adverse Event 
Contingency Report Form, the data must be entered into the EDC system when the 
system is again available.   
The investigator must assess whether the serious adverse event is possibly related to 
the investigational product(s).  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 the investigational product(s)?  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 serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  


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Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
9.2.1.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period (as defined in Section 9.2.1.2) or after end of 
study.  However, these serious adverse events should be reported to Amgen 
(regardless of causality).  Per local requirements, in some countries (eg, European 
Union [EU] member states), investigators are required to report serious adverse events 
that they become aware of after end of study.  If serious adverse events are reported, 
the investigator has to report them to Amgen within 24 hours following the investigator’s 
awareness of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly 
based on relationship to investigational product.  
9.2.1.4 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or 
serious adverse events.  Open-ended and non-leading verbal questioning of the 
subject is the preferred method to inquire about adverse event occurrence. 
9.2.1.5 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety 
of subjects and the safety of a study treatment under clinical investigation are 
met.  
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRBs/IECs, 
and investigators. 


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Individual safety reports must be prepared for suspected unexpected serious 
adverse reactions according to local regulatory requirements and sponsor policy 
and forwarded to investigators as necessary. 
An investigator who receives an individual safety report describing a serious 
adverse event or other specific safety information (eg, summary or listing of 
serious adverse events) from the sponsor will file it along with the Investigator’s 
Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
9.2.1.6 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety 
surveillance and signal management processes. 
9.3 
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 30 days after the last dose of carfilzomib or 3 months after 
the cessation of daratumumab treatment.  For male subjects, investigators should report 
pregnancies that occur during treatment and for an additional 90 days after the last dose 
of carfilzomib and/or daratumumab (whichever was given last). 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s awareness of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Form (Appendix C).  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 or within 30 days after the last 
dose of carfilzomib or within 3 months after the last dose of daratumumab, the 
investigator should attempt to obtain information regarding the birth outcome and health 
of the infant.  
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a Serious Adverse Event.  


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If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below.  In addition to reporting a lactation case during the study, 
investigators should report lactation cases that occur 30 days after the last dose of 
carfilzomib or 3 months after the last dose of daratumumab. 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s awareness of event.  Report a lactation case on the Lactation 
Notification Form (Appendix C).  Amgen Global Patient Safety will follow-up with the 
investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant while taking protocol-required 
therapies or within 90 days after the last dose of carfilzomib and/or daratumumab 
(whichever was given last), the investigator should discuss obtaining information 
regarding the birth outcome and health of the infant from the pregnant partner. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
PFS defined as time from randomization until disease progression or death from any 
cause.  Response and disease progression determined by a blinded Independent 
Review Committee (IRC). 
10.1.1.2 
Secondary Endpoint(s) 
Key secondary endpoints include: 
 
ORR:  defined as the proportion of best overall response of sCR, CR, VGPR, and PR 
by IRC 
 
MRD[-]CR rate, MRD[-]CR defined as achievement of CR by IRC per IMWG-URC 
(see Appendix M) and MRD[-] status as assessed by NGS (at a 10-5 level, pending 
analytical validation) at 12 months 
 
OS 
Additional secondary endpoints: 
 
DOR 
 
time to next treatment  
 
TTP 
 
time to response  
 
sustained MRD[-]CR (defined as the proportion of subjects that maintain MRD[-]CR 
for 12 months or more after achieving MRD[-]CR status) 
 
CRR (defined as the proportion of best overall response of sCR or CR) 


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 
MRD [-] rate 
 
EORTC QLQ-C30- Global Health Status/QoL scale  
 
subject incidence of treatment-emergent adverse events  
 
safety laboratory values, LVEF, FEV1/FVC ratio, and vital signs at each scheduled 
assessment 
10.1.1.3 
Exploratory Endpoint(s) 
10.1.2 
Analysis Sets 
10.1.2.1 
Full Analysis Set 
The full analysis set will include all randomized subjects.  All subjects will be analyzed 
according to treatment to which they are randomized.  Full analysis set will be used for 
the primary and key secondary endpoints. 
10.1.2.2 
Safety Analysis Set 
The safety population will include all randomized subjects who received at least 1 dose 
of any study treatment (ie, carfilzomib, dexamethasone, or daratumumab).  Subjects in 
the analyses based on the safety analysis set will be analyzed according to the 
treatment group corresponding to the actual treatment received. 


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10.1.2.3 
Per Protocol Analysis Set 
The per protocol analysis set is a subset of the full analysis set which includes subjects 
who do not have important protocol deviations that are considered to have an effect on 
efficacy outcomes.  The list of important protocol deviations is maintained by the sponsor 
on an ongoing basis and will be finalized before the primary analysis of the study. 
10.1.3 
Covariates and Subgroups 
In addition to the stratification factors for randomization, original ISS stage (Stage 1 or 
2 versus Stage 3) at screening, prior proteasome inhibitor exposure (yes vs no), number 
of prior lines of therapy (1 vs  2), and prior CD38 antibody therapy (yes vs no) the 
following covariates will be used to examine primary and selected secondary endpoints 
in subgroups as appropriate: 
 
baseline demographics and characteristics:  
 
age 
 
sex 
 
race  
 
region 
 
baseline organ function and comorbid conditions:  
 
ECOG PS 
 
baseline CrCl 
 
baseline hypertension history 
 
baseline history of ischemic heart disease 
 
baseline disease characteristics:  
 
revised ISS stage 
 
IgG vs non-IgG 
 
determination of measurable disease at baseline 
 
2-microglobulin level 
 
risk group as determined by FISH 
 
presence of soft tissue plasmacytoma 
 
prior lenalidomide exposure 
 
refractory to lenalidomide 
10.1.4 
Handling of Missing and Incomplete Data 
Subjects may have missing data points for a variety of reasons.  The procedures 
outlined below describing what will be done when data are missing may be refined 
during the blind review of the data. 


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Incomplete adverse event start dates, concomitant medications start or stop dates, and 
death date will be imputed, and the detailed rules will be specified in statistical analysis 
plan (SAP).  No imputation will be done for the primary analysis of the primary and key 
secondary endpoints.  The frequency of missing disease assessments and deviation of 
the actual disease assessment times from the scheduled assessment times will be 
summarized by treatment arms.  Sensitivity analyses will be performed to assess the 
impact on the analysis of PFS due to any missing data/assessment, and any lost to 
follow-up or discontinuation of assessment of PFS not due to an event.  Similar analysis 
will be performed for QoL endpoints.  
Details of missing data analysis and imputation rules will be described in SAP. 
10.2 
Sample Size Considerations 
One hundred eighty-eight PFS events are required to have at least 90 power to 
demonstrate superiority at an alternative HR of 0.6 (arm 1 vs arm 2), using a log rank 
test at 1-sided overall significance level of 0.025.  
 
 
  With 450 subjects randomized (300 in arm 1 vs 150 in arm 2), 
it is anticipated that 188 events will be accrued at approximately 27 months after the first 
subject is randomized assuming events follow an exponential distribution.  
 
 
 
  
 
 
 
 
  The description of sample size calculation for log-rank test 
factoring in accrual and dropout can be found in Lachin and Foulkes, 1986; 
Lakatos, 1988; and Chow et al, 2003.  The actual timing of primary analysis will be 
determined by actual enrollment rate, dropout rate, and PFS event rate; hence, it is 
subject to change as these factors may vary in the study.  The minimum detectable PFS 
HR is approximately 0.738 (corresponding to about 36 improvement in PFS) at the 
primary analysis.  Amgen may choose to increase sample size upon observation of 
slower than expected PFS event rate. 
 
  It is based 


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on safety and survival follow-up as described in Section 3.5.2.  It is not directly linked to 
sample size calculation based on the primary endpoint of PFS outlined in this section. 
The sample size calculation was performed using East software (Version 6.3 or above). 
10.3 
Planned Analyses 
10.3.1 
Data Monitoring Committee (DMC) 
An independent DMC will be convened for this study and will act in an advisory capacity 
to the sponsor with respect to safeguarding the interests of study subjects, assessing 
 safety and efficacy data, monitoring the overall conduct of the study, and 
providing with recommendations relating to continuing, modifying, or stopping the study 
based on these findings (International Council for Harmonisation Good Clinical Practice 
[ICH GCP 5.5.2]).  Details of the DMC will be described in the DMC Charter.  The initial 
assessment from this committee will be planned after 30 subjects (approximately 20 for 
the experimental arm and 10 for the control arm) have been enrolled and have finished 
the first cycle of treatment to ensure safety of all arms.  A provision will be made allowing 
an early follow-up DMC meeting to be decided at the time of the initial assessment.  The 
DMC will meet approximately every 6 months until the Primary Analysis is 
completed. 
10.3.2 
Independent Review Committee (IRC) 
The membership criteria and operational details of the IRC will be described in the IRC 
Charter.  The primary responsibility of the IRC is the independent assessment of 
individual patient efficacy outcomes in accordance with the IMWG-URC.  The IRC will 
centrally review the disease related tests and assessments (Section 7) to evaluate 
disease progressions and responses without the knowledge of randomization 
assignments.  The IRC assessment will be used for the primary analysis of endpoints. 
10.3.3 
Primary Analysis 
The timing for the primary analyses of PFS for arm 1 vs arm 2 will be event driven and 
will happen when approximately 188 PFS events are reached cumulatively in these 
2 arms. 


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10.4 
Planned Methods of Analysis  
10.4.1 
General Considerations 
The efficacy analyses of PFS and key secondary endpoints will be conducted on the full 
analysis set.  Treatment effects in efficacy endpoints will be evaluated and compared 
KdD vs Kd. 
In principle, summary statistics including mean, standard deviation, median, first and 
third quartiles, will be provided for continuous variables.  Frequency and percentage will 
be summarized by treatment arm for binary and categorical variables.  Proportions and 
the corresponding 95 CI will be based on normal approximations and the treatment 
comparison will be based on Cochran-Mantel-Haenszel test.  Exact tests will be 
considered for subgroup analyses when the cell size is considered small.  Time to-event 
endpoints will be estimated using the Kaplan-Meier (K-M) method.  Stratified log-rank 
test statistics and associated p-values will also be calculated.  Hazard ratios will be 
estimated using stratified Cox proportional hazards models. 
For PFS, response and disease progression will be determined by an IRC in a blinded 
manner.  In addition, response and disease progression outcomes will be determined 
locally by investigators in an unblinded manner and centrally by the sponsor using a 
validated computer algorithm (Onyx Response Computer Algorithm, ORCA) in a blinded 
manner.  The primary analysis of PFS will be based on IRC assessed outcomes; the 
timing will be event driven and will happen when approximately 188 PFS events are 
reached.  The PFS outcomes assessed by the investigators as well as by ORCA will 
serve as supportive analyses of PFS. 


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The primary comparison of PFS will be tested using a log rank test stratified by the 
randomization stratification factors per IxRS at 1-sided significance level of 0.025.  
Testing of the key secondary endpoints will be hierarchal in the order of ORR,  
MRD[-]CR, and OS such that the overall Type I error rate is strongly controlled under 
0.025 (1-sided).  Progression free survival, ORR, and MRD[-]CR will be tested at the 
PFS primary analysis, and OS will be tested at 
 and 
 analyses according to 
sequential testing order. 
The specific testing procedure for the primary and the key secondary endpoints is as 
follows: 
 
PFS (arm 1 vs arm 2) is tested at alpha level of 0.025 at the primary analysis 
 
If PFS is significant at the primary analysis, then ORR and MRD[-]CR are tested 
sequentially at alpha level of 0.025 
 
If PFS, ORR, and MRD[-]CR are all statistically significant, then OS will be tested 
multiple times with an overall alpha of 0.025. 
 
 
 
 
 
 
 
Further details of secondary endpoint testing will be described in the SAP. 
10.4.2 
Primary Efficacy Endpoint 
The primary comparison for PFS between arm 1 and arm 2 will use the log-rank test 
stratified by the randomization stratification factors per IxRS.  The HR (95 CI) will be 
estimated using a stratified Cox proportional hazards regression model as relative 
treatment effect.  The distribution of PFS including median will be summarized 
descriptively using the K-M method for each treatment group. 
The primary endpoint will be analyzed within each of the subgroups listed in 
Section 10.1.3.  Specifically, to determine whether the treatment effect is consistent 
across subgroups including, but not limited to, various geographical regions (eg, North 
America, Europe, Asia, and other), the estimate of the hazard ratios (with 95 CI) by 
Cox proportional hazards regression model for PFS between the treatment groups will 
be provided.  Additionally, a treatment-by-subgroup interaction test will be provided as 
appropriate. 


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10.4.3 
Secondary Efficacy Endpoint(s) 
If PFS is significant, the key secondary endpoints will be tested by sequential testing in 
the order of ORR, MRD[-]CR by NGS, and OS. 
The analysis for ORR and MRD[-]CR will be done if the primary analysis of PFS reaches 
statistical significance.  
The inferential comparison between treatment groups for both the ORR and MRD[-]CR 
will be made using the Cochran-Mantel-Haenszel chi-square test controlling for the 
randomization stratification factors per IxRS.  An estimate of the common odds ratio 
(95 CI) will be provided as a measure of the relative treatment effect.  The primary 
analysis of ORR will be based on IRC assessed outcomes.  The analyses based on 
investigator-assessed and ORCA will serve as supportive analyses.  Similarly, the CR 
portion of the MRD[-]CR endpoint will be based on IRC assessments. 
Overall survival will be analyzed using the same method as described for the PFS 
endpoints after PFS, ORR, MRD[-]CR all reach statistical significance.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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In the case that the PFS results are not statistically significant at the primary PFS 
analysis, the sponsor may stop the study and if so, the subjects will not be followed for 
OS any further. 
For subgroups listed in Section 10.1.3, odds ratio (with 95 CI) will be provided for ORR 
and MRD[-]CR rate between the treatment groups.  A treatment-by-subgroup interaction 
test will be provided as appropriate. 
Subgroup analysis for OS will be performed using the same method described for PFS, 
as appropriate. 
10.4.4 
Safety Endpoints 
The analysis of safety endpoints will be based on the safety analysis set.  The number 
and percentage of subjects experiencing at least 1 adverse event will be summarized by 
treatment group, relationship of adverse event to study treatment, and severity.  Subject 
incidence of all treatment-emergent adverse events will be tabulated by system organ 
class and preferred term.  Laboratory parameters will be summarized using descriptive 
statistics, by postdose shifts relative to baseline, and a summary of subject incidence of 
clinically significant values.  Vital signs will be summarized by changes from baseline 
values for each treatment group using descriptive statistics.  The LVEF and FEV1/FVC 
endpoints will be summarized by changes from baseline values for each treatment group 
using descriptive statistics.  Drug exposure including duration and intensity will be 
summarized descriptively for each treatment group.   
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the template are to be communicated 
formally in writing from the Amgen Clinical Manager to the investigator.  The written ICF 
is to be prepared in the languages of the potential patient population. 


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Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any 
investigational products are administered.  A legally acceptable representative is an 
individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.  
The acquisition of informed consent is to be documented in the subject’s medical 
records, and the ICF is to be signed and personally dated by the subject or a legally 
acceptable representative and by the person who conducted the informed consent 
discussion.  The original signed ICF is to be retained in accordance with institutional 
policy, and a copy of the signed consent form is to be provided to the subject or legally 
acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, other written subject information, and any 
proposed advertising material must be submitted to the IRB/IEC for written approval.  
A copy of the written approval of the protocol and ICF must be received by Amgen 
before recruitment of subjects into the study and shipment of Amgen investigational 
product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 


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document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval [IRBs 
only]/renewal [IRBs and IECs] throughout the duration of the study.  Copies of the 
investigator’s reports and the IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
 
Subjects are to be identified by a unique subject identification number.   
 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
 
On the eCRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
 
Documents that are not submitted to Amgen (eg, ICFs) are to be kept in confidence 
by the investigator, except as described below. 
In compliance with governmental/ICH GCP Guidelines, it is required that the investigator 
and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IRB/IEC direct access to review the subject’s original medical records 
for verification of study-related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  The investigator is obligated to inform and obtain the consent of 
the subject to permit such individuals to have access to his/her study-related records, 
including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
a recognized expert in the therapeutic area 
 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
 
an investigator contributing a high number of eligible subjects 


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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the investigator’s participation in the study 
according to the Clinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
Electronic CRF entries may be considered source data if the eCRF is the site of the 
original recording (ie, there is no other written or electronic record of data). 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
Elements to include: 


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 
Subject files containing completed CRFs, ICFs, and subject identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the eCRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing eCRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
Data capture for this study is planned to be electronic: 
 
All source documentation supporting entries into the CRFs must be maintained and 
readily available. 


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 
Updates to eCRFs will be automatically documented through the software’s “audit 
trail.” 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
 
The investigator signs only the Investigator Verification Form for this EDC study or 
the investigator applies an electronic signature in the EDC system if the study is set 
up to accept an electronic signature.  This signature indicates that investigator 
inspected or reviewed the data on the eCRF, the data queries, and agrees with the 
content. 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 11), the investigator can search publically available 
records (where permitted) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
Electronic CRFs must be completed in English.  TRADENAMES (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
12.6 
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 (ICMJE) Recommendations for 
the Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical 
Journals, which states: 
 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 1, 
2, 3, and 4. 
 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
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. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
If permitted under applicable regional laws or regulatory guidelines, study subjects may 
be reimbursed for reasonable travel costs and other expenses directly related to 
participation in this clinical trial. 


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13. 
REFERENCES 
Amgen Inc.  Carfilzomib Investigator’s Brochure.  Thousand Oaks, CA. 
Arastu-Kapur S, Shenk KD, Kirk CJ, et al.  Nonproteasomal targets of proteasome 
inhibitors bortezomib and carfilzomib [abstract].  Haematologica.  2009;94(s2).  14th 
Congress of the European Hematology Association.  Abstract 0939. 
Barr H, Dempsey J, Waller A, et al.  Ninety-minute daratumumab infusion is safe in 
multiple myeloma.  Blood.  2017;130:1889. 
Chapuy CI, Nicholson RT, Aguad MD, et al.  Resolving the daratumumab interference 
with blood compatibility testing.  Transfusion.  2015;55(6 Pt 2):1545-1554. 
Chow SC, Shao J, and Wang H.  Sample Size Calculation in Clinical Research.  New 
York:  Marcel Dekker; 2003. 
de Weers M, Tai YT, van der Veer MS, et al.  Daratumumab, a novel therapeutic human 
CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological 
tumors.  J Immunol.  2011;186(3):1840-1848. 
Dimopoulos MA, Goldschmidt H, Niesvisky R, et al.  Overall Survival of Patients with 
Relapsed or Refractory Multiple Myeloma Treated with Carfilzomib and Dexamethasone 
versus Bortezomib and Dexamethasone in the Randomized Phase 3 ENDEAVOR Trial.  
Abstract presented at:  16th International Myeloma Workshop; March 1-4, 2017; New 
Delhi, India.  Abstract. 
Dimopoulos MA, Moreau P, Palumbo A, et al.  Carfilzomib and dexamethasone versus 
bortezomib and dexamethasone for patients with relapsed or refractory multiple 
myeloma (ENDEAVOR): a randomized, phase 3, open-label, multicenter study.  Lancet 
Oncol.  2016;17(1):27-38. 
Durie BG, Harousseau JL, Miguel JS, et al.  International uniform response criteria for 
multiple myeloma.  Leukemia.  2006;20(9):1467-1473. 
Ferlay J, Soerjomataram I, Dikshit R, et al.  Cancer incidence and mortality worldwide:  
sources, methods and major patterns in GLOBOCAN 2012.  Int J Cancer.  
2015;136(5):E359-E386. 
Gralow JR, Biermann JS, Farooki A, et al.  NCCN Task Force Report:  Bone Health In 
Cancer Care.  J Natl Compr Canc Netw.  2013;11(Suppl 3):S1-S50. 
Horenstein AL, Chillemi A, Zaccarello G, et al.  A CD38/CD203a/CD73 ectoenzymatic 
pathway independent of CD39 drives a novel adenosinergic loop in human 
T lymphocytes.  Oncoimmunology.  2013;2(9):e26246. 
Howlader N, Noone AM, Krapcho M, et al.  SEER Cancer Statistics Review, 1975-2010, 
National Cancer Institute. 2013.  Available from http://seer.cancer.gov/csr/1975_2010/ 
James PA, Oparil S, Carter BL, et al.  2014 Evidence-Based Guideline for the 
Management of High Blood Pressure in Adults.  Report from the panel members 
appointed to the eighth Joint National Committee (JNC 8).  JAMA.  
2014;311(5):507-520. 
Janssen Pharmaceutica.  Daratumumab Investigator’s Brochure.  Beerse, Belgium. 
Krejcik J, Casneuf T, Nijhof IS, et al.  Daratumumab depletes CD38 immune regulatory 
cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma.  
Blood.  2016;128(3):384-394. 


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Kuhn DJ, Chen Q, Voorhees PM, et al.  Potent activity of carfilzomib, a novel, 
irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of 
multiple myeloma.  Blood.  2007;110(9):3281-3290. 
Kumar S, Paiva B, Anderson KC, et al.  International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple 
myeloma.  Lancet Oncol.  2016;17(8):328-346. 
Lachin JM and Foulkes MA.  Evaluation of sample size and power for analysis of 
survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, 
and stratification.  Biometrics.  1986;42:507–519. 
Lakatos E.  Sample size based on the log-rank statistic in complex clinical trials.  
Biometrics.  1988;44:229–241. 
Li W, Garcia D, Cornell RF, et al.  Cardiovascular and Thrombotic Complications of 
Novel Multiple Myeloma Therapies: A Review.  JAMA Oncol.  2016. Epub ahead of print. 
Lonial S and Nooka AK.  Myeloma Is Not a Single Disease.  J Oncol Pract.  
2016;12(4):287-292. 
Mancia G, Fagard R, Narkiewicz K, et al.  2013 ESH/ESC guidelines for the 
management of arterial hypertension:  the Task Force for the Management of Arterial 
Hypertension of the European Society of Hypertension (ESH) and of the European 
Society of Cardiology (ESC).  Eur Heart J.  2013;34(28):2159-2219. 
McCarthy PL, Palumbo A, Holstein SA, et al.  A meta-analysis of overall survival in 
patients with multiple myeloma treated with lenalidomide maintenance after high-dose 
melphalan and autologous stem cell transplant.  Abstract presented at the 21st EHA 
meeting Copenhagen (Abstract release date:  19 May 2016) EHA Learning Center.  
Palumbo A.  10 June 2016; 135136. 
Mosteller RD.  Simplified calculation of body-surface area.  N Engl J Med.  
1987;317(17):1098. 
Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the Eastern 
Cooperative Oncology Group.  Am J Clin Oncol.  1982;5(6):649–655. 
Palumbo A, Bringhen S, Mateos MV, et al.  Geriatric assessment predicts survival and 
toxicities in elderly myeloma patients:  an International Myeloma Working Group report.  
Blood.  2015;125(13):2068-2074. 
Palumbo A, Chanan-Khan AA, Weisel K, et al.  Phase III randomized controlled study of 
daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and 
dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma 
(RRMM):  CASTOR study [abstract].  J Clin Oncol.  2016;34(suppl):abstract LBA4. 
Rajkumar SV, Harousseau JL, Durie B, et al.  Consensus recommendations for the 
uniform reporting of clinical trials: report of the International Myeloma Workshop 
Consensus Panel 1.  Blood.  2011;117(18):4691-4695. 
Stewart AK, Rajkumar SV, Dimopoulos MA, et al.  Carfilzomib, lenalidomide, and 
dexamethasone for relapsed multiple myeloma.  N Engl J Med.  2015;372(2):142-152. 
Suzuki E, Demo S, Deu E, et al.  Molecular mechanisms of bortezomib resistant 
adenocarcinoma cells.  PLos ONE.  2011;6(12):e27996.  
Terpos E, Morgan G, Dimopoulos MA, et al.  International Myeloma Working Group 
recommendations for the treatment of multiple myeloma-related bone disease.  J Clin 
Oncol.  2013;31(18):2347-2357. 


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Usmani SZ, Weiss BM, Plesner T, et al.  Clinical efficacy of daratumumab monotherapy 
in patients with heavily pretreated relapsed or refractory multiple myeloma.  Blood.  
2016;128(1):37-44. 
van der Veer MS, de Weers M, van Kessel B, et al.  The therapeutic human CD38 
antibody daratumumab improves the anti-myeloma effect of newly emerging multi-drug 
therapies.  Blood Cancer J.  2011a;1(10):e41. 
van der Veer MS, de Weers M, van Kessel B, et al.  Towards effective immunotherapy of 
myeloma:  enhanced elimination of myeloma cells by combination of lenalidomide with 
the human CD38 monoclonal antibody daratumumab.  Haematologica.  
2011b;96(2):284-290. 


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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 is 
available at the following location: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 


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Appendix B.  Sample Electronic Serious Adverse Event Contingency Report Form 
 


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Appendix C.  Pregnancy and Lactation Notification Forms 
 
Pregnancy Notification Form 
 
Report to Amgen at: USTO fax: +1-888-814-8653, Non-US fax: +44 (0)207-136-1046 or email (worldwide): svc-ags-in-us@amgen.com 
 
1. Case Administrative Information 
Protocol/Study Number:  20160275 
 
 
Study Design:  X Interventional 
Observational (If Observational: 
Prospective 
Retrospective) 
 
2. Contact Information 
Investigator Name   
_ 
Site #   
 
 
Phone (  
)  
_ 
Fax (_     _)  
 
 
Email   
 
Institution   
 
Address    
 
 
3.  Subject Information 
Subject ID #   
_ 
Subject Gender: 
Female 
Male 
Subject age (at onset):       (in years) 
 
4.  Amgen Product Exposure 
 
Amgen Product 
Dose at time of 
conception 
Frequency 
Route 
Start Date 
 
mm  
/dd  
/yyyy  
 
 
Was the Amgen product (or study drug) discontinued? 
Yes 
No 
If yes, provide product (or study drug) stop date: mm    
/dd   
/yyyy  
 
Did the subject withdraw from the study? 
Yes 
No 
 
 
5.  Pregnancy Information 
Pregnant female’s last menstrual period (LMP) 
mm   
/ dd______/ yyyy  
  
Unknown 
N/A 
 Estimated date of delivery   mm  
/ dd  
_/ yyyy  
 
If N/A, date of termination (actual or planned) mm   
 
/ dd   _/ yyyy  
 
 
Has the pregnant female already delivered? 
Yes 
No  
Unknown 
N/A 
If yes, provide date of delivery:  mm    
 
/ dd   
 
/ yyyy  
 
Was the infant healthy? 
Yes 
No 
Unknown 
N/A 
If any Adverse Event was experienced by the infant, provide brief details:  
 
 
 
 
 
 
Form Completed by: 
 
Print Name:    
 
 
 
 
 
Title:    
 
 
Signature:    
 
 
Date:    
 
 
 
 
FORM-115199                                                                                       Version 1.0                                                                         Effective Date: 24-Sept-2018 


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g
y
 
Lactation Notification Form 
 
 
Report to Amgen at: USTO fax: +1-888-814-8653, Non-US fax: +44 (0)207-136-1046 or email (worldwide): svc-ags-in-us@amgen.com 
1. Case Administrative Information 
Protocol/Study Number:  20160275 
 
 
Study Design:  X Interventional 
Observational (If Observational: 
Prospective 
Retrospective) 
 
2.  Contact Information 
Investigator Name   
 
 
 
Site #   
 
 
Phone (  
)  
 
 
Fax (  
)  
 
 
Email   
 
Institution   
 
Address    
 
 
 3.  Subject Information 
Subject ID #   
 
 
 
 
 
Subject age (at onset):       (in years)
 
4.  Amgen Product Exposure 
 
Amgen Product 
Dose at time of 
breast feeding 
Frequency 
Route 
Start Date 
mm  
/dd  
/yyyy  
 
 
Was the Amgen product (or study drug) discontinued? 
Yes 
No 
If yes, provide product (or study drug) stop date: mm    
/dd   
/yyyy  
 
Did the subject withdraw from the study? 
Yes 
No 
 
5.  Breast Feeding Information 
 
Did the mother breastfeed or provide the infant with pumped breast milk while actively taking an Amgen product? 
Yes 
No 
 
If No, provide stop date:  mm   
 /dd   
/yyyy  
 
Infant date of birth: mm  
/dd  
/yyyy  
  
Infant gender: 
Female 
Male 
 
Is the infant healthy? 
Yes 
No 
Unknown 
N/A 
 
 
If any Adverse Event was experienced by the mother or the infant, provide brief details:  
 
 
 
 
 
 
 
  Form Completed by: 
 
Print Name:    
 
 
 
Title:    
 
 
Signature:    
 
 
Date:    
 
 
FORM-115201                                                                                      Version 1.0                                                                           Effective Date: 24-Sept-2018 


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


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


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Appendix F.  2013 ESH/ESC Office Blood Pressure Measurement 


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Appendix G.  NHLBI Table of Asthma Severity 
 


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Appendix H.  2014 Antihypertensive Management by 8JNC 
 
2014 Hypertension Guideline Management Algorithm 
ACEI  angiotensin-converting enzyme; ARB  angiotensin receptor blocker; CCB  calcium channel 
blocker; DBP  diastolic blood pressure; and SBP  systolic blood pressure. 
a ACEIs and ARBs should not be used in combination. 
b If blood pressure fails to be maintained at goal, reenter the algorithm where appropriate based on the 
current individual therapeutic plan.  


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Appendix I.  2013 EHC/ESC Antihypertensive Guidelines for Elderly Blood 
Pressure Goal Recommendations 
 


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Appendix J.  EORTC-QLQ-C30-V3
 


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Product:  Carfilzomib 
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Date:  17 March 2021 
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CONFIDENTIAL 
 
 
Appendix M.  International Uniform Response Criteria for Multiple Myeloma 
Summary of International Myeloma Working Group-Uniform Response Criteria 
(IMWG-URC) 
Response Subcategory 
Multiple Myeloma Response Criteria 
sCR 
 
Negative immunofixation on the serum and urine and  
 
Disappearance of any soft tissue plasmacytomas and 
 
 5 plasma cells in bone marrow and  
 
Normal SFLC ratio and  
 
Absence of clonal plasma cells in bone marrow by 
immunohistochemistry or 2- to 4-color flow cytometry  
CR 
 
Negative immunofixation on the serum and urine and  
 
Disappearance of any soft tissue plasmacytomas and 
 
 5 plasma cells in bone marrow  
 
In patients with measurable disease only by SFLC, normal 
SFLC ratio 
VGPR 
 
Serum and urine M-protein detectable by immunofixation but not 
on electrophoresis or  
 
 90 reduction in serum M-component with urine M-component 
 100 mg per 24 hours 
 
In patients with measurable disease only by SFLC, a decrease 
 90 in the difference between involved and uninvolved FLC 
levels 
PR 
 
 50 reduction of serum M-protein and reduction in 24-hour 
urinary M-protein by  90 or to  200 mg per 24 hours (if both 
are measurable at baseline)  
 
In patients with measurable disease only by SFLC, a decrease 
 50 in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria. 
 
In addition to the above criteria, if present at baseline,  50 
reduction in the size of soft tissue plasmacytomas is also 
required.  
MR 
 
 25 but  49 reduction of serum M-protein and reduction in 
24-hour urinary M-protein by 50 to 89.  In addition to the 
above listed criteria, if present a baseline a  50 reduction in 
the size (SPD) of soft tissue plasmacytoma is required 
Stable Disease 
 
Not meeting criteria for CR, VGPR, PR, or PD 
Page 1 of 2 
Footnotes defined on the next page of the table. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
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CONFIDENTIAL 
 
 
Summary of International Myeloma Working Group-Uniform Response Criteria 
(IMWG-URC) 
Response Subcategory 
Multiple Myeloma Response Criteria 
PD 
 
Increase of 25 from lowest response value in 1 or more of 
the following: 
 
Serum M-component (absolute increase must be  
 0.5 g/dL) and/or 
 
Urine M-component (absolute increase must be  
 200 mg per 24 hours) and/or 
 
Only in patients without measurable serum and urine 
M protein levels:  the difference between involved and 
uninvolved FLC levels (absolute increase must be 
 10 mg/dL) 
 
Only in patients without measurable serum and urine M 
protein levels and without measurable disease by FLC 
levels, bone marrow plasma cell percentage (absolute 
percentage must be  10) 
 
Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in size of existing bone 
lesions or soft tissue plasmacytomas  
 
Development of hypercalcemia (corrected serum calcium 
 11.5 mg/dL or 2.75 mmol/L) attributed solely to the plasma 
cell proliferative disorder 
Page 2 of 2 
CR  complete response; FLC  free light chain; MR  minimal response; PD  progressive disease; 
PR  partial response; sCR  stringent complete response; SFLC  serum free light chain; SPD  maximal 
perpendicular diameter; VGPR  very good partial response. 
All response categories (CR, sCR, VGPR, PR) require 2 consecutive assessments 
made at any time before the initiation of any new therapy as well as no known evidence 
of progressive or new bone lesions if radiographic studies were performed.  
Radiographic studies are not required to satisfy these response requirements.  Bone 
marrow, plasmacytoma, and skeletal survey assessments are not required to be 
confirmed by repeat testing.   
For sCR:  presence/absence of clonal cells is based upon the kappa lambda ratio.  An 
abnormal kappa lambda ratio by immunohistochemistry and/or immunofluorescence 
requires a minimum of 100 plasma cells for analysis.   
If patients do not have measurable disease at baseline, they can only be assessed for at 
least a CR or progressive disease (PD), otherwise they will be NE. 
Determination of PD while on study requires 2 consecutive assessments made at any 
time (no minimal interval is required, it can be done the same day; however, to confirm 
response or PD, 2 discrete samples are required) before classification of PD and/or the 


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Date:  17 March 2021 
Page 136 of 140 
CONFIDENTIAL 
 
 
institution of new therapy.  Confirmative samples for PD after new therapy can be used.  
Serum M-component increases of  1 g/dL from nadir are sufficient to define progression 
if nadir M-component is  5 g/dL. 
Plasmacytomas:  A definite increase in the size is defined as a  50 increase from 
nadir as measured serially by the sum of the products of the maximal perpendicular 
diameter (SPD) of the measurable lesion or a  50 increase in the longest diameter of 
a previous lesion with  1 cm short axis.  A plasmacytoma is considered measurable if 
the longest diameter is at least 1 cm and the product of the cross diameters is at least 
1 cm2.  Plasmacytomas of lesser size will be considered non-measurable.  The 
requirement for bi-directional measurements applies only to plasmacytomas.  The 
plasmacytoma specifications for PD are based on the sponsor’s interpretation of the 
IMWG-URC and practical considerations for study execution. 
For defining nadir, in the case where a value is felt to be a spurious result per 
physician/Independent Review Committee (IRC) discretion (eg, a possible laboratory 
error), that value will not be considered when determining the lowest value. 
Sources:  Durie et al, 2006; Kumar et al, 2016; Rajkumar et al, 2011. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 137 of 140 
CONFIDENTIAL 
 
 
Appendix N.  Corticosteroid Dose Equivalents 
Equivalent Dose (mg) 
Steroid 
1.5 
dexamethasone (long-acting) 
8 
methylprednisolone (intermediate-acting) 
10 
prednisone (intermediate-acting) 
10 
prednisolone (intermediate-acting) 
40 
hydrocortisone (short-acting) 


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CONFIDENTIAL 
 
 
Appendix O.  Multiple Myeloma Frailty Score 
Functional Scales for Calculating Frailty Score 
Score 
ADL Scale 
IADL Scale 
0 - 1 
Bathing 
Ability to use the phone 
0 - 1 
Dressing 
Shopping 
0 - 1 
Toileting 
Making meals 
0 - 1 
Transferring 
Housekeeping 
0 - 1 
Continence 
Laundry 
0 - 1 
Feeding 
Transportation 
0 - 1 
-- 
Medication Independence 
0 - 1 
-- 
Financial Independence 
ADL  activities of daily living; IADL  instrumental activities of daily living. 
ADL and IADL are calculated by assigning either a 0 or 1 to each category on the basis of the ability to 
perform the task (0 indicates unable to perform and 1 indicates able to perform). 
Source:  Lonial and Nooka 2016; Palumbo et al, 2015. 


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Charlson Comorbidity Index 
Score 
Comorbidities 
1 
Myocardial infarction (history, not ECG changes only) 
Congestive heart failure 
Peripheral vascular disease (includes aortic aneurysm  6 cm) 
Cardiovascular disease:  CVA with mild or no residual or TIA 
Dementia 
Chronic pulmonary disease 
Connective tissue disease 
Peptic ulcer disease 
Mild liver disease (without portal hypertension, includes chronic hepatitis) 
Diabetes without end-organ damage (excludes diet-controlled alone) 
2 
Hemiplegia 
Moderate or severe renal disease 
Diabetes with end-organ damage (retinopathy, neuropathy, or brittle diabetes) 
Tumor without metastasis (exclude if  5 year since diagnosis) 
Leukemia (acute or chronic) 
Lymphoma 
3 
Moderate or severe liver disease 
6 
Metastatic solid tumor 
AIDS (not just HIV-positive) 
AIDS  acquired immunodeficiency syndrome; CVA  cardiovascular accident; ECG  electrocardiogram; 
HIV  human immunodeficiency virus; TIA  transient ischemic attack. 
Source:  Lonial and Nooka 2016; Palumbo et al, 2015. 


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CONFIDENTIAL 
 
 
Frailty Index Calculation 
Variable 
Score 
Age, years 
 75 
0 
75 - 80 
1 
 80 
2 
ADL 
 4 
0 
 4 
1 
IADL 
 5 
0 
 5 
1 
CCI 
 1 
0 
 2 
1 
Category 
Fit 
0 
Intermediate Fitness 
1 
Frail 
 2 
ADL  activities of daily living; CCI  Charlson Comorbidity Index; IADL  instrumental activities of daily 
living. 
Source:  Lonial and Nooka 2016; Palumbo et al, 2015. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 1 of 61 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
Amendment 6 
Protocol Title:  A Randomized, Open-label, Phase 3 Study Comparing 
Carfilzomib, Dexamethasone, and Daratumumab to Carfilzomib and 
Dexamethasone for the Treatment of Patients With Relapsed or Refractory 
Multiple Myeloma 
CANDOR 
Study of Carfilzomib ANd Daratumumab fOr Relapsed myeloma 
 
Amgen Protocol Number (carfilzomib) 20160275 
EudraCT Number 2016-003554-33 
NCT Number NCT03158688 
Amendment Date: 
17 March 2021 
 
Rationale: 
This protocol is being amended to include the following key changes: 
 
The maximum treatment duration for an individual study participant may be 
extended from 4 years to
 
to obtain additional long-term safety data per 
Food and Drug Administration Postmarketing Commitment. 
 
 
 
 as the primary endpoint for this study 
has been met.  Disease assessments will be performed locally per standard 
of care. 
 
 
. Only local laboratory testing will be utilized to monitor 
the safety of study participants to eliminate the logistic challenges at site 
including the risk of delayed lab kits as seen during the pandemic and reduce 
the volume of blood drawn from a study participant in excess of clinical need. 
 
Specified the timing and details regarding end of study to align with the safety 
reporting requirements for hepatitis B virus (HBV) reactivation in study 
participants receiving daratumumab. 
 
Adding new or clarifying recommended actions for carfilzomib dosage 
adjustments and/or treatment delays for nonhematologic toxicities, namely 
progressive multifocal leukoencephalopathy, renal dysfunction, tumor lysis 
syndrome, and thrombotic microangiopathy. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 2 of 61 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
 
Adding changes for daratumumab intravenous infusion rates based on 
available clinical data (Barr et al, 2017).  Starting with cycle 2, daratumumab 
infusion may be shortened to a 90-minutes accelerated infusion for study 
participants who have received and well-tolerated the 2 prior doses of 
daratumumab standard infusion rates in cycle 1. 
 
Adding precautionary instructions that vaccination with live attenuated 
vaccines is not permitted at any time while the study participant is receiving 
study treatments due to the risk of being immunosuppressed. 
 
Removing bone marrow sample collection for minimal residual disease 
(MRD) assessments after the 
 (48 months after last 
subject enrollment [LSE]) OS DCO. After a minimum treatment duration of 
3 years, it is expected that the number of subjects achieving a complete 
response (CR) is low. In addition, all subjects with MRD[-]CR at 12 months 
landmark have surpassed the MRD collection timepoint for the secondary 
endpoint persistence of MRD[-]CR. Therefore, omitting MRD assessments 
after 
 will not have an impact on previously reported 
MRD outcomes. 
 
To clarify that the Data Monitoring Committee (DMC) will not meet beyond 
the primary analysis. 
 
Removing Clinical Outcome Assessments based on the available data. At the 
primary analysis, a slightly higher health-related Quality of Life was 
associated with 20/56 mg/m2 twice weekly carfilzomib, dexamethasone, and 
daratumumab (KdD), however it was maintained with both KdD and 
20/56 mg/m2 twice weekly carfilzomib and dexamethasone (Kd) treatments.  
Updated analysis at 
 Analysis did not show any new findings 
and it is expected that the difference will continue to be low. 
 
Removing the pregnancy test at the follow-up visit 30 (+3) days after the last 
dose of all study drugs for females of childbearing potential (FCBP). 
 
Removing reference to daratumumab interference testing aimed to mitigate 
the risk of underreporting treatment response of complete response. The key 
secondary endpoint ORR was met at the primary analysis. In addition, 
~ 36 months from LSE, the overall incidence of patients achieving a best 
response of CR is considered low. 
 
Removing daratumumab pharmacokinetics (PK) and anti-Dara antibody 
(ADA) sample collection at Follow up Visit 2 (8 weeks after the last dose of 
daratumumab) including the instructions that subjects with evidence of 
positive anti-drug antibody levels need to be followed until they return to 
baseline.  At present, daratumumab PK data was collected from 
approximately 2/3 of patients and analysis has shown that carfilzomib has no 
observable effect on daratumumab PK. In addition, no patient showed 
evidence of ADA positivity. Consistent with the overall low incidence of 
anti-Dara antibodies across studies (< 1%) the expected ADA rate will 
continue to be low and review of clinical data from antibody-positive subjects 
did not identify any new safety concerns or meaningful impact on efficacy. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 March 2021 
Page 3 of 61 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
 
Removing the Follow up Visit 2 from the Schedule of Activities resulting from 
changes with regards to daratumumab PK and ADA sample collection. 
Adding medical device use, serious adverse event, and safety monitoring 
plan language per updates to the Amgen protocol template. 
 
Removing Investigational Product Instruction Manual (IPIM) language per 
updates to the Amgen protocol template. 
 
Additional administrative, typographical, and formatting changes were made 
throughout the protocol. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  02 October 2019 
Page 1 of 13 
CONFIDENTIAL 
 
 
Amendment 5 
Protocol Title:  A Randomized, Open-label, Phase 3 Study Comparing Carfilzomib, 
Dexamethasone, and Daratumumab to Carfilzomib and Dexamethasone for the 
Treatment of Patients With Relapsed or Refractory Multiple Myeloma 
 
Amgen Protocol Number (carfilzomib) 20160275 
 
Amendment Date: 
02 October 2019 
 
Rationale: 
The protocol is amended to: 
 
Expand hepatitis B testing (hepatitis B surface antigen, hepatitis B surface 
antibody, and hepatitis B core antibody) to include all subjects (KdD arm and Kd 
arm) that do not already have a prior medical history of hepatitis B or who have 
not had testing within the previous 12 weeks.  In addition, guidance has been 
provided regarding HBV DNA testing and monitoring for subjects with positive 
hepatitis B serology or a prior history of HBV. 
 
Clarify that clinical outcome assessments are to be completed on Day 1 of each 
cycle prior to dosing. 
 
Remove bone marrow aspirate sample at 12 months after confirmed CR and 
clarified sampling criteria at 24 months.  In addition, to clarify that all bone 
marrow samples, with the exception of the screening sample, are to only be 
bone marrow aspirate 
 
Add details regarding the disposition of the database at the time of analyses 
 
Clarify International Uniform Response Criteria for Multiple Myeloma 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 May 2019 
Page 1 of 23 
CONFIDENTIAL 
 
 
Amendment 4 
Protocol Title:  A Randomized, Open-label, Phase 3 Study Comparing Carfilzomib, 
Dexamethasone, and Daratumumab to Carfilzomib and Dexamethasone for the 
Treatment of Patients With Relapsed or Refractory Multiple Myeloma 
 
Amgen Protocol Number (carfilzomib) 20160275 
EudraCT number 2016-003554-33 
NCT03158688 
 
Amendment Date: 
17 May 2019 
 
Rationale: 
The protocol is being amended to: 
 
Add 
 after the first 
subject enrolled in addition to the OS 
 analysis.  Details were also added on the 
methods for the analyses and to clarify the timing for the OS 
 analysis. 
 
Update the language for the management of hepatitis B virus (HBV) reactivation, 
safety evaluations, and dose modification guidelines for daratumumab throughout 
the protocol. 
 
Update dexamethasone dosing for subjects who discontinue carfilzomib and for 
subjects with steroid intolerance. 
 
Update Table 4 to clarify recommended carfilzomib dose modifications for congestive 
heart failure. 
 
Extend the window for the 12-month and 24-month bone marrow aspirate collection 
from  2 weeks to “ 4 weeks” throughout the protocol.  Details were also added to 
clarify bone marrow aspirate collection. 
 
Updates to the International Myeloma Working Group-Uniform Response Criteria in 
Appendix M. 
 
Add the collection of subsequent antimyeloma therapy in longterm follow-up. 
 
Update schedule of assessments to clarify clinical outcome assessment timing, add 
subsequent antimyeloma therapy collection, and to add details of HBV serology and 
HBV DNA testing. 
 
Clarify the timing of clinical outcome assessments through follow-up visit 1. 
 
Update Section 6.4 (Conditions Not Requiring Dose Reduction) to include 
hypogammaglobulinemia in conditions not requiring dose reduction. 
 
Update Section 6.5.5 (Bone Health Therapy) to include other bone health 
medications such as monoclonal antibodies as a recommended therapy for subjects 
with lytic destruction of bone or osteopenia. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  17 May 2019 
Page 2 of 23 
CONFIDENTIAL 
 
 
 
Update Section 6.5.7 (Other Permitted Therapies) to include intravenous 
immunoglobulins as a permitted therapy. 
 
Clarify the reporting requirements of adverse events to align with the case report 
form completion guidelines.  
 
Clarify that the pharmacist will calculate the required volume and number of vials 
needed for both carfilzomib and daratumumab. 
 
Update Table 14 to include magnesium and phosphorus under the listing for central 
laboratory chemistry and HBV serology and DNA testing under the listing for local 
laboratory other labs. 
 
Clarify that additional serum samples may be utilized to monitor for daratumumab 
interference with the IFE for subjects in arm 1.  
 
Remove the reference to self-evident corrections. 
 
Administration, typographical, and formatting changes were made throughout the 
protocol. 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  19 April 2018 
Page 1 of 20 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Randomized, Open-label, Phase 3 Study Comparing Carfilzomib, 
Dexamethasone, and Daratumumab to Carfilzomib and Dexamethasone for the 
Treatment of Patients With Relapsed or Refractory Multiple Myeloma 
 
Amgen Protocol Number Carfilzomib 20160275 
EudraCT number 2016-003554-33 
NCT03158688 
Amendment Date: 
19 April 2018 
 
Rationale: 
The protocol is being amended to: 
 
Reduce the window for the 12-month and 24-month bone marrow aspirate collection 
from  4 weeks /  1 month to “ 2 weeks” throughout the protocol 
 
Clarify the exclusion criteria that states subjects who have withdrawn consent from a 
previous Janssen daratumumab phase 3 study are allowed to participate in this 
study if they were in the control arm of the prior Janssen study and withdrew consent 
 
Clarify timing of pregnancy tests before first dose of study drug (rather than 
“randomization”) 
 
Clarify that plasmapheresis is not permitted during the study.  Details were added to 
describe next steps if plasmapheresis is required during the study treatment period. 
 
Clarify the carfilzomib prehydration requirements 
 
Clarify how to manage timing of cycles when dose delays occur 
 
Update Table 4 to clarify the recommended action for congestive heart failure 
 
Update Section 6.2.2.1.2 (Post-infusion Medications for Daratumumab) to align with 
current Janssen template language for daratumumab 
 
Update daratumumab management of infusion-related reactions to align with current 
United States prescribing information 
 
Clarify the criteria regarding thrombocytopenia for withholding daratumumab dose  
 
Update the dexamethasone dose reduction levels to add clarity for subjects 
> 75 years of age 
 
Clarify the dosage requirements/time span of corticosteroid use during the study 
 
Clarify the 28-day cycle for disease assessment collection 
 
Update references to “buccal swab” with “saliva sample” 
 
Update the schedule of assessments and related text to provide clarity on the 
screening evaluations of echocardiogram, pulmonary function tests, biomarkers, and 
plasmacytoma 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  19 April 2018 
Page 2 of 20 
CONFIDENTIAL 
 
 
 
Clarify how the dosing of 20 mg dexamethasone can be split in arm 1 
 
Clarify that dexamethasone must be given as IV on cycle 1 days 1and 2 for subjects 
in arm 2 
 
Clarify that in cases of technical failure, central lab samples can be retested during 
screening and subject will not be considered a screen fail 
 
Update which laboratory assessments are performed in follow-up visits (to align with 
schedule of assessments) 
 
Clarify that subjects who do not complete clinical outcome assessments (COAs) on 
cycle 1 day 1, further COAs will not be collected 
 
Update the hematology parameter list to include “plasma cell percent” as a part of 
plasma cell count assessment 
 
Clarify that COA will be collected electronically (refer to as eCOA throughout the 
protocol) 
 
Administrative and editorial updates were made throughout the protocol 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  09 June 2017 
Page 1 of 26 
Amendment 2 
Protocol Title:  A Randomized, Open-label, Phase 3 Study Comparing Carfilzomib, 
Dexamethasone, and Daratumumab to Carfilzomib and Dexamethasone for the 
Treatment of Patients With Relapsed or Refractory Multiple Myeloma  
CANDOR 
study of Carfilzomib ANd Daratumumab fOr Relapsed myeloma 
 
Amgen Protocol Number 20160275 
EudraCT number 2016-003554-33 
 
Amendment Date: 
09 June 2017 
 
Rationale: 
This protocol is being amended to address concerns raised during European Union 
Voluntary Harmonisation Procedure interactions: 
• 
Modify contraception language to address concerns regarding carfilzomib reducing 
efficacy of oral contraception 
• 
Update sample size calculation with factors that contribute to study length 
(eg, estimated enrollment rates, drop-out rates) 
• 
Modify primary and secondary endpoint analyses to include treatment-by subgroup 
analyses 
Additionally, this protocol is also being amended to: 
• 
Add additional serum collections in the Schedule of Assessments for optional 
biomarker samples 
• 
Remove analysis of minimum residual disease by flow cytometry 
• 
Add priority testing order for bone marrow samples 
• 
Clarify the route of administration for dexamethasone (intravenous [IV] infusion only 
required on cycle 1 days 1 and 2, otherwise, can be IV or orally) 
• 
Clarify timing of echocardiograms and pulmonary function tests after daratumumab 
infusion 
• 
Clarify when confirmation of disease progression is needed 
• 
Make administrative and editorial updates 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  15 February 2017 
Page 1 of 41 
Amendment 1 
Protocol Title:  A Randomized, Open-label, Phase 3 Study Comparing Carfilzomib, 
Dexamethasone, and Daratumumab to Carfilzomib and Dexamethasone for the 
Treatment of Patients With Relapsed or Refractory Multiple Myeloma 
 
Amgen Protocol Number (carfilzomib) 20160275 
EudraCT number 2016-003554-33 
 
Amendment Date: 
15 February 2017 
 
Rationale: 
This protocol is being amended to: 
• 
Include safety objectives and endpoints as additional secondary objectives and 
endpoints 
• 
Clarify that the evaluation of CR (for key secondary endpoint) will be based on IRC 
assessment 
• 
Clarify that the original International Staging System (ISS) will be used in this study 
to stratify subject (as opposed to the revised ISS) 
• 
 
 
 
. 
• 
Update and clarify the International Uniform Response Criteria for Multiple Myeloma 
• 
Update and clarify language in subject eligibility criteria based on regulatory agency 
and steering committee feedback 
• 
Add additional exclusion criteria in order to maintain consistency with dose 
modification table and to clarify the minimal requirements for subjects that have 
undergone an allogeneic transplant 
• 
Update study schema with a footnote regarding subjects with baseline chronic 
hepatic impairment 
• 
Clarify the actual expected dose for subjects that have baseline chronic (mild, 
moderate) hepatic impairment 
• 
Include requirements for prehydration for subjects treated with carfilzomib 
• 
Update language regarding dosage adjustments, delays, rules for withholding or 
restarting, or permanent discontinuation of carfilzomib to reflect the range of 
management options available to investigators in case of toxicity 
• 
Update language to allow for possible re-escalation of carfilzomib dose under certain 
conditions 
CONFIDENTIAL 
 
Approved 
 
 


Product:  Carfilzomib 
Protocol Number:  20160275 
Date:  15 February 2017 
Page 2 of 41 
• 
Update treatment guidelines for nonhematologic toxicities: 
− 
Add guidelines for chronic dialysis base on results from Study CFZ001 
− 
Clarify the parameters for holding carfilzomib during the treatment of an infection 
− 
Add guidance to investigate cause of dyspnea 
− 
Add guidance for lower grade hypertension 
− 
Language reworded for clarity 
• 
Clarify timing of pulmonary function tests in relation to daratumumab infusion 
• 
Remove total protein from laboratory analyte table as this is duplicated in the 
required serum protein electrophoresis needed for disease assessment 
• 
Add DLCO assessment to allow for identification of diffusion abnormalities and in 
some cases to support the diagnosis of other lung diseases such as pulmonary 
hypertension 
• 
Add language regarding the use of local laboratory results to be applied to screening 
requirements in cases where central laboratory is unable to provide these results 
• 
Remove magnetic resonance imaging (MRI) from bone lesion assessment as X-ray, 
CT, or PET-CT are more appropriate in the monitoring of these lesions 
• 
Update list of countries participating in global study 
• 
Generally clarify language throughout the protocol for better readability 
• 
Address typographical, grammatical, and formatting issues throughout the protocol 
CONFIDENTIAL 
 
Approved 
 
 

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NCT Number: 03158688 
This NCT number has been applied to the document  
for purposes of posting on clinicaltrials.gov 
NCT Number: 03158688 
This NCT number has been applied to the document  
for purposes of posting on clinicaltrials.gov 


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