Clinical trial NCT03773107
Conditions: Multiple Myeloma
Keywords: Plasma Cell Neoplasms Blood Malignancy
Sponsor: Wake Forest University Health Sciences
Start date: 2019-01-03; Completion date: 2024-02-21
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of Phase I is to establish the maximum tolerated dose (MTD) of ruxolitinib in combination with carfilzomib and dexamethasone. The primary objective of phase II is to evaluate progression-free survival (PFS) at 4 months in multiple myeloma subjects who receive the combination treatment carfilzomib, dexamethasone, and ruxolitinib.

Detailed description:
This is an open-label, Phase I/II study of carfilzomib, ruxolitinib, and low-dose dexamethasone for carfilzomib-refractory multiple myeloma. Phase I is designed to evaluate overall maximum tolerated dose (MTD) of ruxolitinib in combination with carfilzomib and dexamethasone in the following cohorts: Cohort 1) 5mg ruxolitinib, Cohort 2) 10mg ruxolitinib, Cohort 3) 15mg ruxolitinib. Phase II is designed to evaluate 4-month progression-free survival (PFS) in the following cohorts: Cohort A) non-responders to Phase I regimen, Cohort B) responders to Phase I regimen. Up to 18 evaluable subjects will be enrolled in Phase I over approximately 12 months. An additional 30 evaluable subjects will be enrolled in Phase II over 24 months.

Arms: arm 1: Cohort 1) 5mg ruxolitinib, Cohort 2) 10mg ruxolitinib, Cohort 3) 15mg ruxolitinib arm 2: Cohort A) non-responders to Phase I regimen, Cohort B) responders to Phase I regimen
Interventions: intervention 1: Carfilzomib intervention 2: Ruxolitinib intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Irreversible proteasome inhibitor intervention 2: Oral JAK inhibitor intervention 3: glucocorticoid

Protocol documents:
Prot_SAP_001.pdf: 
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Protocol #:  LCI-HEM-MYE-CRD-004 (MMRC-073 CARJAK) 
TITLE: Phase I/II Study of Carfilzomib, Ruxolitinib and Low-Dose 
Dexamethasone for Carfilzomib-Refractory Multiple Myeloma 
LAY TITLE: Phase I/II Study of Carfilzomib, Ruxolitinib and Low-Dose 
Dexamethasone for Carfilzomib-Refractory Multiple Myeloma 
Coordinating Center: 
Levine Cancer Institute  
Research and Academic Headquarters 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
 
Sponsor-Investigator: 
Shebli Atrash, MD, MS  
Levine Cancer Institute 
Research and Academic Headquarters 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
Telephone: (980) 442-4363 
Email: shebli.atrash@atriumhealth.org 
 
Statistician: 
James Symanowski, PhD 
Department of Biostatistics 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte, NC 28204  
Telephone: (980) 442-2348 
Email: james.symanowski@atriumhealth.org  
Investigational New Drug (IND) # 141696 
 
______________________________________________________________________________ 


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The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Sponsor-Investigator is not permitted. 
 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Original Phase I/II / Version 6 / September 27, 2022 
PROTOCOL SUMMARY 
Study Title 
Pilot Phase I/II Study of Carfilzomib, Ruxolitinib and low-dose Dexamethasone 
for Carfilzomib-Refractory Multiple Myeloma 
Indication 
Multiple Myeloma (MM) 
Clinical Phase 
I/II 
 
Summary of  
Rationale 
 
 
Despite major advances in therapy, MM is still considered an incurable 
malignancy.  While the introduction of immunomodulatory agents (IMiDs) and 
proteasome inhibitors (PIs), and advances in high dose therapy (HDT) 
administration have made an impact on progression free survival (PFS) and 
overall survival (OS) for MM patients in general, the majority of patients suffer 
relapses with progressively shorter disease-free intervals with each relapse. 
Therefore, it is imperative to identify the patients at high-risk of disease relapse 
and develop novel therapeutic regimens that extend PFS and OS in this group 
of MM patients. 
Study Objectives 
The primary objective of Phase I is to establish the maximum tolerated dose 
(MTD) of ruxolitinib in combination with carfilzomib and dexamethasone. The 
primary objective of Phase II is to evaluate PFS at 4 months in multiple 
myeloma subjects who receive the combination treatment carfilzomib, 
dexamethasone and ruxolitinib. Secondary objectives include evaluation of 
objective response rate, clinical benefit rate, disease control rate, time to best 
response, PFS, overall survival, time to progression, duration of response 
(DOR), any occurrence of adverse events or serious adverse events while on 
study. Exploratory objectives include exploring the correlation of peripheral 
blood mononuclear cell (PBMC) SNPs and JAK inhibition with toxicities and 
treatment response, exploring the correlation of PBMC proteasome inhibition 
with toxicities and treatment response, and examining changes in biology of 
BM and BM plasma cells before and after treatment with global gene 
expression profiling/RNA seq/whole genome sequence/proteomics. 
Sample 
Up to 18 subjects in Phase I and an additional 30 subjects in Phase II 
 
 
Inclusion/ 
Exclusion  
 
 
 
(See protocol for complete inclusion/exclusion criteria) 
Inclusion criteria: 
• Age > 18 years  
• Documented history of relapsed and or refractory multiple myeloma 
with > 2 lines of therapy and evidence of relapse or progression within 
60 days of a carfilzomib containing regimen at dose ≥ 27 mg/m2 
• Measurable disease 
• Evidence of adequate bone marrow reserves  
• Evidence of adequate hepatic, renal, and cardiac function  
Exclusion Criteria: 


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• Non-secretory multiple myeloma  
• Known amyloidosis 
• Known POEMS syndrome 
• Clinically significant illness that, in the opinion of the Investigator, 
places the subject at unacceptable risk for adverse outcome if he/she 
were to participate in the study 
• Pregnant or breastfeeding 
• Known human immunodeficiency virus (HIV) infection 
• Active hepatitis B and/or hepatitis C infection 
• “Currently active” second malignancy, other than non-melanoma skin 
cancer and carcinoma in situ of the cervix 
 
Dosage/ Dosage  
Form, Route,  
And Dose  
Regimen 
Phase I: Carfilzomib will be administered at 56 mg/m2 Days 1, 2, 8, 9, 15, 16 of 
a 28-day cycle. Dexamethasone will be administered at 40 mg Days 1, 8 and 15 
of every cycle. Ruxolitinib to determine maximum tolerated dose (MTD) will be 
administered orally at 5, 10 or 15 mg twice daily on Days 1-28. Cycles last for 
28 days. 
Phase II/Run-in Period: Carfilzomib at a twice weekly dose of 56mg/m2 and 
dexamethasone will be administered following the Phase I schedule for all 
subjects who had received a carfilzomib dose less than the twice weekly dose of 
56mg/m2 prior to study enrollment to assess non-response.   
Note: Subjects who previously received carfilzomib regimen with ≥ 56mg/m2 
will proceed directly to Phase II/Ruxolitinib. 
Non-responders (after Cycle 1):  proceed to Phase II/Ruxolitinib. 
 Responders (after Cycle 1): carfilzomib-dexamethasone will be administered 
until disease relapse/ progression, at which time they will cross over to 
carfilzomib-dexamethasone-ruxolitinib (Phase II/Ruxolitinib) until disease 
relapse/progression.   
Phase II/Ruxolitinib: Ruxolitinib will be administered orally at MTD on Days 
1-28 for non-responders until disease relapse/progression. Cycles last for 28 
days. 
Statistical  
Analysis 
Kaplan-Meier techniques will be used to estimate overall survival, progression-
free survival, time to progression, time to best response, and duration of 
response. The 4-month PFS rate will be estimated based on the KM analysis 
with Greenwood’s Formula for the 95% confidence interval. The 4-month 
response rate will be estimated using all enrolled patients as the denominator 
with the associated 95% confidence interval by the Clopper-Pearson method.  
Safety and toxicity will also be assessed using frequencies and proportions.  
Logistic regression and Cox proportional hazards models will be used to assess 
the correlation between biomarkers and efficacy and toxicity outcomes. 


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SCHEMA 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Spelled out abbreviation 
ADL 
Activities of daily living 
ADRs 
Adverse drug reaction 
AE 
Adverse event 
ALL 
Acute lymphoblastic leukemia 
ANC 
Absolute neutrophil count 
AUC 
Area under the curve 
BID 
Twice a day 
BM 
Bone marrow 
BSA 
Body surface area 
BNP 
Brain Natriuretic Peptide 
BTZ 
Bortezomib 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
Cmax 
Maximum concentration 
CMP 
Good manufacturing practices 
CR 
Complete response 
CrCl 
Creatinine clearance 
CRd 
Carfilzomib, revlimid, dexamethasone 
CTCAE 
Common terminology criteria for adverse events 
CTMS 
Clinical Trial Management System 
DCSI 
Development core safety information 
DLT 
Dose limiting toxicity 


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DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DSMC 
Data and Safety Monitoring Committee 
EBMT 
European group for blood and bone marrow criteria 
EC 
Ethics committee 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
FLC 
Free light chain 
FOCBP 
Females of child bearing potential 
GCP 
Good clinical practice 
GMP 
Good manufacturing practice 
HA 
Health authority 
HBV 
Hepatitis B Virus 
HDT 
High dose therapy 
HIV 
Human immunodeficiency virus 
IMiD 
Immunomodulatory agent 
INR 
International normalized ratio 
IMWG 
International Myeloma Working Group 
IRB 
Institutional Review Board 
IV 
Intravenously 
JAK 
Janus kinase 


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LCI 
Levine Cancer Institute 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
MM 
Multiple myeloma 
MR 
Minimum response 
MTD 
Maximum tolerated dose 
MUGA 
Multi gated acquisition scan 
NCI 
National Cancer Institute 
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
PET/CT 
Positron emission tomography/computed tomography 
PFS 
Progression free survival 
PI 
Protease inhibitor 
PO 
By mouth 
POEMS 
Polyneuropathy organomegaly endocrinopathy monoclonal gammopathy and 
skin changes 
RNA 
Ribonucleic acid 
RRMM 
Relapsed refractory multiple myeloma 
SAE 
Serious adverse event 
SCLC 
Small cell lung cancer 
SGOT 
Serum glutamatic oxaloacetic transaminase 
SGPT 
Serum glutamatic pyruvic transaminase 


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SIFE 
Serum immunofixation electrophoresis 
SNP 
Single nucleotide polymorphism 
STATs 
Signal transducers and activator of transcription 
TLS 
Tumor lysis syndrome 
TTP 
Time to progression 
UIFE 
Urine immunofixation electrophoresis 
UPEP 
Urine protein electrophoresis 
UPP 
Ubiquitin-proteasome pathway 
 
 
 


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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY ........................................................................................................... 3 
SCHEMA ....................................................................................................................................... 5 
LIST OF ABBREVIATIONS…………………………………………………………………...7 
1 
OBJECTIVES .................................................................................................................. 14 
1.1 
Primary Objectives ......................................................................................................... 14 
1.2 
Secondary Objectives ..................................................................................................... 14 
1.3 
Exploratory Objectives ................................................................................................... 14 
2 
BACKGROUND AND RATIONALE ........................................................................... 14 
2.1 
Study Disease ................................................................................................................. 14 
2.2 
Carfilzomib..................................................................................................................... 15 
2.3 
Dexamethasone .............................................................................................................. 19 
2.4 
Ruxolitinib ...................................................................................................................... 20 
2.5 
Background/Study Rationale ......................................................................................... 21 
3 
Subject SELECTION ...................................................................................................... 22 
3.1 
Accrual ........................................................................................................................... 22 
4 
INVESTIGATIONAL PLAN ......................................................................................... 24 
4.1 
Milestone Date Definitions ............................................................................................ 24 
4.2 
Overall Study Design ..................................................................................................... 25 
4.3 
Subject Enrollment ......................................................................................................... 30 
5 
STUDY TREATMENT ................................................................................................... 31 
5.1 
Carfilzomib..................................................................................................................... 31 
5.2 
Dexamethasone Dosage and Administration ................................................................. 34 
5.3 
Ruxolitinib Dosage and Administration ......................................................................... 35 
5.4 
Treatment Compliance ................................................................................................... 36 
5.5 
Duration of Therapy ....................................................................................................... 36 
5.6 
Drug Accountability ....................................................................................................... 37 
6 
DOSE MODIFICATIONS .............................................................................................. 37 
6.1 
Phase I and Phase II Dose Modification and Dose Delay .............................................. 37 


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6.2 
Dose Reduction Steps..................................................................................................... 38 
6.3 
Dose Modification Guidelines for Carfilzomib and Ruxolitinib during a Cycle of 
Therapy...................................................................................................................................... 38 
6.4 
Dose Modification Guidelines for Dexamethasone ....................................................... 41 
6.5 
Criteria for Initiation of a New Cycle of Therapy .......................................................... 42 
7 
Concomitant Medications ............................................................................................... 42 
7.1 
Required Concomitant Therapy ..................................................................................... 42 
7.2 
Recommended/Allowed Concomitant Therapy ............................................................. 43 
7.3 
Contraindicated Concomitant Therapy .......................................................................... 43 
8 
STUDY PROCEDURES ................................................................................................. 43 
8.1 
Registration .................................................................................................................... 44 
8.2 
Informed Consent ........................................................................................................... 44 
8.3 
Screening Procedures ..................................................................................................... 44 
8.4 
On Study Procedures: ..................................................................................................... 45 
8.5 
End of Treatment ............................................................................................................ 46 
8.6 
Follow-Up ...................................................................................................................... 47 
8.7 
Off-Study ........................................................................................................................ 47 
9 
ADVERSE EVENTS ....................................................................................................... 48 
9.1 
Adverse Event ................................................................................................................ 48 
9.2 
Serious Adverse Event (SAE): ....................................................................................... 48 
9.3 
Overlapping Toxicities ................................................................................................... 49 
9.4 
Adverse Event Reporting ............................................................................................... 49 
9.5 
Abnormal Laboratory Values Defined as AEs ............................................................... 49 
9.6 
Adverse Event Grading .................................................................................................. 50 
9.7 
Adverse Event Attribution ............................................................................................. 50 
9.8 
Communication between Investigational Sites .............................................................. 51 
10 
SAFETY DATA COLLECTION, RECORDING AND REPORTING...................... 51 
10.1 SAE/Pregnancy and Lactation Reporting to Sponsor-Investigator ................................ 51 
10.2 SAE Reporting to the FDA ............................................................................................ 51 
10.3 SAE Reporting by Sponsor-Investigator to Amgen and Incyte ..................................... 52 
10.4 Safety Reporting to the IRB ........................................................................................... 54 


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DATA AND SAFETY MONITORING PLAN ............................................................. 54 
12 
MEASUREMENT OF EFFECT .................................................................................... 55 
12.1 Timing of Response Evaluation ..................................................................................... 55 
12.2 Response Criteria: .......................................................................................................... 55 
12.3 Measurable Disease: ....................................................................................................... 55 
13 
STATISTICAL CONSIDERATIONS ........................................................................... 55 
13.1 Sample Size .................................................................................................................... 55 
13.2 Endpoint Definitions ...................................................................................................... 56 
13.3 Analysis Populations ...................................................................................................... 58 
13.4 Analysis Methods ........................................................................................................... 59 
13.5 Interim Analyses ............................................................................................................ 61 
14 
STUDY COMPLETION ................................................................................................. 61 
14.1 Completion ..................................................................................................................... 61 
14.2 Termination .................................................................................................................... 62 
15 
Ethical and Legal Issues .................................................................................................. 62 
15.1 Retention of Records ...................................................................................................... 62 
15.2 Ethical and Legal Conduct of the Study......................................................................... 62 
15.3 Confidentiality ................................................................................................................ 63 
16 
PUBLICATION POLICY ............................................................................................... 63 
17 
REFERENCES ................................................................................................................. 65 
18 
APPENDICES .................................................................................................................. 68 
18.1 ECOG Performance Scale .............................................................................................. 68 
18.2 NCI CTCAE VERSION 4.03......................................................................................... 69 
18.3 Response Criteria for Multiple Myeloma....................................................................... 69 
18.4 Estimated Creatinine Clearance rate (eCCr) using Cockcroft-Gault Formula ............... 74 
18.5 Table of Events............................................................................................................... 75 
 


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1 
OBJECTIVES 
1.1 
Primary Objectives 
1.1.1 Phase I 
The primary objective of Phase I is to establish the maximum tolerated dose (MTD) of 
ruxolitinib in combination with carfilzomib and dexamethasone in relapsed refractory 
multiple myeloma. 
1.1.2 Phase II 
The primary objective of the Phase II segment of this study is to evaluate the 4-month 
progression free survival rate (PFS4) in subjects who receive the combination treatment 
carfilzomib, dexamethasone and ruxolitinib. 
1.2 
Secondary Objectives 
Secondary objectives include evaluation of objective response rate (ORR), clinical benefit 
rate, disease control rate, progression-free survival, time to best response, overall survival, 
time to progression and duration of response in subjects that receive treatment with the 
triple drug combination, and further evaluation of the safety and tolerability of the 
combination of carfilzomib, dexamethasone and ruxolitinib (Phase I) and carfilzomib, 
dexamethasone +/- ruxolitinib (Phase II).  
1.3 
Exploratory Objectives 
Exploratory objectives include the following: 
• Explore the correlation of serum cytokine profile with toxicities and treatment response 
• Explore the correlation of PBMC proteasome and JAK inhibition with toxicities and 
treatment response 
• Examine changes in biology of BM and BM plasma cells before and after treatment by 
RNA sequencing 
2 
BACKGROUND AND RATIONALE 
2.1 
Study Disease 
Multiple myeloma (MM) is a neoplasm of plasma cells that is characterized by osteolytic bone 
lesions and organ damage, such as hypercalcemia, anemia, and renal insufficiency.  Despite major 
advances in therapy, MM is still considered an incurable malignancy.  While the introduction of 
immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs), and advances in high dose 
therapy (HDT) administration have made an impact on PFS and OS for MM patients in general, 


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the majority of patients suffer relapses with progressively shorter disease-free intervals with each 
relapse.  Therefore, it is imperative to identify the patients at high-risk of disease relapse and 
develop novel therapeutic regimens that extend progression free survival (PFS) and overall 
survival (OS) in this group of MM patients.  
2.2 
Carfilzomib 
2.2.1 Carfilzomib Indication 
Carfilzomib is a proteasome inhibitor indicated in combination with dexamethasone or with 
lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory 
multiple myeloma who have received one to three lines of therapy. Carfilzomib is also indicated 
as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who 
have received one or more lines of therapy. Approval is based on response rate.  Clinical benefit, 
such as improvement in survival or symptoms, has not been verified. 
2.2.2 Clinical Pharmacology 
Mechanism of Action 
 
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-
terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle 
within the 26S proteasome.  Carfilzomib had antiproliferative and proapoptotic activities in vitro 
in solid and hematologic tumor cells.  In animals, carfilzomib inhibited proteasome activity in 
blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and 
solid tumors. 
Pharmacodynamics 
 
Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like 
activity when measured in blood 1 hour after the first dose.  On Day 1 of Cycle 1, proteasome 
inhibition in peripheral blood mononuclear cells (PBMCs) ranged from 79% to 89% at 15 
mg/m2, and from 82% to 83% at 20 mg/m2.  In addition, carfilzomib administration resulted in 
inhibition of the LMP2 and MECL1 subunits of the immunoproteasome ranging from 26% to 
32% and 41% to 49%, respectively, at 20 mg/m2.  Proteasome inhibition was maintained for ≥ 
48 hours following the first dose of carfilzomib for each week of dosing. 
Pharmacokinetics 
 
Absorption:  The Cmax and AUC following a single intravenous dose of 27 mg/m2 was 4232 
ng/mL and 379 ng•hr/mL, respectively.  Following repeated doses of carfilzomib at 15 and 20 
mg/m2, systemic exposure (AUC) and half-life were similar on Days 1 and 15 or 16 of Cycle 1, 


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suggesting there was no systemic carfilzomib accumulation.  At doses between 20 and 36 
mg/m2, there was a dose-dependent increase in exposure. 
Distribution: The mean steady-state volume of distribution of a 20 mg/m2 dose of carfilzomib 
was 28 L.  When tested in vitro, the binding of carfilzomib to human plasma proteins averaged 
97% over the concentration range of 0.4 to 4 micromolar. 
Metabolism: Carfilzomib was rapidly and extensively metabolized.  The predominant 
metabolites measured in human plasma and urine, and generated in vitro by human hepatocytes, 
were peptide fragments and the diol of carfilzomib, suggesting that peptidase cleavage and 
epoxide hydrolysis were the principal pathways of metabolism.  Cytochrome P450-mediated 
mechanisms played a minor role in overall carfilzomib metabolism. The metabolites have no 
known biologic activity. 
Elimination: Following intravenous administration of doses ≥ 15 mg/m2, carfilzomib was 
rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1. 
The systemic clearance ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, 
suggesting that carfilzomib was largely cleared extrahepatically.  The pathways of carfilzomib 
elimination have not been characterized in humans. 
Age: Analysis of population pharmacokinetics data after the first dose of Cycle 1 (Day 1) in 154 
patients who had received an IV dose of 20 mg/m2 showed no clinically significant difference in 
exposure between patients < 65 years and ≥ 65 years of age. 
Gender:  Mean dose-normalized AUC and Cmax values were comparable between male and 
female patients in the population pharmacokinetics study. 
Hepatic Impairment:  The pharmacokinetics and safety of carfilzomib were evaluated in 
patients with advanced malignancies who had either normal hepatic function, or mild (bilirubin > 
1 to 1.5 × ULN or AST > ULN), moderate (bilirubin > 1.5 to 3 × ULN), or severe (bilirubin > 3 
× ULN) hepatic impairment. The AUC of carfilzomib increased by approximately 50% in 
patients with mild and moderate hepatic impairment compared to patients with normal hepatic 
function. PK data were not collected in patients with severe hepatic impairment. The incidence 
of serious adverse events was higher in patients with mild, moderate, and severe hepatic 
impairment combined (22/35 or 63%) than in patients with normal hepatic function (3/11 or 
27%).  
 
Renal Impairment: A pharmacokinetic study was conducted in which 43 multiple myeloma 
patients who had various degrees of renal impairment and who were classified according to their 
creatinine clearances (CLcr) into the following groups:  normal function (CLcr > 80 mL/min, n = 
8), mild impairment (CLcr 50–80 mL/min, n = 12), moderate impairment (CLcr 30–49 mL/min, 
n = 8), severe impairment (CLcr < 30 mL/min, n = 7), and chronic dialysis (n = 8).  Carfilzomib 


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was administered intravenously over 2 to 10 minutes, on two consecutive days, weekly for three 
weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period every 28 days.  Patients 
received an initial dose of 15 mg/m2, which could be escalated to 20 mg/m2 starting in Cycle 2 
if 15 mg/m2 was well tolerated in Cycle 1.  In this study, renal function status had no effect on 
the clearance or exposure of carfilzomib following a single or repeat-dose administration. 
Cytochrome P450:  In an in vitro study using human liver microsomes, carfilzomib showed 
modest direct and time-dependent inhibitory effect on human cytochrome CYP3A4/5.  In vitro 
studies indicated that carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured fresh 
human hepatocytes.  Cytochrome P450-mediated mechanisms play a minor role in the overall 
metabolism of carfilzomib.  A clinical trial of 17 patients using oral midazolam as a CYP3A 
probe demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant 
carfilzomib administration.  Carfilzomib is not expected to inhibit CYP3A4/5 activities and/or 
affect the exposure to CYP3A4/5 substrates.  
P-gp: Carfilzomib is a P-glycoprotein (P-gp) substrate and showed marginal inhibitory effects on 
P-gp in a Caco-2 monolayer system.  Given that carfilzomib is administrated intravenously and 
is extensively metabolized, the pharmacokinetic profile of carfilzomib is unlikely to be affected 
by P-gp inhibitors or inducers. 
2.2.3 Nonclinical Toxicology 
Carcinogenesis, Mutagenesis, and Impairment of Fertility 
 
Carcinogenicity studies have not been conducted with carfilzomib. 
Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood 
lymphocytes.  Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) 
test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay. 
Fertility studies with carfilzomib have not been conducted.  No effects on reproductive tissues 
were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-
month monkey chronic toxicity studies. 
2.2.4 Clinical Studies 
The carfilzomib clinical investigation program began in September 2005.  Carfilzomib is 
currently being investigated for potential treatment of both hematologic and solid tumor 
malignancies, but not necessarily being developed in the solid tumor setting.  
As discussed below, the clinical development of carfilzomib initially focused on patients with 
relapsed and refractory multiple myeloma, assessing carfilzomib as monotherapy in these 
patients with few therapeutic options.  Subsequently, carfilzomib is being evaluated as a 


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component of combination therapy for treatment in earlier lines of therapy for patients with 
multiple myeloma, including newly diagnosed multiple myeloma patients.  The clinical program 
has also expanded to include investigation in solid tumors (e.g., small cell lung cancer lung 
cancer [SCLC]) and pediatric acute lymphoblastic leukemia (ALL), but not necessarily 
developed in these settings. 
Initial Clinical Development – Carfilzomib as Monotherapy 
 
Carfilzomib for Injection was originally approved in 2012 in the United States (US) (brand name 
Kyprolis) under the US Food and Drug Administration’s (FDA) accelerated approval program 
for the treatment of patients with relapsed and refractory 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. 
Accelerated approval in the US, was based on the results of the single-arm Phase II study PX-
171-003 – Part 2 (A1) where an ORR of 23.7%, DOR of 7.8 months, PFS of 3.7 months, and OS 
of 15.4 months were observed.  The approved carfilzomib dose is 20 mg/m2 during Cycle 1, and 
if tolerated, the dose is increased to 27 mg/m2 during Cycle 2, given twice weekly for 3 of every 
4 weeks (Days 1, 2, 8, 9, 15, and 16), with infusion durations of 2 to 10 minutes.  In an even 
more advanced and refractory population, the Phase III Study PX-171-011 (FOCUS) did not 
meet the primary objective of demonstrating superiority of carfilzomib monotherapy over the 
active doublet therapy in the control arm (corticosteroids and optional cyclophosphamide) in OS 
(hazard ratio [HR] = 0.975 [95% confidence interval (CI):  0.760–1.249], 1-sided p-value = 
0.4172).  The median OS with carfilzomib monotherapy was 10.2 months versus 10.0 months for 
active control.  The PFS was similar in both study arms of PX-171-011 (carfilzomib 
monotherapy 3.7 months versus active control arm 3.3 months, HR = 1.091 [95% CI:  0.843–
1.410]). 
Subsequent Clinical Development – Carfilzomib in Combination Therapy 
 
The efficacy observed in the monotherapy program supported the development of carfilzomib in 
combination with lenalidomide and low-dose dexamethasone, based on the hypothesis that this 
combination may result in the ability to deliver optimized proteasome inhibition leading to 
improved efficacy.  Results from the randomized, pivotal, Phase III Study PX-171-009 
(ASPIRE) demonstrated that carfilzomib in combination with lenalidomide (Revlimid) and low-
dose dexamethasone (CRd) in subjects with relapsed multiple myeloma has unprecedented 
efficacy with an 8.7-month improvement in median PFS when compared with (Revlimid) 
lenalidomide with low-dose dexamethasone (Rd) (HR = 0.69), and a median PFS of 26.3 months 
with CRd treatment. 
Current Status of Carfilzomib Clinical Development 
 


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As of 19 July 2019, approximately 4508 individual subjects have been treated with carfilzomib 
as participants of Amgen-sponsored clinical studies.  As of 31 July 2019, approximately 6582 
subjects have received carfilzomib in investigator-sponsored trials.   
A thorough and comprehensive assessment of carfilzomib safety was conducted by Amgen with 
safety information available from a large clinical development program. Important adverse drug 
reactions (ADRs) identified based on a comprehensive analysis of safety data from all relevant 
sources, including clinical studies and the Amgen Global Safety Database have been well-
characterized.  There was no evidence of cumulative or new-onset toxicity with prolonged 
exposure to carfilzomib. Overall, the safety and efficacy data from the clinical program support 
continued development of carfilzomib in subjects with multiple myeloma  and expansion to the 
pediatric ALL population.  
2.3 
Dexamethasone 
2.3.1 Description 
Dexamethasone (Decadron) is a synthetic adrenocortical steroid and is readily absorbed from the 
gastrointestinal tract.  Chemically, dexamethasone is 9-fluoro-11b, 17, 21-trihydroxy-16a-methyl-
pregna-1, 4-diene-3, 20-dione. 
2.3.2 Toxicology 
Human Toxicology:  Possible adverse effects associated with the use of dexamethasone are:  
fluid and electrolyte disturbances, congestive heart failure in susceptible persons, hypertension, 
euphoria, personality changes, insomnia, exacerbation of infection (e.g., tuberculosis), 
exacerbation or symptoms of diabetes, psychosis, muscle weakness, osteoporosis, vertebral 
compression fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, 
convulsions, vertigo and headache, endocrine abnormalities, ophthalmic changes, and metabolic 
changes.  Some patients have experienced itching and other allergic, anaphylactic or other 
hypersensitivity reactions.  Withdrawal from prolonged therapy may result in symptoms 
including fever, myalgia and arthralgia.  Phenytoin, phenobarbital and ephedrine enhance 
metabolic clearance of corticosteroids. 
Corticosteroids should be used cautiously in patients with hypothyroidism, cirrhosis, ocular 
herpes simplex, existing emotional instability or psychotic tendencies, nonspecific ulcerative 
colitis, diverticulitis, fresh intestinal anastomoses, peptic ulcer, renal insufficiency, hypertension, 
osteoporosis and myasthenia gravis.   


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2.3.3 Pharmacology 
Kinetics:  Natural and synthetic glucocorticoids are readily and completely absorbed from the 
GI tract.  Dexamethasone is insoluble in water.  Glucocorticoids have salt-retaining properties, 
although dexamethasone nearly completely lacks this property.  Dexamethasone may suppress 
the body's response to viral and bacterial infections.   
2.4 
Ruxolitinib 
2.4.1 Mechanism of Action 
Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which 
mediate the signaling of a number of cytokines and growth factors that are important for 
hematopoiesis and immune function.  JAK signaling involves recruitment of STATs (signal 
transducers and activators of transcription) to cytokine receptors, activation and subsequent 
localization of STATs to the nucleus leading to modulation of gene expression. 
2.4.2 Pharmacodynamics 
Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy 
subjects and MF patients.  Ruxolitinib administration resulted in maximal inhibition of STAT3 
phosphorylation 2 hours after dosing which returned to near baseline by 10 hours in both healthy 
subjects and myelofibrosis patients. 
2.4.3 Pharmacokinetics 
Absorption 
In clinical studies, ruxolitinib is rapidly absorbed after oral administration with maximal plasma 
concentration (Cmax) achieved within 1 to 2 hours post-dose.  Based on a mass balance study in 
humans, oral absorption of ruxolitinib was estimated to be at least 95%.  Mean ruxolitinib Cmax 
and total exposure (AUC) increased proportionally over a single dose range of 5 to 200 mg. There 
were no clinically relevant changes in the pharmacokinetics of ruxolitinib upon administration 
with a high-fat meal, with the mean Cmax moderately decreased (24%) and the mean AUC nearly 
unchanged (4% increase). 
Distribution 
The apparent volume of distribution of ruxolitinib at steady-state is 53 to 65 L in myelofibrosis 
patients.  Binding to plasma proteins in vitro is approximately 97%, mostly to albumin. 
 
Metabolism 
In vitro studies suggest that ruxolitinib is metabolized by CYP3A4 and to a lesser extent by 
CYP2C9. 


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Elimination 
Following a single oral dose of [14C]-labeled ruxolitinib in healthy adult subjects, elimination 
was predominately through metabolism with 74% of radioactivity excreted in urine and 22% 
excretion via feces.  Unchanged drug accounted for less than 1% of the excreted total 
radioactivity.  The mean elimination half-life of ruxolitinib is approximately 3 hours and the 
mean half-life of ruxolitinib + metabolites is approximately 5.8 hours. 
2.4.4 Clinical Studies in Myeloproliferative Neoplasms 
Two randomized Phase III studies (Studies 1 and 2) were conducted in patients with myelofibrosis 
(either primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential 
thrombocythemia-myelofibrosis).  In both studies, patients had palpable splenomegaly at least 5 
cm below the costal margin and risk category of intermediate 2 (2 prognostic factors) or high risk 
(3 or more prognostic factors) based on the International Working Group Consensus Criteria 
(IWG). 
The starting dose of ruxolitinib was based on platelet count. Patients with a platelet count between 
100 and 200 X 109/L were started on ruxolitinib 15 mg twice daily and patients with a platelet 
count greater than 200 X 109/L were started on ruxolitinib 20 mg twice daily.  Doses were then 
individualized based upon tolerability and efficacy with maximum doses of 20 mg twice daily for 
patients with platelet counts between 100 to less than or equal to 125 X 109/L of 10 mg twice daily 
for patients with platelet counts between 75 to less than or equal to 100 X 109/L, and of 5 mg 
twice daily for patients with platelet counts between 50 to less than or equal to 75 X 109/L. 
2.4.5 Clinical Studies in Multiple Myeloma 
There is pre-clinical data1 (Burger R et al, ASCO 2012) that demonstrates direct cytotoxic effects 
of ruxolitinib on JAK-STAT pathway dependent cell lines and IL-6 mediated dexamethasone 
resistance could be reversed by addition of ruxolitinib.  
2.5 
Background/Study Rationale 
The ubiquitin-proteasome pathway (UPP) is responsible for the vast majority of regulated 
intracellular proteolysis1 and has been best validated as a target for cancer therapy in MM2-Pre-
clinical2-8 and clinical studies 9-19 have led to regulatory approvals of the PIs bortezomib and 
carfilzomib.  Plasma cells are uniquely sensitive to PIs since the UPP capacity for protein 
turnover is impaired during their differentiation, creating an unfavorable match between 
proteasome load and capacity20.  This balance has been proposed as a determinant of the 
apoptotic sensitivity to PIs, with plasma cells having a low protein load and/or high proteasome 
capacity showing relative resistance, while a high load and/or low capacity confers sensitivity21.  
In the clinic, the PIs are used in virtually all patients22-26.  


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Despite their demonstrated benefits, response rates to bortezomib or carfilzomib in unselected 
patients in the relapsed and/or refractory settings are less than 50%17-18 and 25%21-23, 
respectively, and their use is associated with substantial toxicities and cost.  Moreover, virtually 
all patients who initially respond eventually develop disease that is refractory to further PI-based 
therapy through poorly defined mechanisms. 
The current Phase I/II study of carfilzomib, ruxolitinib and low-dose dexamethasone is to 
evaluate the potential to overcome PI resistance in RRMM who have previously relapsed or 
progressed on carfilzomib.  
The primary purpose of this trial is to determine if the combination of carfilzomib, ruxolitinib 
and low-dose dexamethasone improves the 4-month progression free survival rate compared to 
historical controls. 
3 
SUBJECT SELECTION 
3.1 
Accrual 
This trial will enroll subjects with a diagnosis of relapsed or relapsed-refractory MM. Up to 18 
DLT evaluable subjects will be enrolled in Phase I with 3 dose levels of ruxolitinib to be tested.  
Up to an additional 30 PFS4 evaluable subjects may be enrolled in the Phase II part at the MTD 
determined in Phase I. 
All races and ethnic groups are eligible for this study. 
3.1.1 Inclusion Criteria 
Subjects must meet all the following criteria:  
1. Documented history of relapsed and/or refractory multiple myeloma with > 2 lines of 
therapy. One of the prior lines of therapy must have been a carfilzomib containing 
regimen with evidence of relapse or progression within the last 60 days of the carfilzomib 
containing regimen with a carfilzomib dose of at least 27 mg/m2. Carfilzomib containing 
regimen at the standard dose of 20/27 mg/m2 is acceptable. 
2. Measurable disease, as defined by at least one of the following: 
a. Serum monoclonal protein level ≥0.5 g/dL for IgG, IgA, or IgM disease 
b. Urinary M-protein excretion of ≥200 mg over a 24-hour period 
c. Involved free light chain level ≥10 mg/dL, along with an abnormal free light 
chain ratio 
3. Adequate bone marrow reserves, as defined by the following: 
a. Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 within 1 week of the 
initiation of treatment. G-CSF may not have been administered within 7 days of 
Cycle 1 Day. 


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b. Platelet count of ≥75 ,000 cells/mm3 for subjects who have bone marrow 
plasmacytosis of <50%, or ≥50,000 cells/mm3 for subjects who have bone 
marrow plasmacytosis of ≥50%  
4. Adequate hepatic function, as defined by the following: 
a. Total bilirubin ≤2 times the upper limit of the institutional normal values 
b. Total AST and ALT ≤3 times the upper limit of the institutional normal values 
5. Adequate renal function, as defined by the following: creatinine clearance (CrCl) ≥30 
mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and 
Gault formula. 
6. Adequate cardiac function defined as LVEF ≥ 40% by MUGA, echocardiogram or 
cardiac MRI.  
7. Be 18-75 years of age 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. 
9. FOCBP and male subjects who are sexually active with FOCBP must agree to use two 
highly effective (as determined per the Investigator) methods of contraception during the 
study and for 30 days (female subjects) or for 90 days (male subjects) following the last 
dose of study treatment including a male condom. 
10. Written informed consent and HIPAA authorization for release of personal health 
information signed by the subject or his/her legally authorized representative. 
11. Recovered from all reversible acute toxic effects of prior therapy (other than alopecia) to 
≤ Grade 1 or baseline. 
3.1.2 Exclusion Criteria 
Subjects must not meet any of the following criteria: 
1. Non-secretory multiple myeloma  
2. Known amyloidosis 
3. Known POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes) 
4. Clinically significant illness including, but not limited to the following: active systemic 
infection, uncontrolled hypertension (as defined by BP > 160/90), New York Heart 
Association Class III and IV heart failure, unstable angina pectoris, myocardial infarction 
within the past 6 months of consent, uncontrolled cardiac arrhythmia, or any other 
condition (including laboratory abnormalities) that, in the opinion of the Investigator, 
places the subject at unacceptable risk for adverse outcome if he/she were to participate 
in the study 
5. Prior cerebrovascular accident with persistent neurologic deficit. 
6. Psychiatric illness/social situations that would limit compliance with study treatment and 
requirements 


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7. Pregnant or breast feeding. Females of childbearing potential (FOCBP) must have a 
negative serum pregnancy test within the 7 days prior to study drug administration and a 
negative urine pregnancy test within the 3 days prior to the first study drug 
administration.   
8. Known human immunodeficiency virus (HIV) infection 
9. Active hepatitis B and/or hepatitis C infection 
• Subjects with resolved HBV infection (i.e. subjects who are HBsAg negative but 
positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to 
hepatitis B surface antigen [anti-HBs]) must be screened using real-time 
polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA 
levels. Subjects who are PCR positive will be excluded. Exception: subjects with 
serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only 
serologic marker) and a known history of prior HBV vaccination do not need to be 
tested for HBV DNA by PCR. 
10.  “Currently active” second malignancy, other than non-melanoma skin cancer and 
carcinoma in situ of the cervix, should not be enrolled.  Subjects are not considered to 
have a “currently active” malignancy if they have completed therapy for a prior 
malignancy, are disease free from prior malignancies for >5 years and are considered by 
their physician to be at less than 30% risk of relapse.  In addition, subjects with basal cell 
carcinoma of the skin, superficial carcinoma of the bladder, carcinoma of the prostate 
with a current PSA value of <0.5 ng/mL, or cervical intraepithelial neoplasia will be 
eligible.  Finally, subjects who are on hormonal therapy for a history of either prostate 
cancer or breast cancer may enroll, provided that there has been no evidence of disease 
progression during the previous three years. 
11. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize 
carfilzomib). 
12. Contraindication to any of the required concomitant drugs or supportive treatments or 
intolerance to hydration due to preexisting pulmonary or cardiac impairment including 
pleural effusion requiring thoracentesis or ascites requiring paracentesis. 
13. Known intolerance to carfilzomib. 
14. Co-administration with strong CYP3A4 inhibitors (such as, but not limited to, boceprevir, 
clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, 
voriconazole) as well as fluconazole (a dual inhibitor of CYP3A4 and CYP2C9). 
4 
INVESTIGATIONAL PLAN 
4.1 
Milestone Date Definitions 
Registration date: the date the subject signs the informed consent form. 


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Enrollment date: the date of initiation of study treatment on Cycle 1, Day 1.  For the 
Phase I part of the study, this will be the date of initiation of treatment with carfilzomib, 
dexamethasone and ruxolitinib.  For the Phase II part of the study, this is the date of 
initiation of treatment with carfilzomib and dexamethasone +/- ruxolitinib.   
 
Treatment discontinuation date: the date the Investigator decides to discontinue the 
subject from study treatment.   
 
4.2 
Overall Study Design 
This is an open label, Phase I/II protocol. This study will open as a multi-center study 
being conducted at Levine Cancer Institute (LCI) and additional investigational sites.  
Potentially, a total of 18 DLT evaluable subjects will be enrolled on the Phase I portion 
and up to 30 PFS4 evaluable subjects may be enrolled on the Phase II portion of this 
study. The study accrual period will be an estimated 36 months.  
4.2.1 Phase I Design 
Phase I will follow the standard 3 + 3 design with 3 to 6 subjects, depending on dose 
limiting toxicity (DLT) observed, at each dose level to be tested.  Up to 3 dose levels will 
be tested. The overall duration of the Phase I portion of the study is expected to be no 
longer than 12 months. 
Subjects will receive carfilzomib 56 mg/m2/day* IV over 30 minutes on Days 1, 2, 8, 9, 
15 and 16 of a 28 day cycle. *Note: Subjects who have received CFZ < 56mg/m2 more 
than 60 days prior to informed consent should receive CFZ 20mg/m2 on Days 1 and 2 of 
the first cycle of protocol therapy with subsequent doses of 56mg/m2.   
Dexamethasone is administered orally prior to carfilzomib at 40 mg on Days 1, 8, and 15 
of a 28 day cycle. Note: a 20 mg dose may be considered for subjects ≥ 75 years of age 
and for diabetic subjects.  
Ruxolitinib is administered orally with or without food twice daily for 28 days of a 28 
day cycle 
Table 1: Dose Levels to be Tested 
Cohort 
Each cycle is 28 days 
Carfilzomib 
IV over 30 min 
Dexamethasone  
PO 
Ruxolitinib 
PO 


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Days 1, 2, 8, 9, 15, 16 
Days 1, 8 and 15 
Twice Daily Days 1-28 
Cohort 1 
56 mg/m2a 
40 mg POb 
5 mg 
Cohort 2 
 
56 mg/m2a 
 
40 mg POb 
10 mg 
Cohort 3 
 
56 mg/m2a 
 
40 mg POb 
15 mg 
 
a. Subjects who have received CFZ < 56mg/m2 more than 60 days prior to informed 
consent should receive CFZ 20mg/m2 on Days 1 and 2 of the first cycle with 
subsequent doses of 56mg/m2.  See section 4.2.1.1 for MTD guidance 
b. A 20 mg dose may be considered for subjects ≥ 75 years of age and for diabetic 
subjects. 
4.2.1.1 
Phase I Dose Escalation Guidelines 
The first cohort of subjects enrolled in the Phase I portion of the study will receive dose level 1.  
A full safety evaluation will be conducted when these subjects have completed one cycle of 
combination therapy. Based on the evaluation after the first cycle, the dose escalation for 
subsequent subjects will proceed as follows: 
• 
If no DLT is reported in the first three subjects at a dose level, that dose level will be 
considered safe, and three subjects will be enrolled at the next higher dose level. 
• 
If 1 out of 3 subjects in a cohort at a dose level has a DLT, the dose level will be 
expanded to obtain six evaluable subjects. If 2 or more subjects in a cohort of 6 subjects 
at a dose level has a DLT, that dose level will not be considered safe, no further dose 
escalation will take place, and the MTD will have been exceeded*.   
• 
If there is at most 1 subject with a DLT among an expanded cohort of six evaluable 
subjects, that dose level will be considered safe and a cohort of three subjects will be 
enrolled in the next higher dose level. 
When the MTD has been exceeded: 


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If less than 6 subjects have been treated in the next lower dose level (the possible MTD level), 
additional subjects will be entered into this dose level until there are 6 subjects treated.  If at 
most 1 of these 6 subjects encountered DLT, then this dose level will be declared to be the MTD.  
If 2 or more of the 6 subjects encounter DLT, then the MTD has been exceeded.   
NOTE: If a subject discontinues treatment for reasons unrelated to adverse events such that 
safety in cycle one cannot be fully evaluated, an additional subject may be enrolled; this will be 
reviewed on a case by case basis.  
4.2.1.2 
Definition of Maximum Tolerated Dose  
The MTD of the combination of carfilzomib, dexamethasone and ruxolitinib in multiple 
myeloma subjects shall be defined as the highest dose level resulting in at most 1 out of 6 
subjects experiencing DLT in Cycle 1. The dose will be escalated in a new cohort until an MTD 
is identified or the maximum planned dose is achieved.  
4.2.1.3 
Definition of DLT 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as related or possibly related to the study regimen that occurs within the first cycle of 
treatment and meets any of the criteria outlined below. National Cancer Institute CTCAE version 
4.03 will be used for all adverse event grading. 
• Grade 3 or greater non-hematologic toxicity possible/probable/definitely related 
to treatment. The following exceptions will apply: 
 Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate 
antiemetic and other supportive care 
 Grade 3 fatigue for less than 1 week 
 Grade 3 or higher isolated electrolyte abnormalities that last up to 72 
hours, are not clinically complicated, and resolve spontaneously or 
respond to conventional medical interventions 
 Grade 3 or higher amylase or lipase elevation that is not associated with 
symptoms or clinical manifestations of pancreatitis 
 Grade 3 tumor lysis syndrome (TLS) that lasts up to 72 hours, is not 
clinically complicated, and resolves spontaneously or responds to 
conventional medical interventions 
• Grade 3-4 thrombocytopenia (platelet count < 50,000/ mm3) with clinically 
significant bleeding.    
• Grade 4 neutropenia must occur for more than 5 days to be considered a DLT.  A 
grade 4 neutropenia with duration of less than or equal to 5 days or grade 3 
neutropenia must result in neutropenic fever with elevated temperature (defined as 


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ANC < 1000/mm3 with a single temperature of > 38.3°C or sustained temperature 
of ≥ 38°C for more than one hour) to be considered dose-limiting.  
• Other grade 4 hematological toxicity (other than thrombocytopenia, neutropenia, 
leukocytopenia and lymphopenia)   
The prophylactic use of G-CSF and platelet transfusions in cycle one of the dose escalation 
cohorts in Phase I is not permitted.  
Once the MTD has been determined in Phase I, an additional 30 evaluable subjects will be 
enrolled and treated at the MTD.  The evaluation of the MTD will be based on the toxicity 
observed during Cycle 1 of Phase I.   
4.2.2 Phase II Design 
 Subjects in the Phase II/Run-in period will receive an initial cycle with carfilzomib at the twice 
weekly dose of 56mg/m2 and dexamethasone.  Following Cycle 1, a response assessment will be 
done. Subjects with a response of PR or better (“Responders”) will continue therapy with 
carfilzomib and dexamethasone. After these responding subjects subsequently progress, they will 
be treated with ruxolitinib (at the dose established in Phase 1) in combination with carfilzomib 
and dexamethasone. Subjects with a response of less than PR (“Non-responders”) will add 
ruxolitinib at the dose established in Phase I to carfilzomib and dexamethasone for all subsequent 
cycles. The cycle when ruxolitinib is added will be considered Cycle 1 (cycle numbers will start 
over).  Disease evaluation assessment results should be available prior to dosing on Day 1 of 
each cycle of Phase II until initiation of ruxolitinib treatment (to ensure initiation of ruxolitinib 
occurs on Day 1 of a cycle).  
Enrollment in the Phase II part of the study will be carried out in two stages.  During the first 
stage, 10 PFS evaluable subjects (Section 13.3) will be enrolled.  Enrollment and Stage 1 
analysis of the first ten subjects on the three drugs (carfilzomib-ruxolitinib-dexamethasone) will 
be completed to determine if at least 3 of 10 subjects are alive and progression free at 4 months.  
If so, an additional 20 subjects will be enrolled (a total of 30 subjects) during the second stage.  
If at least 11 of 30 subjects are alive and progression free at 4 months, the null hypothesis will be 
rejected (based on binomial probabilities, see Section 13.1.2).  The overall duration of the Phase 
II portion of the study is expected to be no longer than 24 months.  For both Phase I and Phase II, 
subjects will be assessed for response after each cycle with confirmation of response according 
to IMWG response criteria regardless of dose level treated. Doses of each study drug may be 
interrupted or reduced in an attempt to manage toxicity. 
Table 2: Phase II/Run-In Dosinga 
Drug 
Dose 
Route 
Schedule 
Cycle Length 


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Dexamethasone 
40 mgb 
PO 
D1, 8, and 15 
(Prior to 
carfilzomib) 
 
28 days 
Carfilzomib 
56 mg/m2c 
Intravenously 
(IV) over 30 
minutes 
D1, 2, 8, 9, 15, 
and 16 
 
a All subjects enrolled in Phase II will initiate treatment in the Run-in Phase with the exception of subjects who 
previously received a carfilzomib regimen (prior to study enrollment) of ≥ 56 mg/m2. These subjects will proceed 
directly to Phase II/Ruxolitinib (see Table 3). Subjects will have a disease response assessment prior to Cycle 2 
(results must be available prior to Day 1 dosing) and will continue treatment in the Run-In until one of the 
following: 
• 
Determined to be a “Non-responder” after Cycle 1 (defined as < PR per IMWG criteria) OR 
• 
Determined to be a “Responder” after Cycle 1 (defined as ≥ PR per IMWG criteria) with subsequent 
disease progression 
After one of the above criteria are met, subjects will move into the Phase II/Ruxolitinib Phase (see Table 3) 
b A 20 mg dose may be considered for subjects ≥ 75 years of age or for diabetic subjects. 
c Subjects who previously received carfilzomib < 56mg/m2 more than 60 days prior to informed consent should 
receive carfilzomib 20mg/m2 on Days 1 and 2 of the first cycle with subsequent doses of 56mg/m2 
Table 3: Phase II/Ruxolitinib Dosinga  
Drug 
Dose 
Route 
Schedule 
Cycle Length 
 
Dexamethasone 
 
40 mgb 
 
PO 
D1, 8, and 15 
Prior to 
carfilzomib 
28 days 
*note: Cycle numbers start 
over at Cycle 1 once 
ruxolitinib is initiated 
 
Carfilzomib 
 
56 mg/m2  
Intravenously 
(IV) over 30 
minutes 
D1, 2, 8, 9, 15, 
and 16 
Ruxolitinib 
MTD from 
Phase I 
PO 
Twice daily 
from C1D1, 
continuously 
 
a. 
Subjects enrolled in Phase II will initiate ruxolitinib at one of the following time-points: 
 


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• 
Initiated treatment in the Run-In Phase and determined to be a “Non-responder” after Cycle 1 
• 
Initiated treatment in the Run-In Phase, determined to be a “Responder” after Cycle 1 with subsequent 
disease progression 
• 
Determined to have received carfilzomib regimen (prior to study enrollment) of ≥ 56 mg/m2. These 
subjects will skip the Run-In Phase and proceed directly to ruxolitinib (in combination with 
carfilzomib and dexamethasone). 
 
b. A 20 mg dose may be considered for subjects ≥ 75 years of age or for diabetic subjects 
 
4.3 
Subject Enrollment 
Phase I 
Enrolled subjects in Phase I will be DLT evaluable if they experience a DLT during Cycle 1 of 
treatment with the carfilzomib, ruxolitinib and dexamethasone regimen.  
Enrolled subjects in Phase I who do not experience a DLT must meet all of the criteria below to 
be DLT evaluable: 
• complete Cycle 1 of ruxolitinib therapy defined as followed 
o initiate Cycle 2, or 
o discontinue ruxolitinib therapy prior to Cycle 2 if the discontinuation date (as 
defined in Section 4.1) is on Cycle 1 Day 25 or later    
• return no more than 20% of the number of ruxolitinib pills prescribed for Cycle 1 (while 
taking into account the actual length of Cycle 1)  
• do not receive G-CSF or platelet transfusions during Cycle 1  
 
Subjects who discontinue study treatment without experiencing a DLT and do not meet the DLT 
criteria as stated above will not be included in the 3+3 MTD evaluation but will be included in 
the overall analyses.  Enrollment of new subjects to the current cohort will only be considered if 
there is less than the required number of DLT evaluable subjects to determine toxicity for the 
cohort.  For example, of 3 subjects in a cohort, one withdraws due to disease progression, but 2 
others have DLT, there is no need to continue enrollment to the given cohort as the MTD has 
already been exceeded.  Alternatively, of 3 subjects in a cohort, one withdraws due to disease 
progression, but 2 others have not experienced a DLT, enrollment to the cohort will continue to 
fully evaluate the cohort with three DLT evaluable subjects).   
Phase II 
All enrolled subjects will remain in the intent to treat population. Enrollment to the Phase II part 
of the study will continue until the sample size requirements for the PFS4 evaluable population 
are achieved (Section 13.3).   


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5 
STUDY TREATMENT  
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in the Investigational Brochure and Prescribing Information.  Appropriate 
dose modifications are described in Section 6.  
The study drugs must be exclusively used for the investigation specified in this protocol and will 
only be accessible to authorized staff.  
5.1 
Carfilzomib  
5.1.1 Carfilzomib Dose 
Subjects will receive carfilzomib 56 mg/m2/day IV over 30 minutes on Days 1, 2, 8, 9, 15 and 16 
of a 28-day cycle.  Subjects who have received CFZ < 56mg/m2 more than 60 days prior to 
informed consent should receive CFZ 20mg/m2 on Days 1 and 2 of the first cycle of carfilzomib 
with subsequent doses of 56mg/m2.   
 
The dose will be calculated using the subject’s actual BSA at baseline.  Subjects with a BSA > 
2.2 m2 will receive a dose based upon a 2.2 m2 BSA.  Dose adjustments do not need to be made 
for weight changes of less than or equal to 20% from baseline weight. 
5.1.2 Carfilzomib Administration 
5.1.2.1 
Hydration and Fluid Monitoring 
• At least 48 hours before the first dose of carfilzomib, oral hydration should be given as 
follows:  30 mL/kg/day (approximately 6 to 8 cups of liquid per day) continuing up to the 
time of treatment.  Subject compliance must be assessed before initiating treatment, 
which is to be delayed if oral hydration is not adequate.  In subjects considered at risk for 
TLS, oral hydration should be continued in Cycle 2 and beyond as required by the 
subject’s medical condition and at the Investigator’s discretion. 
• IV hydration will be given immediately prior to carfilzomib during the first cycle of 
carfilzomib.  This will consist of 250 to 500 mL normal saline or other appropriate IV 
fluid. Co-morbidities should be considered when determining the appropriate volume of 
fluid to administer (e.g. consider 250 ml for subjects with increased cardiac risk). If 
lactate dehydrogenase (LDH) or uric acid is elevated (and/or in subjects considered still 
at risk for TLS) at the completion of the first cycle of carfilzomib (Cycle 2 Day 1), then 
the recommended IV hydration should be given additionally before each dose in the 
second cycle.  The goal of the hydration program is to maintain robust urine output (e.g. 
≥ 2 L/day).  Subjects should be monitored periodically during this period for evidence of 
fluid overload.  


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• If the subject has a dedicated line for carfilzomib administration, the line must be flushed 
with a minimum of 20 mL of normal saline prior to and after drug administration.    
5.1.2.2 
Carfilzomib Infusion  
• Carfilzomib will be given as an IV infusion over approximately 30 minutes.  The dose 
will be administered at a facility capable of managing hypersensitivity reactions.  
Subjects will remain at the clinic under observation for at least 1 hour following each 
dose of carfilzomib in the first cycle of carfilzomib.  During these observation times, post 
dose IV hydration (between 250 mL and 500 mL normal saline or other appropriate IV 
fluid formulation) is recommended but will be administered per the investigator’s 
discretion .  Subjects should be monitored periodically during this period for evidence of 
fluid overload. 
5.1.3 SAFETY CONSIDERATIONS 
• A “first dose effect” has been seen, which is notable for fever, chills, rigors, and/or 
dyspnea occurring during the evening following the first day of infusion and an increase 
in creatinine on Day 2, which may be the clinical sequelae of rapid tumor lysis and/or 
cytokine release.    
• Should a “first dose” effect occur at any point during the first or second cycle of 
carfilzomib, treatment with high dose glucocorticoids (e.g. methylprednisolone 50–100 
mg) is recommended.  In addition, intravenous fluids, vasopressors, oxygen, 
bronchodilators, and acetaminophen should be available and instituted, as medically 
indicated.  
• Acyclovir or similar should be given to all subjects, per institutional prophylaxis 
guidelines, unless contraindicated. 
• For subjects who are carriers of HBV, prophylaxis with antivirals should be considered. 
• CrCl changes are mostly transient, reversible, and non-cumulative. All subjects should be 
well hydrated.  Clinically significant electrolyte abnormalities should be corrected prior 
to dosing with carfilzomib.  Renal function must be monitored closely during treatment 
with carfilzomib.  Serum chemistry values, including creatinine, must be obtained and 
reviewed prior to each dose of carfilzomib on Day 1, 8, and 15 of all cycles.  Carfilzomib 
must be held for subjects with a CrCl < 15 mL/min at any time during study participation 
as outlined in Section 6.3. 
• Subjects with active or suspected infection of any kind that required IV systemic 
treatment should not be dosed with carfilzomib until the infection has resolved and if 
being treated with anti-infective, the course of antibiotics has been completed.  
• Thrombocytopenia has been transient and typically resolves during the week between 
treatments.  For platelet counts ≤ 25,000/mm3, carfilzomib dosing must be held.  If 


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platelet counts do not recover, the dose of carfilzomib may be reduced or held according 
to the Dose Reductions / Adjustments rules outlined in Section 6.3. 
• Subjects should have anemia treated in accordance with the Institutional guidelines. 
• Carfilzomib treatment can cause nausea, vomiting, diarrhea, or constipation sometimes 
requiring the use of antiemetics or antidiarrheals.  Fluid and electrolyte replacement 
should be administered as clinically indicated to prevent dehydration.  
• Subjects with a history of HBV should be closely monitored for signs and symptoms of 
active HBV infection throughout treatment with carfilzomib, including the 30-day safety 
monitoring follow-up period. 
• Subjects receiving carfilzomib should be monitored for any new or worsening neurologic, 
cognitive or behavioral signs and symptoms that may be suggestive of Progressive 
Multifocal Leukoencephalopathy (PML) as part of the differential diagnosis of central 
nervous system disorders. If PML is suspected, subjects should be referred to a specialist 
and appropriate diagnostic testing should be initiated. If a PML diagnosis is confirmed, 
carfilzomib should be permanently discontinued. 
• Contraception/Female: 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, females of childbearing potential and/or their male partners should use 
effective contraception methods or abstain from sexual activity during and for 30 days 
after treatment with carfilzomib. If pregnancy occurs during this time, patients should be 
apprised of the potential hazard to the fetus. 
 
Based on its mechanism of action and findings in animals, carfilzomib can cause fetal 
harm when administered to a pregnant woman. Carfilzomib caused embryo‐fetal toxicity 
in pregnant rabbits at doses that were lower than in subjects receiving the recommended 
dose. Carfilzomib administered to pregnant rats and rabbits during the period of 
organogenesis was not teratogenic at doses up to 2 mg/kg/day in rats or up to 0.8 
mg/kg/day in rabbits. If carfilzomib is used during pregnancy, or if the subject becomes 
pregnant while taking this drug, she should inform the investigator or study staff 
immediately. The investigator should notify Amgen of the pregnancy and discuss follow-
up with the subject. It is not known if carfilzomib will reduce the efficacy of 
oral contraceptives. Due to an increased risk of venous thrombosis associated with 
carfilzomib, subjects currently using oral contraceptives, or a hormonal method of 
contraception associated with a risk of thrombosis should consider an alternative method 
of effective contraception. 
 
• Breastfeeding: No studies of carfilzomib have been conducted in breastfeeding women. 
Carfilzomib should not be used during breastfeeding. Breastfeeding women and women 
planning on breastfeeding may not participate in clinical trials with carfilzomib. 


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If a woman breastfeeds during the study, she must inform the investigator or study staff 
immediately. The investigator should notify Amgen that the subject has breastfed the 
infant and discuss follow‐up with the subject. 
 
• Contraception/Male: Males of reproductive potential should be advised to avoid fathering 
a child while being treated with carfilzomib. The potential for carfilzomib to be 
transferred via semen and its effect on sperm are unknown. Male subjects should refrain 
from donating sperm for at least 90 days after the last dose of carfilzomib. Male subjects 
treated with carfilzomib and/or their female partners (if of childbearing potential) should 
use effective contraceptive methods or abstain from sexual activity while treated with 
carfilzomib and for 90 days after treatment. If pregnancy occurs during this time, patients 
should be apprised of the potential hazard to the fetus. 
 
Male subjects should be advised to inform the investigator or study staff immediately in 
the event that their female partner becomes pregnant during the study. Upon receipt of 
this information, the investigator should notify Amgen of the pregnancy and discuss 
follow-up regarding the pregnancy outcome with the subject. 
5.1.4 Carfilzomib Drug Supply 
Vials of carfilzomib contain 60 mg of sterile white to off-white lyophilized cake or powder. The 
vial amount may exceed the required dose; however vials are for single use only.  Mixing 
carfilzomib with or administering as an infusion with other medicinal products is not allowed. 
Unopened vials will be stored in the original package to protect from light exposure at 2oC to 
8oC (36oF to 46oF). Carfilzomib will be supplied by Amgen. 
5.2 
Dexamethasone Dosage and Administration 
Formulation:  Dexamethasone is available in seven potencies (0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 
mg, 4 mg, and 6 mg) in tablet form. 
Storage and Stability:  Dexamethasone is to be stored at room temperature. 
Administration:  For this study, dexamethasone is administered orally. Dexamethasone is 
administered prior to carfilzomib at 40 mg on Days 1, 8, and 15 of each 28 day cycle for all 
cycles. A 20 mg dose may be considered for subjects ≥ 75 years of age and for diabetic subjects. 
Supplier:  Dexamethasone will be commercially supplied.  Please refer to the package insert for 
complete information. 


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5.3 
Ruxolitinib Dosage and Administration 
Ruxolitinib is administered orally with or without food at the assigned cohort dose (5, 10 or 15 
mg) during Phase I or the MTD twice daily continuously for 28 days during Phase II (see Section 
4.2.1 for dosing cohorts).  If a dose is missed, the subject should not take an additional dose, but 
should take the next usual prescribed dose. 
5.3.1 Safety Considerations 
• Treatment with ruxolitinib can cause thrombocytopenia, anemia and neutropenia. 
Manage thrombocytopenia by reducing the dose or temporarily interrupting ruxolitinib. 
Platelet transfusions may be necessary. Subjects developing anemia may require blood 
transfusions and/or dose modifications of ruxolitinib. Severe neutropenia (ANC less than 
0.5 X 109/L) was generally reversible by withholding ruxolitinib until recovery. Perform 
a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until 
counts are stabilized, and then as clinically indicated. 
• Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting 
therapy with ruxolitinib until active serious infections have resolved. Observe subject 
receiving ruxolitinib for signs and symptoms of infection and manage promptly. 
• Tuberculosis infection has been reported in patients receiving ruxolitinib. Observe 
subjects receiving ruxolitinib for signs and symptoms of active tuberculosis and manage 
promptly. Prior to initiating ruxolitinib, subjects should be evaluated for tuberculosis risk 
factors, and those at higher risk should be tested for latent infection. For subjects with 
evidence of active or latent tuberculosis, consult a physician with expertise in the 
treatment of tuberculosis before starting ruxolitinib. The decision to continue ruxolitinib 
during treatment of active tuberculosis should be based on the overall risk-benefit 
determination. 
• Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib 
treatment. If PML is suspected, stop ruxolitinib and evaluate. 
• Advise subjects about early signs and symptoms of herpes zoster and to seek treatment as 
early as possible if suspected. 
• Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations 
in alanine aminotransferase and aspartate aminotransferase, have been reported in 
patients with chronic HBV infections taking ruxolitinib. The effect of ruxolitinib on viral 
replication in patients with chronic HBV infection is unknown. Subjects with chronic 
HBV infection should be treated and monitored according to clinical guidelines. 
• Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell 
carcinoma have occurred in patients treated with ruxolitinib. Perform periodic skin 
examinations. 


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• Treatment with ruxolitinib has been associated with increases in lipid parameters 
including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. 
The effect of these lipid parameter elevations on cardiovascular morbidity and mortality 
has not been determined in patients treated with ruxolitinib. Assess lipid parameters 
approximately 8-12 weeks following initiation of ruxolitinib therapy at investigator 
discretion. Monitor and treat according to clinical guidelines for the management of 
hyperlipidemia. 
5.3.2 Ruxolitinib Drug Supply 
Ruxolitinib 5 mg tablets are round and white to off-white in color. 
 
Ruxolitinib will be supplied as 5 mg tablets packaged in 60-count high-density polyethylene 
bottles. All tablet excipients comply with the requirements of the applicable compendial 
monographs. 
 
Ruxolitinib will be supplied by Incyte. All Incyte investigational product labels will be in the 
local language and will comply with the legal requirements of each country and will state 
"Caution: New Drug--Limited by Federal (or United States) law to investigational use." 
Bottles of ruxolitinib tablets should be stored at room temperature, 15°C to 30°C (59°F to 86°F). 
5.4 
Treatment Compliance 
Subject compliance with the treatment and protocol includes ability and willingness to comply 
with all aspects of the protocol.  At the discretion of the Sponsor-Investigator, a subject may be 
discontinued from the protocol for non-compliance with follow-up visits or study drug.  
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment will continue until one of 
the following criteria applies: 
• Disease progression (after ruxolitinib is initiated) 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Subject decides to withdraw consent for treatment  
• General or specific changes in the subject’s condition render the subject unacceptable for 
further treatment in the judgment of the Investigator. 


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5.6 
Drug Accountability 
Ruxolitinib and carfilzomib will be stored at the investigational sites in accordance with Good 
Clinical Practice (GCP) and Good Manufacturing Practice (GMP) requirements and will be 
inaccessible to unauthorized personnel.  
An adequate record of receipt, distribution, and destruction of all study drugs must be kept in the 
form of a drug accountability log per investigational site, Amgen, and Incyte requirements.  The 
site Principal Investigator, or responsible party designated by the site Principal Investigator, will 
maintain a careful record of the inventory. Drug accountability logs will be subject to monitoring 
by the Sponsor. 
Study drug will be dispensed to subjects from the site investigational pharmacy. Unused drug 
will be returned to the investigational pharmacy from which it was dispensed.  Upon termination 
or completion of the study, all unused Amgen study drug should be returned to Amgen and all 
unused Incyte study drug should be returned to Incyte. If Amgen and/or Incyte directs that study 
drug should be destroyed upon termination or completion of the study, appropriate 
documentation will be provided by the site investigational pharmacy. 
  
6 
DOSE MODIFICATIONS  
6.1 
Phase I and Phase II Dose Modification and Dose Delay 
Dose reductions are not permitted during Cycle 1 of Phase I unless the subject experiences a 
DLT.  The subject may continue protocol therapy if the toxicity resolves, and the subject can be 
managed by a dose modification as detailed in this section.  However, the occurrence of the DLT 
will be counted toward the assessment of the MTD.  Dose reductions are permitted in subsequent 
cycles of Phase I and during all cycles of Phase II for clinically significant hematologic and non-
hematologic toxicities. Held doses are not made up. 
The prophylactic use of G-CSF and platelet transfusions in Cycle 1 of the dose escalation cohorts 
in Phase I is not permitted.  Dose adjustments are permitted according to rules described in this 
section.  Dose modifications different from those stated in the protocol should only be made in 
consultation with the Sponsor-Investigator; unless required for immediate subject safety.   
Administration of the study drugs will be discontinued in the event of a treatment-related toxicity 
that persists despite appropriate dose reductions or any other toxicity that, in the opinion of the 
Investigator, warrants discontinuation.   
Toxicity will be assessed using the CTCAE version 4.03 (Appendix 18.2).   


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All dose modifications should be based on the worst preceding toxicity 
6.2 
Dose Reduction Steps 
6.2.1 Carfilzomib Dose Reduction Steps 
Carfilzomib Dose Reduction Steps 
Starting Dose 
Dose reduction 
step - 1 
Dose reduction 
step - 2 
Dose reduction  
step - 3 
56 mg/m2 
45 mg/m2 
 36 mg/m2 
27 mg/m2 
 
6.2.2 Dexamethasone Dose Reduction Steps  
If a subject is unable to tolerate dexamethasone due to dexamethasone related toxicity despite 
dose reduction to 12 mg, dexamethasone may be discontinued.  However, the subject may 
continue on study treatment after discussing with the Sponsor-Investigator.   
Dexamethasone Dose Reduction Steps 
Starting Dose 
Dose reduction step - 1 
Dose reduction step - 2 
40 mg 
20 mg 
12 mg 
 
6.2.3 Ruxolitinib Dose Reduction Steps 
Ruxolitinib Dose Reduction Steps 
Starting Dose 
Dose reduction step - 1 
Dose reduction step -2 
15 mg bid 
10 mg bid 
5 mg bid 
10 mg bid 
  5 mg bid 
5 mg qd (consider) 
  5 mg bid  
  5 mg qd (consider) 
- 
 
6.3 
Dose Modification Guidelines for Carfilzomib and Ruxolitinib during a Cycle of 
Therapy 
Hematologic Toxicity 
Recommended Action 


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• Grade 3a or 4 Neutropenia  
(ANC < 1000 mm3) 
• Grade 4 Thrombocytopenia 
(Platelets < 25,000 mm3) or any grade 
with bleeding. 
 
• Withhold ruxolitinib and carfilzomib and re-evaluate in one week 
• If recovered to Grade 1 or better before next scheduled dose, 
continue ruxolitinib and carfilzomib at same dose level. 
• If recovered to Grade 2 neutropenia or Grade 3 
thrombocytopenia, reduce ruxolitinib and carfilzomib dose by one 
dose level. 
Reductions in one drug and not the other may be considered with 
alternating dose reductions for subsequent occurrence.   
 
• If tolerated, the reduced dose may be escalated to the previous  
dose at the discretion of the physician. 
Non-Hematologic Toxicity 
Recommended Action 
Cardiac Toxicity 
Grade 3 or 4, new onset or worsening of: 
• congestive heart failure; 
• decreased left ventricular function; 
• or myocardial ischemia 
• Withhold carfilzomib until resolved or returned to baseline. 
• After resolution, consider restarting carfilzomib at a reduced 
next dose level if appropriate.  
• If tolerated, the reduced dose may be escalated to the previous 
dose at the discretion of the physician. 
Pulmonary Hypertension 
 
• Withhold carfilzomib until resolved or returned to baseline. 
• Restart at the dose used prior to the event or next dose level at the 
discretion of the physician. 
• If tolerated, the reduced dose may be escalated to the previous 
dose at the discretion of the physician. 
Pulmonary Complications 
• Grade 3 or 4 
 
• For drug related Grade 3 or 4 pulmonary toxicity, permanently 
discontinue carfilzomib. 
Hepatic Toxicity 
• Grade 3 or 4 elevation of 
transaminases, bilirubin or other liver 
abnormalities 
• Withhold carfilzomib and ruxolitinib until resolved or returned to 
baseline. 
• After resolution, consider if restarting carfilzomib and ruxolitinib is 
appropriate; may be reinitiated at a reduced dose with frequent 
monitoring of liver 
function. 
• 25% dose reduction of carfilzomib in case of baseline or treatment 
emergent mild or moderate hepatic impairment. 
• Restart ruxolitinib with one dose level reduction. 
• If tolerated, the reduced doses of both drugs may be escalated 
to the previous doses at the discretion of the physician. 


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Renal Toxicity 
• Serum creatinine equal to or greater 
than 2 × baseline 
 
• Withhold carfilzomib and ruxolitinib until renal function has 
recovered to Grade 1 or to baseline and monitor renal 
function. 
• Carfilzomib must be held for subjects with a CrCl < 15 
mL/min at any time during study participation. 
• If attributable to carfilzomib, restart at the next scheduled 
treatment at a reduced dose  
• If not attributable to carfilzomib, restart at the dose used prior 
to the event. If attributable to ruxolitinib, restart with one 
dose level reduction. 
• If not attributable to ruxolitinib, restart at the dose used prior to 
the event 
• If tolerated, the reduced dose may be escalated to the previous 
dose at the discretion of the physician. 
Posterior Reversible Encephalopathy 
Syndrome (PRES) 
• If PRES is suspected, hold carfilzomib. Consider evaluation 
with MRI for onset of symptoms suggestive of PRES. 
• If PRES is confirmed, permanently discontinue carfilzomib. 
• If PRES is excluded, may resume carfilzomib at same dose 
if clinically appropriate. 
• If PRES recurs, permanently discontinue carfilzomib. 
Thrombotic Microangiopathy (TMA) 
• If TMA is suspected, hold carfilzomib and manage per 
standard of care. 
• If TMS is confirmed and related to carfilzomib, permanently 
discontinue carfilzomib. 
• If TMA is excluded, may restart carfilzomib. 
If Progressive Multifocal 
Leukoencephalopathy (PML) is 
suspected 
• Hold carfilzomib 
• Refer to a specialist; appropriate diagnostic testing should 
be initiated 
• If a diagnosis of PML is confirmed, permanently 
discontinue carfilzomib 
Active HBV reactivation 
• Withhold carfilzomib until the infection is adequately 
controlled. If the benefits outweigh the risks, carfilzomib 
may be resumed with concomitant prophylaxis as per local 
standard of care. Consult a liver disease specialist as 
clinically indicated. 
Active or suspected infection of any 
kind that requires systemic treatment 
• Hold carfilzomib until the infection has resolved and the 
course of antibiotics has been completed, if being treated 
with an anti-infective(s) 
Other Grade 3 or 4 non-hematologic 
toxicity  
• Evaluate attribution and withhold the appropriate therapy.  
If resolved to ≤ Grade 1 or baseline, restart the withheld 
therapy with one level dose reduction of suspected drug.  
• If tolerated, the reduced dose may be escalated to the 
previous dose at the discretion of the physician. 


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a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 
4.03 
6.4 
Dose Modification Guidelines for Dexamethasone 
Dose Modifications for Toxicity Related to Dexamethasone 
Body System 
Symptom 
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grade 1–2  
(requiring medical management) 
Treat with H2 blockers, sucralfate, 
or omeprazole. If symptoms persist 
despite above measures, decrease 
dexamethasone dose by 1 dose level. 
Gastrointestinal 
> Grade 3  
(requiring hospitalization or 
surgery) 
Hold dexamethasone until symptoms 
adequately controlled. Restart and 
decrease one dose level of current 
dose along with concurrent therapy 
with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist 
despite above measures, discontinue 
dexamethasone and do not resume. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone and do 
not resume 
Cardiovascular 
Edema 
> Grade 3 (limiting function and 
unresponsive to therapy or 
anasarca) 
Diuretics as needed, and decrease 
dexamethasone dose by 1 dose level; 
if edema persists despite above 
measures, decrease dose another 
dose level. Discontinue 
dexamethasone and do not resume if 
symptoms persist despite second 
reduction. 
Neurology 
Confusion or Mood alteration  
> Grade 2 (interfering with 
function +/- interfering with 
activities of daily living) 
Hold dexamethasone until symptoms 
resolve. Restart with one dose level 
reduction. If symptoms persist 
despite above measures, discontinue 
dexamethasone and do not resume. 
Musculoskeletal 
Muscle weakness  
> Grade 2 (symptomatic and 
interfering with function +/- 
interfering with activities of 
daily living) 
Decrease dexamethasone dose by 
one dose level. If weakness persists 
despite above measures, decrease 
dose by one dose level. Discontinue 
dexamethasone and do not resume if 
symptoms persist. 
Metabolic 
Hyperglycemia > Grade 3 or 
higher 
Treatment with insulin or oral 
hypoglycemics as needed. If 
uncontrolled despite above 


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measures, decrease dose by one dose 
level until levels are satisfactory. 
 
6.5 
Criteria for Initiation of a New Cycle of Therapy 
For a new cycle of treatment to begin, the subject must meet the following criteria: 
• ANC must be ≥ 1,000/mm3. 
• Platelet count must be greater than or equal to 25,000/mm3 
• All other non-hematologic treatment-related toxicity (except for alopecia) must have 
resolved to ≤ Grade 1 or to the subject’s baseline condition, with the exception of fatigue 
which must have resolved to ≤ Grade 2. 
If the subject fails to meet the above-cited criteria for initiation of the next cycle of treatment, 
dosing should be delayed for 1 week. At the end of that time, the subject should be re-evaluated 
to determine whether the criteria have been met. If the subject continues to fail to meet the 
above-cited criteria, delay therapy and continue to re-evaluate. The maximum delay before 
treatment should be discontinued will be 3 weeks or at the discretion of the Investigator. Phase 
II/Run-In only: beginning with Cycle 1, disease evaluation results should be available prior to 
dosing on Day 1 of each cycle until initiation of ruxolitinib (Phase II/Ruxolitinib). 
7 
CONCOMITANT MEDICATIONS 
All baseline medications that the subject is taking within 14 days prior to the initiation of therapy 
must be recorded in the subject medical record.  All additional medications (other than study 
drug or changes in baseline medications) administered during the study must be listed in the 
subject’s medical record. 
All medication that is considered necessary for the subject’s welfare, and which is not expected 
to interfere with the evaluation of the study treatment, may be given at the discretion of the 
Investigator.  
7.1 
Required Concomitant Therapy 
• Female subjects of child-bearing potential must agree to use dual methods of 
contraception for the duration of the study and for 30 days following the last dose of 
study treatment.  Male subjects must agree to use a barrier method of contraception for 
the duration of the study and for 90 days following the last dose of study treatment if 
sexually active with a female of child-bearing potential. 
• In addition, subjects must receive acyclovir or similar (famciclovir, valacyclovir) anti-
varicella (anti-herpes) agent prophylaxis. All subjects must receive prophylaxis with 
hydration as per Section 5.1.2.1. 


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• Thromboprophylaxis is recommended for subjects being treated with the combination of 
carfilzomib with dexamethasone. The thromboprophylaxis regimen should be based on 
an assessment of the subject’s underlying risks. 
7.2 
Recommended/Allowed Concomitant Therapy 
• Prophylactic treatment with anti-emetic(s) prior to carfilzomib administration is 
recommended. Subsequent anti-emetic drugs against delayed emesis will be administered 
at the discretion of the investigator.  
• Full supportive care is recommended, including transfusions of blood and blood products 
(including platelets), antibiotics, anti-diarrheals, analgesics, etc. and prophylactic 
treatment for tumor lysis syndrome when appropriate.  
• Bisphosphonate therapy IV or PO is recommended to be administered if indicated in 
accordance with institutional guidelines. 
• Prophylaxis with antivirals should be given to all subjects unless contraindicated, 
especially subjects who are carriers of HBV. 
• The prophylactic use of G-CSF and platelet transfusions is permitted except in Cycle 1 of 
the dose escalation cohorts (Phase I) unless the subject has hematologic DLT. 
Erythropoiesis-stimulating agents are permitted throughout the duration of study 
treatment (any cycle). 
• Palliative radiation is allowed  
7.3 
Contraindicated Concomitant Therapy 
• Strong CYP3A4 inhibitors (such as but not limited to boceprevir, clarithromycin, 
conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole) and fluconazole are not permitted in combination with 
ruxolitinib. 
• Concurrent therapy with any approved or investigative anticancer therapeutic drug with 
activity against multiple myeloma is not allowed.  
• Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel disease) 
> prednisone 10 mg/day (or its equivalent) are not permitted.   
• Other investigative agents for multiple myeloma or any other indication should not be 
used during the study. 
8 
STUDY PROCEDURES 
Please see Table of Events (Appendix 18.5) for details regarding the timing and description of all 
study procedures.  


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8.1 
Registration 
Potentially eligible and interested subjects will be presented with the study informed 
consent. Following informed consent, subjects will be registered by the Coordinating 
Center and assigned a four digit number Sequence Number, where 1001 will be the 
Sequence Number assigned to the first registered subject. 
No protocol-related assessments may be performed prior to obtaining informed consent.  Men 
and women of child bearing potential on study will be counseled regarding the need to use 
contraception throughout the course of the study and for 30 days (female subjects) or 90 days 
(male subjects) after the last dose of study treatment. 
8.2 
Informed Consent  
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved informed consent form (ICF) 
confirming his or her willingness to participate in this study before any study-specific screening 
procedures are performed. Subjects must also grant permission to use protected health 
information per the Health Insurance Portability and Accountability Act (HIPAA). In addition, 
subjects must sign all applicable IRB- approved ICF amendments per the site IRB/REB/IEC 
guidelines during the course of the study. 
8.3 
Screening Procedures 
All screening procedures must be completed within 21 days prior to start of study treatment 
unless otherwise specified in the Table of Events (Appendix 18.5) 
• Informed consent 
• Inclusion/exclusion 
• Medical and disease history 
• Physical examination 
• Vital signs 
• ECOG performance status 
• Pregnancy test for females of child bearing potential 
• Electrocardiogram (ECG)  
• ECHO, MUGA, or cardiac MRI 
• Concomitant medications - all on-going medications and those taken within 14 days prior 
to first dose of study treatment 
• Disease Assessments (see section 8.4.1) 
• Laboratory Assessments (see section 8.4.2) 
 


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8.3.1 Disease assessments: Baseline measurements 
• Bone marrow aspirate and serum for disease assessment and correlative studies: for % 
plasma cells, morphology, standard karyotype, cytogenetics by FISH and biomarkers 
• Correlative bone marrow specimen: minimum of 12 mL of bone marrow aspirate will be 
collected and sent to the LCI HOT lab. 
• Response assessments, including serum or urine protein electrophoresis (SPEP/UPEP), 
serum and Urine immunofixation (IFE), serum free light chains (SFLC)/ratio 
• β2 microglobulin 
• Radiologic imaging of plasmacytoma as clinically indicated (same technique to be used 
throughout the trial).  Positron emission tomography/computed tomography (PET/CT) 
scan or magnetic resonance imaging (MRI) as clinically indicated 
• Bone skeletal survey  
 
Please note that for subjects in Phase II/Run-In who cross over to Phase II/Ruxolitinib, a new 
baseline should be established for disease assessments prior to initiating ruxolitinib. Response to 
treatment with ruxolitinib will be calculated using this new baseline. 
8.3.2 Screening Laboratory assessments: 
• Hematology - hemoglobin, WBC with differential, and platelet count 
• Coagulation - PT/INR 
• Blood chemistries - sodium, chloride, potassium, magnesium, phosphate, uric acid, BUN, 
glucose (fasting at baseline), ALT/AST (SGPT/SGOT), alkaline phosphatase, total 
protein, total bilirubin, albumin, serum creatinine and estimated creatinine clearance (see 
Appendix 18.4), calcium and lactate dehydrogenase (LDH).  Viral hepatitis panel 
including HBsAg, HB core antibody, HB surface antibody, HepC antibody and HIV at 
baseline only. 
o HBV DNA testing (by PCR):  only for subjects positive for Anti-HBc or Anti-
HBs  
• Disease specific laboratory evaluations as noted above. 
• Correlative blood specimen 
 
8.4 
On Study Procedures: 
• Vital signs 
• Physical Exam 
• Laboratory assessments 
• ECOG performance status 
• Concomitant medications and procedures 
• Adverse event monitoring 
• ECHO, MUGA, or cardiac MRI 
• Correlative studies (Blood and bone marrow aspirate) 


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o Note: Post-baseline correlative samples should only be collected on subjects 
receiving ruxolitinib (Phase I and Phase II/Ruxolitinib). 
8.4.1 Disease assessments:  
• Response assessments, including serum or urine protein electrophoresis (SPEP/UPEP), 
serum and Urine immunofixation (IFE), serum free light chains (SFLC)/ratio 
o The following assessments will be performed at each urine disease evaluation: 
 Total protein 
 UPEP 
 Urine immunofixation electrophoresis (UIFE) 
o For subjects whose disease is not measurable by UPEP at Baseline, a 24-hour urine 
sample for UPEP and Urine immunofixation (UIFE) will be collected every 3 
cycles at a minimum.  
• If disease has not progressed and new anti-cancer treatment has not been started after study 
treatment discontinuation, response assessment samples should also be collected per 
standard of care during the follow-up visits. 
• Radiologic imaging of plasmacytoma as clinically indicated (same technique to be used 
throughout the trial).  Positron emission tomography/computed tomography (PET/CT) 
scan or magnetic resonance imaging (MRI) as clinically indicated 
• Bone skeletal survey as clinically indicated and to confirm progression if needed. 
• Phase II/Run-In only: Beginning with Cycle 1, disease evaluation results to assess response 
should be available for investigator review prior to dosing on Day 1 (up to 7 days prior) of 
each cycle until initiation of ruxolitinib. Cycle numbers start over with the initiation of 
ruxolitinib (the first cycle of ruxolitinib will be Cycle 1) and a new disease response 
baseline will be established (Phase II/Run-in subjects who cross over to Phase 
II/Ruxolitinib). 
 
8.4.2 Laboratory assessments: 
• Hematology - hemoglobin, WBC with differential, and platelet count 
• Blood chemistries - sodium, chloride, potassium, magnesium, phosphate, uric acid, BUN, 
glucose (fasting at baseline), ALT/AST (SGPT/SGOT), alkaline phosphatase, total protein, 
total bilirubin, albumin, serum creatinine and estimated creatinine clearance, calcium and 
lactate dehydrogenase (LDH).  
• Brain Natriuretic Peptide (BNP)  
• Disease specific laboratory evaluations as noted above. 
• Correlative studies (blood and bone marrow). Note: ruxolitinib must have been initiated 
in order to collect correlatives post-baseline.  
8.5 
End of Treatment 
The end of treatment (EOT) visit is done when the subject discontinues study treatment for any 
reason. The decision to discontinue study treatment due to progression must be based on the 


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evaluation of lab assessment. If the decision to permanently discontinue the study treatment is 
made during a scheduled visit, then the EOT visit should be performed instead of the scheduled 
visit. If the decision is made between scheduled visits, an EOT visit should be performed no later 
than 30 days after the last treatment administration or prior to the start of new subsequent anti-
cancer therapy, whichever occurs first. 
8.6 
Follow-Up 
Subjects who received ruxolitinib on study and discontinue therapy for reasons other than 
disease progression should continue to have standard of care disease assessments done until 
progression or start of subsequent therapy.  At such time, follow-up or overall survival status will 
take place every three months +/- 7 days until death, lost to follow up, or until the criteria defined 
for the final analyses (Section 13.4.1) are reached.  However, in the event the criteria for the final 
analysis are met, and there are subjects who have not yet been discontinued from study 
treatment, subjects in follow up will continue to be followed until all subjects have discontinued 
study treatment and completed the required 30 day safety monitoring period (Section 9.3).  
Follow-up beyond the safety monitoring period is only required for subjects who received 
ruxolitinib. 
8.7 
Off-Study 
Subjects will remain on study until the criteria for the final analysis have been met. Reasons a 
subject may be removed from the study early include, but are not limited to: 
• Subject non-compliance with study participation, in the opinion of the investigator 
• The subject or legal representative (such as a parent or legal guardian) withdraws study 
consent 
• The subject is lost to follow-up 
• Investigator’s decision to withdraw the subject 
• Subject death 
• Early study termination 
 
Subjects who do not receive ruxolitinib will be taken off study after completion of the safety 
monitoring period (Section 9.3) 
When subjects are removed from the study, the reason for study removal and date the subject 
was removed should be documented. 
Subjects that are Off Study will not participate in any study related procedures, including data 
collection. The study will be considered complete when one or more of the following conditions 
is met:  
• All subjects have completed all study visits.  


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• All subjects have discontinued from the study.  
• The IRB, LCI DSMC, Sponsor-Investigator or Amgen or Incyte discontinues the study 
because of safety considerations.  
• The Sponsor-Investigator defines an administrative or clinical cut-off date.  
8.7.1 Subject Withdrawal 
In all cases, the reason for withdrawal must be recorded in the subject’s medical record and/or 
research chart and CTMS. 
8.7.2 Screen Failures 
A subject who, for any reason (e.g. failure to satisfy the selection criteria or withdraws consent), 
terminates the study before receiving first dose of the study regimen (Cycle 1, Day 1) is regarded 
as a “screen failure”.   
9 
ADVERSE EVENTS 
9.1 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
AEs.  Abnormal results of diagnostic procedures are considered to be AEs if the abnormality: 
• results in study withdrawal 
• is associated with a serious AE 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the Investigator to be of clinical significance 
9.2 
Serious Adverse Event (SAE):  
An event is “serious” if it involves considerable detriment or harm to one or more persons (who 
may or may not be participants) or required intervention to prevent one or more persons from 
experiencing considerable detriment or harm. SAEs include: 
• Death 
• Life-threatening experience – Disease or condition where the likelihood of death is high 
unless the course of the disease/condition is interrupted or diseases/conditions with 
potentially fatal outcomes where the end point of the clinical trial analysis is survival 
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity 


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• Congenital anomaly/birth defect in subject’s offspring 
• Any other important medical event that, based upon appropriate medical judgment, may 
jeopardize the participant, and may require medical or surgical intervention to prevent 
one of the outcomes listed above.  Examples include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, the development of drug dependency or 
drug abuse, suicidal ideation or attempts, or the unintentional revealing of some genetic 
information to insurers. 
9.2.1 Related:  
An event is “related” if, in the opinion of the Investigator, it was definitely or possibly was 
caused by the research activity. 
9.2.2 Unexpected:  
An event is “unexpected” when its specificity, nature, severity or incidence is not accurately 
reflected in the investigator’s brochure or Package Insert previously reviewed and approved by 
the IRB.  Examples include a lower rate of response to treatment or a side effect that is more 
severe than initially expected.  
9.3 
Overlapping Toxicities 
There is a possibility that hematologic toxicities and non-hematologic toxicities may overlap 
during study treatment. Overlapping toxicities will be monitored closely in both the Phase I and 
Phase II portions of the study. 
9.4 
Adverse Event Reporting 
All Adverse Events (AE) will be recorded by the Investigator from the time of the start of study 
treatment through the end of the designated safety monitoring follow-up period (30 days after 
last dose of study treatment).  AEs and study treatment administration must be recorded in the 
eCRF within 5 business days of awareness. All relevant historical medical conditions that are 
known/diagnosed prior to the administration of study drug(s) and ongoing at the time of study 
treatment initiation are to be recorded. 
9.5 
Abnormal Laboratory Values Defined as AEs 
An abnormal laboratory value is considered to be an AE if the laboratory abnormality is 
characterized by any of the following: 
• Results in discontinuation from the study 
• Requires treatment, modification of study drug dose, or any other therapeutic intervention 


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• Is judged by the Investigator to be of significant clinical impact/importance 
• Meets the criteria for a DLT as defined in Section 4.2.1.3 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded as an AE.  If the laboratory abnormality was not a part of a 
diagnosis or syndrome, then the abnormality should be recorded as the AE. 
9.6 
Adverse Event Grading 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be 
utilized for AE reporting.   
Grade refers to the severity (intensity) of the AE: 
 
CTCAEv4.03 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention is not indicated. 
CTCAEv4.03 Grade 2: moderate; minimal, local, or noninvasive intervention is indicated; 
limiting to age-appropriate instrumental activities of daily living (ADL; instrumental ADL refers 
to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc.). 
CTCAEv4.03 Grade 3: severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization is indicated; disabling; limiting to self-care 
ADL (self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden). 
CTCAEv4.03 Grade 4: life-threatening consequences; urgent intervention is indicated. 
CTCAEv4.03 Grade 5: death due to an AE 
9.7 
Adverse Event Attribution 
The Investigator will assess the relationship of the event to the study treatment. An adverse event 
is considered to be associated with the use of the study regimen if the attribution is determined as 
possible, probable or definite.  The relationship assessment of the adverse event by the 
Investigator should be documented as follows: 
• Unrelated: The AE is clearly NOT related to the treatment. 
• Unlikely Related: The AE is doubtfully related to the treatment. 
• Possibly Related: The AE may be related to the treatment. 


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• Probably Related: The AE is likely related to the treatment 
• Definitely Related: The AE is clearly related to the treatment. 
9.8 
Communication between Investigational Sites 
Investigational sites will be required to report AEs for all grades and attributions, SAEs, study 
drug administration, or any other problem that could affect the validity/integrity of the study data 
to the Sponsor-Investigator.  Study drug administration issues or any other problem potentially 
affecting the validity/integrity of the study data should be communicated to the Sponsor by email 
or phone as soon as possible but within 2 business days of the Investigator learning of the event. 
10 
SAFETY DATA COLLECTION, RECORDING AND REPORTING 
Safety variables include the following: AEs and SAEs (whether related to study treatment or 
not), laboratory changes, changes in vital signs and, in some instances, changes in images, as 
evaluated at the Investigator’s discretion.  Adverse events will be evaluated continuously 
throughout the study. Safety and tolerability, relationship to treatment and intensity will be 
assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03.  All adverse events (Grades 1 – 5) will be determined by the Investigator and documented 
in subject study charts.  
It is the responsibility of the Sponsor-Investigator, Investigators and the Protocol Team to ensure 
SAEs are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, Institutional Review Board, and FDA policy.  
10.1 SAE/Pregnancy and Lactation Reporting to Sponsor-Investigator 
Upon learning of an event, Investigators/Investigational Sites must notify the Sponsor-
Investigator of any SAE and pregnancy/lactation exposure within 1 business day of awareness 
from study treatment initiation through 30 days from the last dose of study treatment.  All SAEs 
must be followed to resolution or to stabilization if improvement or resolution is not expected.  
SAEs that are determined to be related to study treatment or protocol-mandated procedures are 
reportable for the duration of the subject’s participation in the trial. Each investigational site will 
be responsible to report SAEs that occur at their institution to their respective IRB in accordance 
with the IRB reporting policy. 
When new significant information becomes available, a follow-up report must be reported to the 
Sponsor-Investigator within 1 business day of awareness. 
10.2 SAE Reporting to the FDA 
The Sponsor-Investigator will be responsible for all communications with the FDA. Upon 
learning of the event, the Sponsor-Investigator will report to the FDA, regardless of the site of 


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occurrence, any serious adverse event (SAE) that meets the FDA’s criteria for expedited 
reporting following the reporting requirements and timelines in accordance with federal 
regulations.  
Unexpected fatal or life-threatening experiences associated with the use of an investigational 
product will be reported to the FDA as soon as possible but in no event later than 7 calendar days 
after initial receipt of the information.  All other serious, unexpected experiences associated with 
the use of the investigational product will be reported to the FDA as soon as possible but in no 
event later than 15 calendar days after initial receipt of the information. 
 
The Sponsor-Investigator will notify any participating sites of SAEs reported to the FDA. 
10.3  SAE Reporting by Sponsor-Investigator to Amgen and Incyte 
The Sponsor-Investigator must notify Amgen regarding all SAEs occurring with carfilzomib.  
Subsequently, the Sponsor-Investigator must notify Incyte regarding all SAEs occurring with 
ruxolitinib. The MedWatch Form FDA 3500A must be completed for each event and the form 
must be sent to the respective funding company based on the contact information and reporting 
timelines listed below. 
Note: Investigational sites are not responsible for submitting SAEs to funding companies as 
this is a sponsor responsibility. 
The Sponsor-Investigator shall be responsible for collecting all SAEs and Pregnancy and 
Lactation Exposure Reports from all investigational sites and will exercise reasonable due 
diligence to obtain follow-up information from all investigational sites on incomplete SAE or 
Pregnancy and Lactation Exposure Reports.  In the event that the funding company requires 
clarification or further information on individual SAE or Pregnancy and Lactation Exposure 
Reports, the funding company will not contact non-party investigators directly, but will route all 
such inquiries through Sponsor-Investigator for forwarding to such investigator(s). LCI will be 
responsible to ensure such inquiries are completed and provided to Amgen and Incyte in a timely 
manner.  
Information not available at the time of the initial report (e.g., an end date for the SAE, discharge 
summaries, lot numbers, relevant laboratory values, scan data and autopsy reports) which are 
received after the initial report must be documented on a follow-up MedWatch and submitted to 
Amgen and Incyte.  The Sponsor-Investigator will be responsible for obtaining follow-up 
information for the SAEs and demonstrate diligence in attempting to obtain such information 
from investigational sites by, among other things, maintaining written records of such attempts.  
The Sponsor-Investigator will provide an annual IND report to Amgen and Incyte. Other reports 
containing safety data generated during the course of the study will be submitted to Amgen and 


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Incyte at the time the Sponsor-Investigator submits to anybody governing research conduct (i.e. 
regulatory authorities and IRBs).  The Sponsor-Investigator will support reconciliation of all 
SAEs at the end of the study at a minimum.  
10.3.1 Pregnancy Reporting to Amgen and Incyte  
Sponsor-Investigator will report Pregnancy and potential infant exposure including Lactation to 
Amgen and Incyte within the timeframes listed below: 
• Incyte: within 24 hours of Sponsor-Investigator awareness 
• Amgen: within ten (10) calendar days of Sponsor-Investigator awareness.  
10.3.2 Amgen Reporting/Contact Information 
All Serious Adverse Events (SAEs) occurring with carfilzomib required to be reported pursuant 
to section 10.3 of the protocol shall be provided to Amgen and its representatives by LCI or the 
Sponsor-Investigator on a MedWatch Form FDA 3500A according to the timelines below. 
• Expedited/SUSAR reports: Provide to Amgen within 24 hours after submission to the 
FDA. 
Copies of safety reports submitted to the FDA by the Sponsor-Investigator will be shared with 
the contact below so that these reports can be evaluated and included in investigator brochure or 
Amgen IND safety submissions as required to ensure safety of other subjects who are receiving 
the product from Amgen for sponsored trials.  Additionally, the Sponsor will provide any 
additional reports agreed upon by LCI or the Sponsor-Investigator and Amgen which will 
include a line listing of all SAEs sent to Amgen every 6-12 months. 
Amgen Drug Safety and Pharmacovigilance Contact Information: 
Amgen Global Safety 
Toll-free #: 1-888-814-8653 
Email (Only for sponsors with a secure email connection with Amgen): svc-ags-us@amgen.com 
10.3.3 Incyte Reporting/Contact Information 
All Serious Adverse Events (SAEs) occurring with ruxolitinib required to be reported pursuant to 
section 10.3 of the protocol shall be provided to Incyte and its representatives by LCI or the 
Sponsor-Investigator on a MedWatch Form FDA 3500A within 24 hours of the Sponsor-
Investigator becoming aware of the event. Copies of IND safety reports submitted to the FDA by 
LCI will be shared with the contact below so that these reports can be evaluated and included in 


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investigator brochure or Incyte IND safety submissions as required to ensure safety of other 
subjects who are receiving the product from Incyte for sponsored trials. 
Incyte Corporation:  SafetyReporting@incyte.com for e-mail transmission of individual SAE 
reports; 
Safety Contacts:     Kathy Lenard Roberts, VP, Global PhV Ops & Systems Quality Management 
                                                                Phone: 302-498-6727 
                                                                Fax:     302-425-2780 
                                                                 
Robert Livingston, MD, VP, Incyte PhV & Drug Safety 
                                                                Phone: 302-498-7098 
                                                                Fax:     302-425-2780 
10.4 Safety Reporting to the IRB 
All events occurring during the conduct of a protocol and meeting the definition of an SAE will 
be reported to the central IRB per IRB requirements.   
Protocol deviations will be reported promptly to the central IRB per IRB requirements.    
11 
DATA AND SAFETY MONITORING PLAN 
Data will be collected in electronic case report forms (eCRFs). Study personnel will be trained 
on data entry by the sponsor and provided protocol-specific eCRF guidelines. 
This protocol will be monitored according to the processes in effect for all Levine Cancer 
Institute Investigator- Initiated Trials and will abide by applicable regulations and guidelines 
(e.g. Good Clinical Practice [GCP]) .  It is the responsibility of the Sponsor-Investigator to 
monitor the safety data for this study.  For the Phase I portion of the study, the Sponsor-
Investigator, Statistician, and other study team members, as applicable, will conduct a 
teleconference after accrual of each cohort to review safety data before approving opening of 
subsequent cohorts for accrual.  The Sponsor-Investigator,  and other sponsor-level study team 
members,  will meet to regularly to monitor subject consents, enrollment and retention, safety 
data and timeliness/validity/integrity of the data on a recurring basis.  Documentation of 
recurring meetings will be kept in the study files. The Sponsor-Investigator will submit reports to 
the LCI Data and Safety Monitoring Committee according to the institutional LCI Data and 
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12 
MEASUREMENT OF EFFECT 
12.1 Timing of Response Evaluation 
Response will be evaluated according to the schedule of evaluations listed on the Table of Events 
(Appendix 18.5)  
12.2 Response Criteria: 
The IMWG Response Criteria will be used for all evaluations of response. (Appendix 18.3) 
12.3 Measurable Disease:   
All subjects must have baseline assessment of disease that meet the criteria of measurable 
disease defined below: 
• Serum M protein ≥ 0.5 g/dL (≥ 5 g/L) for IgG, IgA, or IgM disease, quantified by using 
densitometry on serum protein electrophoresis (SPEP).  
AND / OR 
• Urine M protein [Bence-Jones Protein] ≥ 200 mg/24 hrs (> 0.2 g/24 hrs), quantified by 
24-hour urine protein electrophoresis (UPEP see Appendix III: Notes, h.).  
OR 
• Subjects who have both serum M protein levels < 0.5 g/dL AND urine M protein levels < 
200 mg/24 hrs at baseline may be followed by serum free light chain (FLC) assay if 
involved free light chain level ≥ 10 mg/dL (≥ 100mg/L). 
 
13 
STATISTICAL CONSIDERATIONS 
13.1 Sample Size  
13.1.1 Phase I 
Phase I up to 18 subjects may be required to evaluate 3 dose levels of ruxolitinib in combination 
with carfilzomib and dexamethasone in a standard 3 + 3 design.   
13.1.2 Phase II 
Progression-free survival at 4 months is the primary endpoint for this study.  The current study is 
investigating the impact of adding ruxolitinib to the combination of carfilzomib and 
dexamethasone in a carfilzomib refractory population.  Published study results on carfilzomib 
plus dexamethasone in a carfilzomib refractory population (as defined in this protocol) have not 


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been identified.  However, it is reported that the time on treatment in multiple myeloma patients 
receiving three or more lines of therapy had a median time on treatment of approximately 2 
months29.  Therefore, it is assumed that if multiple myeloma subjects who are carfilzomib-
refractory were retreated with carfilzomib plus low-dose dexamethasone, they would experience 
a median PFS of 2 months.  A 2-month median PFS corresponds to a 4-month progression-free 
survival rate of 25%. In this patient population, if subjects treated with carfilzomib, ruxolitinib, 
and low-dose dexamethasone achieved a median PFS of 4 months, this would be considered a 
significant clinical benefit. A 4-month median PFS corresponds to a 4-month progression-free 
survival rate of 50%. A Simon’s 2-stage design will be used to test the hypothesis that the 4-
month PFS rate is less than or equal to 25%.  Ten subjects will be enrolled in the first stage, and 
if at least 3 of the 10 subjects are alive and progression free at 4 months, an additional 20 
subjects will be enrolled (a total of 30 subjects).  If at least 11 of 30 subjects are alive and 
progression free at 4 months, the null hypothesis will be rejected (based on binomial 
probabilities).  Assuming a one-sided alpha = 0.10 significance level, this sample size will 
provide at least 90% power to reject the null hypothesis, assuming the true 4-month PFS rate is 
50%.   
13.2 Endpoint Definitions 
For response and progression-related endpoints, the baseline disease assessment will be the one 
that occurred prior to the start of ruxolitinib therapy. 
13.2.1 Primary/Phase I:  Dose Limiting Toxicity (DLT) 
DLTs will be determined for each subject enrolled in Phase I as a binary variable indicating 
whether or not the subject experienced a DLT (as described in Section 4.2.1.3) during Cycle 1 of 
ruxolitinib treatment administration.  
13.2.2 Primary/Phase II:  4-Month Progression-Free Survival 
4-month progression-free survival (PFS4) will be determined for each subject as a binary 
variable indicating whether or not the subject is alive and progression free at 4 months. The 
timing of PFS4 begins at the time subjects start treatment with ruxolitinib. The criteria for 
progression are described in the IMWG Criteria (Appendix 18.3).  
13.2.3 Progression-Free Survival and Time to Progression 
PFS is defined as the duration of time from the initiation of study treatment with ruxolitinib to 
first occurrence of either progressive disease or death.  Disease progression as described by 
IMWG Criteria (Appendix 18.3).  The date of progressive disease is the date of the initial 
assessment that identified progressive disease.  If the subject dies without documented disease 
progression, the date of progression will be the date of death.  For surviving subjects who do not 


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have documented disease progression, PFS will be censored at the date of last disease 
assessment.  For subjects who receive subsequent anti-cancer therapy prior to documented 
disease progression, PFS will be censored at the date of last disease assessment prior to the 
commencement of subsequent therapy.  Subjects who have an initial PFS event immediately 
following 2 or more consecutive missed assessments will be censored at the date of the last 
assessment prior to those missed assessments.  For subjects with only one missed assessment, the 
documented progressive disease status and assessment date will be used.  Time to progression 
(TTP) will be determined in a similar fashion as PFS, with the only difference being TTP will be 
censored at the death date for subjects who die without progressive disease.  
13.2.4 Overall Survival 
Overall survival is defined as the duration from initiation of ruxolitinib treatment to the date of 
death from any cause.  Subjects who are alive or lost to follow-up at the time of the analysis will 
be censored at the last known date they were alive. 
13.2.5 Objective Response 
Objective response will be determined for each subject as a binary variable indicating whether or 
not the subject achieved a best overall response of PR or better as per the IMWG criteria after 
initiating treatment with ruxolitinib.  
13.2.6 Clinical Benefit 
Clinical benefit will be determined for each subject as a binary variable indicating whether or not 
the subject achieved a best overall response of minimal response (MR) or better as determined 
by the IMWG criteria (MR adapted from EBMT) after initiating treatment with ruxolitinib.  
13.2.7 Time to Best Response  
This will be calculated for all subjects achieving an sCR, CR, VGPR or PR and separately for 
subjects achieving an MR and will be defined as the time from initiation of ruxolitinib treatment 
to the time of best objective status assessment of sCR/CR/VGPR/PR or of MR. 
13.2.8 Disease control 
Disease control will be determined for each subject as a binary variable indicating whether or not 
the subject achieved an sCR, CR, VGPR, PR, MR or SD ≥ 8 weeks in duration after initiating 
treatment with ruxolitinib. 


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13.2.9 Duration of response 
Duration of response will be calculated for all subjects achieving an sCR, CR, VGPR or PR and 
separately for subjects achieving an MR (defined per the EBMT criteria) and will be defined as 
the time from first objective status assessment of sCR/CR/VGPR/PR or of MR to the time of first 
documented disease progression or death.  The censoring mechanism for duration of response 
will be the same as that described for PFS. 
13.2.10 Safety Endpoints 
Safety endpoints will include ruxolitinib treatment administration, AEs, SAEs, deaths while on 
study therapy, vital signs, ejection fraction (%), and selected quantitative laboratory 
determinations. Treatment administration will be determined for each subject in terms of 
cumulative dose administration and dose intensity of ruxolitinib (adjusting for dose delays and 
reductions). Additionally, the relative dose intensity will be calculated for each subject in terms 
of the actual dose intensity as a percent of the intended dose intensity. 
Phase II:  Adverse Events of Special Interest (AESI)    
AESIs will be continuously monitored during the Phase II part of the study in subjects receiving 
ruxolitinib for the purposes of the pre-specified stopping rule described in Section 13.4.3.  AESIs 
will be determined for each subject as a binary variable indicating whether or not the subject 
experienced a Grade 3/4/5 adverse event related to the ruxolitinib-containing regimen.  AESIs 
will consist of the following CTCAE terms: 
• Heart failure 
• Pneumonia 
• Dyspnea 
• Peripheral edema 
• Hypertension 
13.3 Analysis Populations 
For the Phase I part of the study, the dose escalation and MTD evaluation will be conducted on 
the population who initiate Cycle 1, Day 1 treatment, and who meet the DLT evaluable criteria 
as described in Section 4.3.  For the Phase II part of the study, the PFS4 evaluable population 
will include all subjects who initiate treatment with ruxolitinib, have experienced a PFS event 
within 4 months from the start of ruxolitinib treatment, or have at least 4 months of follow up 
time from the start of ruxolitinib treatment.  The primary efficacy analysis will be conducted on 
the PFS4 evaluable population.  Response-evaluable population will include all subjects (both 
Phase I and Phase II) who have baseline evaluation, measurable disease, and initiate study 


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treatment followed by at least one efficacy measurement. All response endpoints will be 
conducted on the response-evaluable population.  
All other efficacy and ruxolitinib safety analyses will be conducted on the population of subjects 
(both Phase I and Phase II) who initiate treatment with ruxolitinib. Additionally, an analysis will 
be conducted on safety data collected from Cycle 1 through the cycle prior to initiation of 
ruxolitinib treatment (for all Phase II subjects initiating Cycle 1 with carfilzomib plus 
dexamethasone).  
13.4 Analysis Methods 
13.4.1 Timing of Analyses 
For the Phase I part of the study, an evaluation of the data will take place after each subject 
completes Cycle 1.  For the Phase II part of the study, AESIs will be continuously evaluated in 
order to assess the Bayesian stopping rules for toxicity described in Section 13.4.3.  Additionally, 
the stage 1 analysis will occur after the first 10 PFS evaluable subjects enrolled have progressive 
disease, have died, or have at least 4 months of follow up time from ruxolitinib treatment start.  
The stage 2 analysis will occur after 30 PFS evaluable subjects have progressive disease, have 
died, or have at least 4 months of follow up time.  For both Phase I and Phase II, a follow up 
analysis will occur when all enrolled subjects have progressed, have died, have become lost to 
follow up or withdrawn from the study, or have at least two years of follow up time after 
initiation of treatment with ruxolitinib.  A final analysis (for both Phase I and Phase II) will occur 
when all subjects have died, have become lost to follow up or withdrawn from the study, or have 
at least 3 years of follow up time after initiation of treatment with ruxolitinib.   
13.4.2 Efficacy Analyses  
13.4.2.1 Primary Analysis (Phase II) 
The frequency and proportion of subjects who are alive and progression free at 4 months will be 
calculated with a corresponding 95% confidence interval using the Clopper-Pearson method.  A 
one-sided test for binomial proportions using the rejection regions described in Section 13.1.2 
will be carried out, testing the null hypothesis that the PFS4 rate is less than or equal to 25%.    
13.4.2.2 Secondary Analyses 
OS, PFS, time to progression, duration of response, and time to best response will be analyzed 
using Kaplan Meier techniques.  Medians, 25th, and 75th percentiles will be estimated.  Selected 
landmark rates will be estimated using the product limit function.  Objective response rate, 
disease control rate, and clinical benefit rate will be analyzed using frequencies and proportions.  
Ninety-five percent confidence intervals will be estimated using the Clopper-Pearson method.   


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13.4.3 Safety Analyses 
Treatment administration will be summarized descriptively in terms of cumulative dose 
administration and dose intensity of ruxolitinib (adjusting for dose delays and reductions). 
Additionally, the relative dose intensity will be calculated in terms of the actual dose intensity as 
percent of the intended dose intensity.  The maximum grade for each type of adverse event will 
be recorded for each subject and treatment-emergent adverse events (TEAEs) will be identified.  
TEAEs are defined as follows: 
• An adverse event that occurs after treatment start that was not present at the time of 
treatment start; or 
• An adverse event that increases in severity after treatment start if the event was present at 
the time of treatment start. 
TEAEs will be summarized using frequencies and proportions, and these will be reviewed to 
determine patterns.  Additionally, the relationship of the adverse event(s) to the study treatment 
will be taken into consideration. 
Clinical laboratory tests (hematology, chemistry, coagulation panel, BNP), vital signs, and 
ECHO/MUGA/cardiac MRI (ejection fraction (%)) will be summarized with descriptive 
statistics.  
Phase II Stopping Rule 
It is estimated that the composite rate of Grade 3/4/5 AESIs (as defined in Section 13.2.10) in 
relapsed or refractory multiple myeloma patients treated with carfilzomib plus dexamethasone is 
approximately 0.3030.  If it becomes evident that the Grade 3/4/5 AESI rate convincingly exceeds 
0.30, the study will be halted. Enrollment will be suspended if the posterior probability of the 
Grade 3/4/5 AESI rate exceeding 0.30 is 0.75 or higher.  The prior distribution for this 
monitoring rule is beta (3,7).  This means that our prior assumption regarding the proportion of 
Grade 3/4/5 AESI’s is 0.30, and there is 90% probability that this proportion is between 0.098 
and 0.550.  The operating characteristics of the stopping rule are given in the following table and 
are based on 5000 simulations. 
Operating Characteristics of the Stopping Rule 
Number of Subjects with an 
AESI 
Number of Treated Subjects 
Posterior Probability: 
Pr(AESI Rate>0.30|Data) 
3 
5 
0.781 
4 
8 
0.779 
5 
11 
0.761 
6 
14 
0.777 


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7 
17 
0.767 
8 
20 
0.768 
9 
23 
0.772 
10 
26 
0.770 
11 
29 
0.761 
 
13.4.4 Exploratory Analyses 
Logistic regression and Cox proportional hazards models will be used to assess the correlation 
between biomarkers and efficacy and toxicity outcomes.  Exploratory objectives include 
exploring the correlation of toxicities and disease response with: 
• Baseline serum cytokine profile 
• Baseline PBMC JAK inhibition 
• Baseline PBMC proteasome inhibition 
Genomic studies will be performed on BM aspirate samples after sorting the CD138 positive and 
CD138 negative cells to understand mechanisms of carfilzomib sensitivity and resistance, along 
with modulation of the BM micro-environment. BM aspirate samples will be collected at: 
• Baseline (screening) 
• After Cycle #1 (between Days 20 – 27) of ruxolitinib 
• At time of disease relapse and/or progression after initiation of ruxolitinib 
13.5 Interim Analyses 
After 10 PFS evaluable subjects have been enrolled to the Phase II part of the study, the study 
will be suspended for a planned interim analysis. The interim analysis will occur 4 months from 
the tenth evaluable subject’s enrollment (unless they have progressed or died first) and will 
determine if at least 3 of 10 subjects are alive and progression free at 4 months.  If the answer is 
yes, then the study will re-open to accrual and enroll an additional 20 subjects for a total of 30 
subjects. 
14 
STUDY COMPLETION 
14.1 Completion 
The study will be considered complete when one or more of the following conditions is met:  
• All subjects have completed all study visits.  
• All subjects have discontinued from the study.  


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• The IRB, LCI DSMC, Sponsor-Investigator or funding companies discontinue the study 
because of safety considerations.  
• The Sponsor-Investigator defines an administrative or clinical cut-off date.  
14.2 Termination 
The study will be terminated when one or more of the following conditions occur: 
• If risk-benefit ratio becomes unacceptable owing to, for example: 
o Safety findings from this study (e.g. SAEs) 
o Results of any interim analysis 
o Results of parallel clinical studies 
o Results of parallel animal studies (e.g. toxicity, teratogenicity, carcinogenicity or 
reproduction toxicity). 
• If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame. 
The Sponsor-Investigator has the right to close the trial at any site and at any time. 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties. 
• All affected institutions must be informed as applicable according to local law.   
• In case of a partial study closure, ongoing subjects, including those in follow- up, must be 
taken care of in an ethical manner. 
15 
ETHICAL AND LEGAL ISSUES 
15.1 Retention of Records 
Essential documentation (e.g. adverse events, records of study drug receipt and dispensation), 
including all IRB correspondence, will be retained for at least 2 years after the investigation is 
completed.  Documentation will be readily available upon request. 
15.2 Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the Investigator abide by Good Clinical Practice (GCP) 
guidelines and under the guiding principles detailed in the Declaration of Helsinki.  The study 
will also be carried out in keeping with applicable local law(s) and regulation(s). 


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Documented approval from appropriate agencies (e.g. DSMC, IRB, FDA) will be obtained for 
all participating centers before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of IRB approval must be 
obtained and forwarded to Amgen and Incyte. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the Investigators may not modify or alter the procedures described in this protocol.   
Modifications to the study protocol will not be implemented by the Sponsor-Investigator without 
discussion and agreement by Amgen and Incyte.  However, the Investigators may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial 
subjects without prior approval from applicable agencies.  As soon as possible, the implemented 
deviation or change, the reasons for it and if appropriate the proposed protocol amendment 
should be submitted to the appropriate agencies.  Any deviations from the protocol must be 
explained and documented by the Investigator. If a deviation occurs, the event should be reported 
to the Sponsor-Investigator promptly. Any IRB reportable event that occurs must be reported to 
the IRB per IRB requirements. All planned (intentional) deviations must be submitted to the 
Sponsor-Investigator for approval prior to implementation or planned occurrence. After Sponsor 
approval has been obtained, planned deviations must be submitted and approved by the IRB 
prior to the anticipated deviation occurring. Exceptions for eligibility criteria are not allowed. 
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the sites in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  
The Sponsor-Investigator is responsible for personally overseeing the treatment of all study 
subjects.  The Sponsor-Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all applicable 
regulations and guidelines regarding clinical trials both during and after study completion. 
The Sponsor-Investigator will be responsible for assuring that all the required data will be 
collected and properly documented. 
15.3 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
16 
PUBLICATION POLICY 
The Sponsor-Investigator must send a draft manuscript of the publication or abstract to Amgen 
and Incyte prior to submission of the final version for publication or congress presentation. All 
relevant aspects regarding data reporting and publication will be part of the contract between 
Amgen, Incyte and the Sponsor-Investigator. 


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The Sponsor-Investigator will ensure that the information regarding the study be publicly 
available on the internet at www.clinicaltrials.gov.  


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17 
REFERENCES 
1. Burger R, Bugdahn T, Staudinger M, et al. Preclinical activity of the JAK1/2 inhibitor 
ruxolitinib on malignant plasma cell growth and survival. J Clin Oncol 30, 2012 (suppl; abstr 
e18565)  
2. Orlowski RZ, Eswara JR, Lafond-Walker A, Grever MR, Orlowski M, Dang CV. Tumor 
growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome 
inhibitor. Cancer Res. 1998;58:4342-8. 
3. Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, et al. The 
proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug 
resistance in human multiple myeloma cells. Cancer Res. 2001;61:3071-6. 
4. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, et al. Molecular 
sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S 
A. 2002;99:14374-9. 
5. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T, et al. 
Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic 
applications. Blood. 2002;99:4079-86. 
6. Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, et al. The 
proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to 
conventional chemotherapeutic agents: therapeutic applications. Blood. 2003;101:2377-80. 
7. Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, et al. Potent activity of 
carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against 
preclinical models of multiple myeloma. Blood. 2007;110:3281-90. 
8. Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN, et al. Antitumor activity of 
PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67:6383-91. 
9. Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I 
trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. 
J Clin Oncol. 2002;20:4420-7. 
10. Orlowski RZ, Voorhees PM, Garcia RA, Hall MD, Kudrik FJ, Allred T, et al. Phase 1 trial of 
the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with 
advanced hematologic malignancies. Blood. 2005;105:3058-65. 
11. O'Connor OA, Stewart AK, Vallone M, Molineaux CJ, Kunkel LA, Gerecitano JF, et al. A 
phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome 
inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 
2009;15:7085-91. 
12. Alsina M, Trudel S, Furman RR, Rosen PJ, O'Connor OA, Comenzo RL, et al. A phase I 
single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor 
carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin 
Cancer Res. 2012;18:4830-40. 
13. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 
study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609-17. 


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14. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. 
Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 
2005;352:2487-98. 
15. Orlowski RZ, Nagler A, Sonneveld P, Blade J, Hajek R, Spencer A, et al. Randomized phase 
III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib 
alone in relapsed or refractory multiple myeloma: combination therapy improves time to 
progression. J Clin Oncol. 2007;25:3892-901. 
16. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. 
Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl 
J Med. 2008;359:906-17. 
17. Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, et al. A phase 2 study of 
single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple 
myeloma. Blood. 2012;120:2817-25. 
18. Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, et al. An open-label, 
single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive 
patients with relapsed and/or refractory multiple myeloma. Blood. 2012;119:5661-70. 
19. Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, et al. An open-
label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or 
refractory multiple myeloma who have been previously treated with bortezomib. Br J 
Haematol. 2012;158:739-48. 
20. Cenci S, Mezghrani A, Cascio P, Bianchi G, Cerruti F, Fra A, et al. Progressively impaired 
proteasomal capacity during terminal plasma cell differentiation. EMBO J. 2006;25:1104-13. 
21. Bianchi G, Oliva L, Cascio P, Pengo N, Fontana F, Cerruti F, et al. The proteasome load 
versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to 
proteasome inhibition. Blood. 2009;113:3040-9. 
22. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved 
survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-20. 
23. Brenner H, Gondos A, Pulte D. Expected long-term survival of patients diagnosed with 
multiple myeloma in 2006-2010. Haematologica. 2009;94:270-5. 
24. Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, et al. Long-term 
follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted 
by the intergroupe francophone du myelome, southwest oncology group, and university of 
arkansas for medical sciences. J Clin Oncol. 2010;28:1209-14. 
25. Usmani SZ, Crowley J, Hoering A, Mitchell A, Waheed S, Nair B, et al. Improvement in 
long-term outcomes with successive Total Therapy trials for multiple myeloma: are patients 
now being cured? Leukemia. 2013;27:226-32. 
26. Anderson KC. The 39th David A. Karnofsky Lecture: bench-to-bedside translation of 
targeted therapies in multiple myeloma. J Clin Oncol. 2012;30:445-52. 
27. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma 
relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma 


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working group study. Leukemia. 2012 Jan;26(1):149-57.Navon A, Ciechanover A. The 26 S 
proteasome: from basic mechanisms to drug targeting. J Biol Chem. 2009;284:33713-8. 
28. 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 Aug;17(8): e328-46. 
29. Kumar SK, Dimopolous MA, Kastritis E et al. Natural history of relapsed myeloma, 
refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG 
study. Leukemia (2017) 31, 2443–2448. 
30. Dimopolous MA, Goldschmidt H, Niesvizky R et al. Carfilzomib or bortezomib in relapsed 
or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an 
open-label, randomised, phase 3 trial. Lancet Oncol 2017; 18: 1327–37. 
 
 
 
 


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18 
APPENDICES 
18.1 ECOG Performance Scale 
 
Grade 
Description 
0 
Normal activity, fully active, able to carry on all pre-disease 
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 (e.g. 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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18.2 NCI CTCAE VERSION 4.03 
 
 
Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute 
(NCI) v4.03 
 
Publish Date: (v4.03: June 14, 2010)  
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
 
18.3 Response Criteria for Multiple Myeloma  
IMWG Response Criteria*  
IMWG MRD Criteria (Requires a complete response as defined below)  
Sustained MRD-
negative 
MRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined below, 
confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify 
the duration of negativity (eg, MRD-negative at 5 years)† 
Flow MRD-negative 
Absence of phenotypically aberrant clonal plasma cells by NGF‡ on bone marrow aspirates 
using the EuroFlow standard operation procedure for MRD detection in multiple myeloma 
(or validated equivalent method) with a minimum sensitivity of 1 in 10⁵ nucleated cells or 
higher 
Sequencing MRD-
negative 
Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a 
clone is defined as less than two identical sequencing reads obtained after DNA sequencing 
of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent 
method) with a minimum sensitivity of 1 in 10⁵ nucleated cells§ or higher 
Imaging-positive 
MRD-negative 
MRD negativity as defined by NGF or NGS plus disappearance of every area of increased 
tracer uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood 
pool SUV or decrease to less than that of surrounding normal tissue¶ 
Standard IMWG Response Criteria||; NOTE: see [28] for additional details 
Stringent Complete 
Response 
(sCR) 
• 
Complete response as defined below plus normal FLC ratio** and absence of clonal 
cells in bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for 
             κ and λ patients, respectively, after counting ≥100 plasma cells)†† 
Complete Response 
(CR) 
• 
Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and <5% plasma cells in bone marrow aspirates. In patients 
with only FLC disease, a normal FLC ratio of 0.26–1.65 is required.  
Very Good Partial 
Response 
• 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis 
or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg 


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(VGPR) 
per 24 h 
Partial Response 
(PR) 
• 
≥50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by 
≥90% or to <200 mg per 24 h; 
• 
If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria; 
• 
If serum and urine M-protein are unmeasurable, and serum-free light assay is also 
unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, 
provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to 
these criteria, if present at baseline, a ≥50% reduction in the size (SPD)§§ of soft 
tissue plasmacytomas is also required 
Minimal Response 
(MR) 
• 
≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein 
by 50–89%. In addition to the above listed criteria, if present at baseline, a ≥50% 
reduction in the size (SPD)§§ of soft tissue plasmacytomas is also required. 
Stable Disease (SD) 
• 
Not recommended for use as an indicator of response; stability of disease is best 
described by providing the time-to-progression estimates 
• 
Not meeting criteria for CR, VGPR, PR, MR or progressive disease 
Progressive disease 
(PD)¶¶, |||| 
Increase of > 25% from lowest response value in any one or more of the following: 
• 
Serum M-protein (absolute increase must be ≥0.5 g/dL); 
• 
Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL; 
• 
Urine M-protein (absolute increase must be ≥200 mg/24 h); 
• 
In patients without measurable serum and urine M-protein levels, the difference 
between involved and uninvolved FLC levels (absolute increase must be >10 
mg/dL); 
• 
In patients without measurable serum and urine M-protein levels and without 
measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of 
baseline status (absolute increase must be ≥10%); 
• 
Appearance of a new lesion(s), ≥50% increase from nadir in SPD§§ of >1 lesion, or 
≥50% increase in the longest diameter of a previous lesion >1 cm in short axis;  
• 
≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the 
only measure of disease 
r 
Clinical Relapse 
Clinical relapse requires one or more of the following criteria: 
• 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB 
features) related to the underlying clonal plasma-cell proliferative disorder. It is not 
used in calculation of TTP or PFS but is listed as something that can be reported 
optionally or for use in clinical practice; 
• 
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic 
fractures do not constitute progression); 
• 
Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and ≥1 cm) increase as measured serially by the 
SPD§§of the measurable lesion; 
• 
Hypercalcaemia (>11 mg/dL); 


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71 
 
• 
Decrease in haemoglobin of ≥2 g/dL not related to therapy or other non-myeloma-
related conditions; 
• 
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and 
attributable to myeloma; 
• 
Hyperviscosity related to serum paraprotein 
For MRD assessment, the first bone marrow aspirate should be sent to MRD (not for morphology) and this 
sample should be taken in one draw with a volume of minimally 2 mL (to obtain sufficient cells), but 
maximally 4–5 mL to avoid haemodilution. IMWG=International Myeloma Working Group. MRD=minimal 
residual disease. NGF=next-generation flow. NGS=next-generation sequencing. FLC=freelight chain. M-
protein=myeloma protein. SPD=sum of the products of the maximal perpendicular diameters of measured 
lesions. CRAB features=calcium elevation, renal failure, anaemia, lytic bone lesions. FCM=flow cytometry. 
SUVmax=maximum standardised uptake value. MFC=multiparameter flow cytometry. 18F-FDG PET=18F-
fluorodeoxyglucose PET. ASCT=autologous stem cell transplantation. 
* All response categories require two consecutive assessments made any time before starting any new 
therapy; for MRD there is no need for two consecutive assessments, but information on MRD after each 
treatment stage is recommended (e.g., after induction, high-dose therapy/ASCT, consolidation, 
maintenance). MRD tests should be initiated only at the time of suspected complete response. All categories 
of response and MRD require no known evidence of progressive or new bone lesions if radiographic studies 
were performed. However, radiographic studies are not required to satisfy these response requirements 
except for the requirement of FDG PET if imaging MRD-negative status is reported. †Sustained MRD 
negativity when reported should also annotate the method used (e.g., sustained flow MRD-negative, 
sustained sequencing MRD-negative).  
‡ Bone marrow MFC should follow NGF guidelines.30 The reference NGF method is an eight-colour two-
tube approach, which has been extensively validated. The two-tube approach improves reliability, 
consistency, and sensitivity because of the acquisition of a greater number of cells. The eight-colour 
technology is widely available globally and the NGF method has already been adopted in many flow 
laboratories worldwide. The complete eight-colour method is most efficient using a lyophilised mixture of 
antibodies which reduces errors, time, and costs. 5 million cells should be assessed. The FCM method 
employed should have a sensitivity of detection of at least 1 in 10⁵ plasma cells.  
§ DNA sequencing assay on bone marrow aspirate should use a validated assay such as LymphoSIGHT 
(Sequenta).  
¶ Criteria used by Zamagni and colleagues,85 and expert panel (IMPetUs; Italian Myeloma criteria for PET 
Use).81,97 Baseline positive lesions were identified by presence of focal areas of increased uptake within 
bones, with or without any underlying lesion identified by CT and present on at least two consecutive slices. 
Alternatively, an SUVmax=2.5 within osteolytic CT areas >1 cm in size, or SUVmax=1.5 within osteolytic CT 


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72 
 
areas ≤1 cm in size were considered positive. Imaging should be performed once MRD negativity is 
determined by MFC or NGS.  
|| Derived from international uniform response criteria for multiple myeloma.11 Minor response definition 
and clarifications derived from Raj Kumar and colleagues.14 When the only method to measure disease is by 
serum FLC levels: complete response can be defined as a normal FLC ratio of 0.26 to 1.65 in addition to the 
complete response criteria listed previously. Very good partial response in such patients requires a ≥90% 
decrease in the difference between involved and uninvolved FLC levels. All response categories require two 
consecutive assessments made at any time before the institution of any new therapy; all categories also 
require no known evidence of progressive or new bone lesions or extramedullary plasmacytomas if 
radiographic studies were performed. Radiographic studies are not required to satisfy these response 
requirements. Bone marrow assessments do not need to be confirmed. Each category, except for stable 
disease, will be considered unconfirmed until the confirmatory test is performed. The date of the initial test 
is considered as the date of response for evaluation of time dependent outcomes such as duration of 
response.  
** All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on 
results obtained with the validated Freelite test (Binding Site, Birmingham, UK).  
†† Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio. An abnormal 
κ/λ ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio 
reflecting presence of an abnormal clone is κ/λ of >4:1 or <1:2.  
‡‡ Special attention should be given to the emergence of a different monoclonal protein following treatment, 
especially in the setting of patients having achieved a conventional complete response, often related to 
oligoclonal reconstitution of the immune system. These bands typically disappear over time and in some 
studies have been associated with a better outcome. Also, appearance of monoclonal IgG κ in patients 
receiving monoclonal antibodies should be differentiated from the therapeutic antibody.  
§§ Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or 
dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be 
measured with a ruler. Measurement of tumour size will be determined by the SPD. 
¶¶ Positive immunofixation alone in a patient previously classified as achieving a complete response will not 
be considered progression. For purposes of calculating time to progression and progression-free survival, 
patients who have achieved a complete response and are MRD-negative should be evaluated using criteria 
listed for progressive disease. Criteria for relapse from a complete response or relapse from MRD should be 
used only when calculating disease-free survival.  


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73 
 
 
 
 
|||| In the case where a value is felt to be a spurious result per physician discretion (eg, a possible laboratory 
error), that value will not be considered when determining the lowest value. 
 


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74 
 
 
18.4 Estimated Creatinine Clearance rate (eCCr) using Cockcroft-Gault Formula 
 
 
 
 
 
 
 
 


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75 
 
18.5 Table of Events 
 
 
Evaluation 
 
Days -21 
to -1 
(Baseline) 
Phase I and Phase II 
All Cyclest (cycle = 28 days) 
Subjects in Phase II/Run-In period only: Please note cycle numbers will start 
over with ‘Cycle 1’ after initiation of ruxolitinib 
End of 
Treatmentq 
Follow-
upr 
Day 1 
Day 2x 
Day 8x 
Day 9x 
Day 15x 
Day 16x 
Day 22x 
 
 
Informed consent a 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
Medical and disease history b 
X 
 
 
 
 
 
 
 
 
 
Physical examination/BSA c 
X 
Xs 
 
 
 
 
 
 
X 
 
Vital signsd  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
Xs 
 
 
 
 
 
 
X 
 
Pregnancy test e 
X 
 
 
 
 
 
 
 
X 
 
Electrocardiogram  
X 
 
 
 
 
 
 
 
 
 
Echocardiogram, MUGA, or 
cardiac MRIf 
X 
X  
(prior to 
every 2 
cycles) 
 
 
 
 
 
 
         X. 
 
Hematology g 
X 
X s 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation h 
X 
X s 
 
 
 
 
 
 
 
 
Blood chemistries i 
X 
X s 
 
X 
 
X 
 
X 
X 
 
BNPw 
 
Xs 
 
 
 
 
 
 
 
 
Viral hepatitis panelv 
X 
 
 
 
 
 
 
 
 
 
HBV DNA testingy 
X 
 
 
 
 
 
 
 
 
 
Bone marrow j 
X 
(X) 
 
 
 
 
 
 
Xl 
(X)r 
Correlative studies  
(Blood and bone marrow)l 
X 
 
 
Xl 
 (Cycle 1 of 
ruxolitinib 
only; 
Blood only) 
 
 
 
Xl  
(Cycle 1 of 
ruxolitinib 
only day 20 
-27) 
Xl 
 
Response assessments 
(SPEP/UPEP, IFE, SFLC) k,u 
X 
X  
 
 
 
 
 
 
X 
(X)r 
Serum β2-microglobulin  
X 
 
 
 
 
 
 
 
 
 
Assessment of plasmacytomam 
X 
(X) 
 
 
 
 
 
 
(X) 
(X)r 
Bone skeletal surveyn 
X 
(X) 
 
 
 
 
 
 
(X) 
 
Carfilzomib administrationo 
 
X 
X 
X 
X 
X 
X 
 
 
 


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76 
 
Ruxolitinib administrationo 
 
Twice Daily days 1 – 28  
Phase I all subjects. Phase II: Subjects with < PR following Phase II/Run-In period, subjects ≥ PR 
following Phase II/Run-In period who then subsequently progress, and subjects who proceed 
directly to Phase II/Ruxolitinib  
 
 
Dexamethasone 
administrationo 
 
X 
 
X 
 
X 
 
 
 
 
Concomitant medications p 
X 
 
X 
 
Adverse event monitoring 
 
 
X 
 
Follow-up 
 
 
 
Xr 
 
(X) only if clinically indicated 
a) All subjects must sign an IRB-approved informed consent document prior to enrollment and prior to any study related procedures.  
b) Medical History including demographics, prior and current medical illness and conditions (including baseline symptoms and toxicities), prior surgical 
procedures. Disease history includes date of initial diagnosis, stage and extent of the disease, Prior anticancer therapy (types and response), surgery and/or 
radiation including documentation of sensitive or refractory status, (refractory defined as documented disease progression during or within 60 days of 
completing the last anti-myeloma regimen), and documentation of Proteasome Inhibitor refractory disease status. 
c) A complete physical exam, including height (screening only) and weight, neurologic assessment and assessment for extramedullary myeloma will be 
conducted at screening, day one of each cycle and End of Treatment visit. A symptom directed physical examination will be conducted as needed during 
a cycle.  Plasmacytomas that can be followed by physical exam are to be evaluated on day one of each cycle.  Weight to be measured on day one of each 
cycle with calculation of BSA (Subjects with a BSA > 2.2 m2 should receive a carfilzomib dose based on a 2.2 m2 BSA). Dose adjustments do not need 
to be made for weight changes of less than or equal to 20% from baseline weight. Baseline symptoms and residual toxicity from previous therapy assessed 
within 14 days prior to initiation of therapy.  
d) Vital signs including blood pressure, pulse, respiration rate, temperature.  To be performed prior to each carfilzomib infusion and as clinically indicated. 
e) For females of childbearing potential, a negative serum pregnancy test must be documented within 7 days and a negative urine pregnancy test within 3 
days of C1D1. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; 
or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
f) 
Echocardiogram, MUGA, or cardiac MRI to be performed at baseline, every 2 cycles (within5 days of Day 1), and end of therapy to calculate LVEF.  
Subjects who develop signs/symptoms of congestive heart failure at any point during the study are required to have an evaluation of LVEF measurements 
by ECHO, MUGA, or cardiac MRI, preferably by the same method used at screening. If echocardiogram, MUGA, or cardiac MRI is done within 2 months 
from End of Treatment visit, it does not need to be repeated. 
g) Hematology: hemoglobin, WBC with differential, and platelet count. 
h) Coagulation: prothrombin time (PT), international normalized ratio (INR). 
i) 
Blood chemistry:  sodium, chloride, potassium, magnesium, phosphate, uric acid, BUN, glucose (fasting at baseline), ALT/AST (SGPT/SGOT), alkaline 
phosphatase, total protein, total bilirubin, albumin, serum creatinine, and estimated creatinine clearance by Cockcroft-Gault Equations (Appendix 18.4) 
calcium and lactate dehydrogenase (LDH). Creatinine clearance required on days of the cycle other than Day 1 may be calculated using the Day 1 weight 
of the current cycle. 
j) 
Bone marrow aspirate to be collected at screening for % plasma cells, morphology, standard karyotype, cytogenetics by FISH and biomarkers. Repeat for 
% plasma cells at the time of CR and/or progression. Screening timepoint only: If bone marrow previously collected for pathology evaluation as previously 
described within 21 days prior to initiation of study therapy, the pathology evaluation does not need to be repeated as part of the screening 
assessments.  However, a bone marrow aspirate must be performed for correlative studies (see Footnote L for information on correlative studies).  


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77 
 
k) Serum or urine protein electrophoresis (SPEP, UPEP), serum and urine immunofixation (IFE) and serum free light chain (SFLC) assay.  To be conducted 
prior to each cycle (within 7 days of Day 1) until documentation of initial disease progression. For cycles delayed ≤ 7 days, repeat evaluations are not 
required.  If the start of a new cycle is delayed > 7 days a repeat disease evaluation must be performed prior to the subsequent cycle. Phase II/Run-In 
subjects who cross over to Phase II/Ruxolitinib only: Disease responses will be calculated from disease evaluation performed just prior to initiating 
ruxolitinib (a new baseline will be established). 
l) 
Blood and bone marrow samples will be collected for correlatives prior to study treatment initiation (collection is recommended after eligibility is 
established; baseline samples may be collected during screening or pre-treatment on C1D1); Cycle 1 of ruxolitinib, between Day 20-27; and at disease 
relapse or progression after ruxolitinib has been initiated. Blood only will be collected on C1D8 of ruxolitinib. These correlative labs include serum 
cytokines panel, peripheral blood mononuclear cells (PBMC) for proteasome inhibition, and PBMCs for JAK inhibition. Approximately 28 mLs of blood 
will be collected (please refer to the Correlative Guidelines for the type of tubes required) and will be sent to the LCI HOT lab. A minimum of 12 mL 
(first or second pull permitted) of bone marrow aspirate will be collected and sent to the LCI HOT lab. Note: ruxolitinib must have been initiated to collect 
correlative samples post-baseline (do not collect post-baseline correlative samples on subjects receiving study treatment in Phase II/Run-In period). Every 
effort should be made to collect post-baseline correlative samples prior to carfilzomib and dexamethasone administration; after the morning ruxolitinib 
dose and before the afternoon dose of ruxolitinib. Correlatives collected during screening do not need to be re-collected in the event that the screening 
period extends beyond 21 days. 
m) Known or suspected plasmacytomas are to be assessed at baseline, as clinically indicated and to confirm response and/or progression. FDG-PET is not 
required but suggested. The same method of evaluation should be used throughout the study (CT/MRI/PET). Phase II/Run-In subjects who cross over to 
Phase II/Ruxolitinb only: For subjects with plasmacytomas present at screening, imaging using the same modality utilized at screening will be repeated 
prior to initiating ruxolitinib (a new baseline will be established). 
n) Skeletal survey includes plain X-rays of (including skull, all long bones, pelvis and chest) required if previous survey >12 weeks from study entry and at 
any time when clinically indicated. 
o) See section 5 for complete details on study drug administration, dose modifications and start of a new cycle of therapy.  
p) Concomitant medications and procedures: - all procedures and medications within 14 days prior to first dose until 30 days after the last dose. 
q) End of Treatment visit should be completed within 30 days of last dose of study drug with evaluation of safety at 30 days or prior to initiation of subsequent 
therapy (whichever comes first) 
r) 
Subjects who received ruxolitinib on study and discontinue therapy for reasons other than disease progression should continue to have disease assessments 
per standard of care done until progression or start of subsequent therapy.  At such time, follow-up for overall survival status will take place every three 
months +/- 7 days until death, lost to follow-up, or until the criteria defined for the final analysis (Section 13.4.1) are reached. Follow-up beyond the safety 
follow-up period is only required for subjects who received ruxolitinib. Follow-up may be completed by phone contact. Death information from public 
sources, e.g. death registry, obituary listing, etc. can also be used when it is available and verifiable 
s) 
C1D1 procedures do not need to be repeated if the screening procedure occurred within 5 days (this applies to C1D1 following screening; does not apply 
to C1D1 of Phase II/Ruxolitinib in subjects who cross over from Phase II/Run-In); Day 1 procedures for subsequent cycles do not need to be repeated if 
done within 3 days of Day 1.  
t) 
+/- 3 day window permitted for holidays/administrative reasons 
u) Phase II/Run-In period only: Beginning with Cycle 1, disease evaluation results to assess response should be available for investigator review prior to 
dosing on Day 1 of each cycle (within 7 days of Day 1) until initiation of ruxolitinib (after ruxolitinib has been initiated, disease evaluation assessments 
will continue to be collected prior to dosing on Day 1, but results will not be required to be available prior to Day 1 dosing). Cycle numbers start over 
with the initiation of ruxolitinib and a new disease response baseline will be established. 
v) Viral hepatitis panel including HBsAg, HB core antibody, HB surface antibody, Hep C antibody and HIV at baseline only. 
w) BNP to be done Day 1 (+/- 3 days) of every cycle. 


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78 
 
x) A +/- 1 day window is allowed for study treatment on Days 2, 8, 9, 15, and 16 and procedures on Day 22, unless otherwise noted. All procedures required 
for Days 2, 8, 9, 15, and 16 should be performed within 1 day of study treatment, unless otherwise noted. 
y) For subjects with serologic evidence of resolved HBV infection (i.e. positive anti-HBs or positive anti-HBc) at Screening. HBV DNA testing by PCR 
must be performed locally. Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the only serologic marker) and a 
known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. 
 
 
 

ICF_000.pdf: 
Official  Title: L CI- H E M- M Y E- C R D- 0 0 4 ( M M R C- 0 7 3 C A RJ A K): P hase I /II St u dy of Carfilz o mi b, 
R u x oliti ni b, a n d L o w D ose De xa met has o ne f or Carfilz o mi b- Refract ory M ulti ple Myel o ma  
N C T 0 3 7 7 3 1 0 7 
I R B- A p pr o ve d Date: 1 1 / 2 2 / 2 0 2 2 




Levi ne C a ncer I nstit ute / Pr ot oc ol N u m ber L CI -H E M -M Y E -C R D -0 0 4  
P a ge 2  of 2 5  
 
S he bli Atr as h, M D, M S  
A dv arr a I R B A p pr ove d Versi o n 2 2 N ov 2 0 2 2  
 
Revise d 2 2 N ov 2 0 2 2  
 
 
 
 
 
 
T his st u dy is bei ng carrie d o ut u n der t he s p o ns ors hi p of Le vi ne Ca ncer I nstit ute ( L CI). A mge n a n d 
I ncyte are t he c o m pa nies s u p plyi ng dr ug a n d / or f u n di ng t hat will be use d i n t his st u dy. 
 
R u x oliti ni b is a ki nase i n hi bit or ( dr ug t hat bl oc ks e nzy mes f ueli ng ca ncer gr o wt h) t hat is F o o d a n d 
Dr ug A d mi nistrati o n ( F D A) a p pr o ve d f or myel ofi br osis ( dis or der t hat disr u pts n or mal bl o o d cell 
pr o d ucti o n) a n d p olycyt he mia vera ( pr o d ucti o n of t o o ma ny re d bl o o d cells) b ut is i n vestigati o nal 
( n ot F D A a p pr o ve d) i n m ulti ple myel o ma. Carfilz o mi b is a pr otease i n hi bit or ( dr ug t hat st o ps 
ca ncer cells fr o m gr o wi ng) a n d is F D A a p pr o ve d f or m ulti ple myel o ma.  De xa met has o ne is a 
c ortic oster oi d t hat pre ve nts t he release of s u bsta nces i n t he b o dy t hat ca use i nfla m mati o n a n d is 
F D A a p pr o ve d. 
 
Ta ki ng part i n t his st u dy is e ntirely v ol u ntary. 
 
P U R P O S E O F T H E R E S E A R C H S T U D Y  
 
T he p ur p ose of t his st u dy is t o deter mi ne if  treat me nt wit h carfilz o mi b, r u x oliti ni b a n d l o w- d ose 
de xa met has o ne i m pr o ve s pr ogressi o n free s ur vi val ( disease d oes n’t w orse n) i n patie nts wit h R R M M .   
 
I N F O R M A TI O N A B O U T T H E S T U D Y 
 
T his st u dy is bei ng d o ne beca use, des pite maj or a d va nces i n t hera py, m ulti ple myel o ma is still 
c o nsi dere d a n i nc ura ble ca ncer. T he maj ority of patie nts rela pse ( disease ret ur ns) wit h pr o gressi vely 
s h orter ti mes bet wee n eac h f oll o wi ng rela pse.  T here is a nee d t o i de ntify patie nts at hig h ris k of 
disease rela pse a n d de vel o p ne w treat me nts t hat e xte n d s ur vi val. T he fir st part ( P hase I) of t his st u dy 
will deter mi ne  t he m ost t olerate d d ose of r u x oliti ni b  i n c o m bi nati o n wit h 
carfilz o mi b / de xa met has o ne a n d t he sec o n d part ( P hase II) will  deter mi ne  t he safety a n d efficacy of 
t he st u dy treat me nt (carfilz o mi b / de xa met has o ne wit h or wit h o ut r u x oliti ni b) al o ng wit h e val uati o n 
of pr ogressi o n free s ur vi val (t he le ngt h of ti me d uri ng a n d after treat me nt of disease t hat a patie nt 
li ves wit h t he disease b ut it d oes n ot get w orse) a n d o verall s ur vi val. C orrelati ve tests ( meas ure 
relati o ns hi p bet wee n pr ocesses i n t he b o dy a n d t heir effect o n disease) usi ng b o ne marr o w (s oft 
tiss ue i nsi de b o ne) a n d bl o o d will als o be d o ne t o e val uate c o n necti o ns bet wee n cell a b n or malities, 
c ha nges i n bi ol ogy (str uct ure), a n d res p o nse t o treat me nt.  
 
Y o u will be o ne of u p t o 4 8 s u bjects partici pati ng i n t his st u dy. Y o ur partici pati o n is e x pecte d t o last 
a p pr o xi mately 5 years. 
 
 
 
W H A T WI L L H A P P E N D U RI N G T H E S T U D Y 
 
T o partici pate i n t his st u dy, y o u or y o ur legally a ut h orize d re prese ntati ve will nee d t o re vie w, sig n 
a n d date t his c o nse nt fr o m a n d pr o vi de a ut h orizati o n f or t he release of y o ur me dical rec or ds f or 
researc h p ur p oses. By d oi ng s o, y o u are gi vi ng us per missi o n t o deter mi ne if y o u are eligi ble t o 
partici pate i n t his st u dy. T o deter mi ne if y o u are eligi ble (scree ni ng) , t he f oll o wi ng pr oce d ures /tests 


Levi ne C a ncer I nstit ute / Pr ot oc ol N u m ber L CI -H E M -M Y E -C R D -0 0 4  
P a ge 3  of 2 5  
 
S he bli Atr as h, M D, M S  
A dv arr a I R B A p pr ove d Versi o n 2 2 N ov 2 0 2 2  
 
Revise d 2 2 N ov 2 0 2 2  
 
 
 
 
 
 
will be d o ne . If y o u ha ve ha d s o me of t he tests or pr oce d ures bel o w rece ntly, t hey may n ot nee d t o 
be re peate d at scree ni ng : 
 
 
B ef or e y o u b e gi n t h e st u d y ( B as eli n e):  
 
•  Me dical a n d disease hist ory  
•  P hysical e xa m  
•  Vital sig ns ( b o dy te m perat ure, breat hi ng  rate, p ulse, bl o o d press ure) 
•  E C O G perf or ma nce stat us  (assesses daily li vi ng a bilities)  
•  Preg na ncy test s ( bl o o d a n d uri ne) f or fe males of c hil d beari ng p ote ntial 
•  Electr ocar di ogra m ( E C G) – a meas ure of t he heart’s electrical acti vity 
•  E C H O (ec h ocar di ogra m  – heart test d o ne usi ng s o u n d wa ves), M U G A ( m ultigate d  
ac q uisiti o n sca n - c hec ks t he p u m pi ng acti o n of t he heart) or car diac M RI  (mag netic 
res o na nce i magi ng of t he heart – pict ures ma de usi ng str o ng mag nets a n d a c o m p uter) 
•  C hec k f or c o nc o mita nt me dicati o n s (all o ng oi ng me dicati o ns a n d t h ose ta ke n wit hi n 1 4 days 
pri or t o first d ose)  
•  B o ne marr o w bi o psy / as pirate (sa m ple) f or disease e val uati o n a n d c orrelati ve st u dies  
•  Bl o o d dra w f or disease e val uati o n a n d t o c hec k bl o o d c o u nt, bl o o d c he mistries, bl o o d 
cl otti ng a bility a n d f or c orrelati ve st u dies. Bl o o d will als o be teste d f or HI V a n d he patitis 
(li ver disease). 
•  Uri ne sa m ple  c ollecte d o ver a 2 4- h o ur peri o d 
•  P E T / C T ( p ositr o n e missi o n t o m ogra p hy /c o m p ute d t o m ogra p hy – s pecial ty pes of x-rays) 
sca n or M RI ( mag netic res o na nce i ma gi ng – pict ures ma de usi n g str o ng mag nets a n d a 
c o m p uter) if y o ur p hysicia n feels it is necessary t o e val uate y o ur disease 
•  B o ne s keletal s ur vey ( vari o us x-rays of all t he b o nes i n t he b o dy) 
 
D uri n g t h e st u d y:  
 
All st u dy treat me nt will be gi ve n o n a n o ut patie nt basis.  If y o u are ha vi ng u nfa v ora ble si de effects, 
t he st u dy treat me nt may be st o p pe d f or a w hile, or t he d ose of t he st u dy dr u g may be re d uce d. Y o ur 
st u dy d oct or will als o disc uss wit h y o u w het her it is i n y o ur best i nterest t o c o nti n ue t he treat me nt 
wit h t he s t u dy dr ugs. Y o u will c o nti n ue treat me nt u ntil y o ur disease pr ogresses ( o nce y o u ha ve 
starte d r u x oliti ni b) or treat me nt is st o p pe d f or a ny reas o n. Y o u will recei ve a d diti o nal a nti viral 
me dicati o ns w hile recei vi ng st u dy treat me nt t o pre ve nt reacti vati o n of V Z V ( varicella z oster vir us).  
 
P h as e I  
If y o u are partici pati ng i n t he P hase I p orti o n of t his st u dy, y o u will be place d i n o ne of t hree gr o u ps 
i n or der t o deter mi ne t he ma xi m u m t olerate d d ose ( M T D) of t he st u dy dr ug r u x oliti ni b. T his 
pr oce d ure is k n o w n as d ose escalati o n.  Eac h cycle lasts 2 8 days. Pri or t o eac h carfilz o mi b d ose, y o u 
will recei ve a d diti o nal a nti viral me dicati o ns, t o pre ve nt reacti vati o n of V Z V ( varicella z oster vir us  


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[s hi ngles]). N ote: If y o u are 7 5 years of age or ol der a n d / or dia betic, y o u may recei ve 2 0 mg of 
de xa met has o ne i nstea d of 4 0 mg (see bel o w).  
 
•  If y o u are i n gr o u p o ne, y o u will recei ve 5 6 mg /m
2 carfilz o mi b t hr o ug h a n I V (i ntra ve n o us – 
t hr o ug h a vei n) o ver 3 0 mi n utes o n Days 1, 2, 8, 9, 1 5 a n d 1 6 of all cy cles. Y o u will recei ve 
4 0 mg de xa met has o ne orally ( by m o ut h) o n Days 1, 8, a n d 1 5 of all cycles a n d  5 mg  
r u x oliti ni b orally wit h or wit h o ut f o o d t wice daily f or 2 8 days.  
•  If y o u are i n gr o u p t w o, y o u will recei ve 5 6 mg / m 2 of carfilz o mi b t hr o ug h a n I V o ver 3 0 
mi n utes o n Days 1, 2, 8, 9, 1 5 a n d 1 6 of all cycles. Y o u will recei ve 4 0 mg dexa met has o ne 
orally  o n Days 1, 8 a n d 1 5 of all cycles a n d 1 0 mg r u x oliti ni b orally wit h or wit h o ut f o o d 
t wice daily f or 28 days.  
•  If y o u are i n gr o u p t hree, y o u will recei ve 5 6 mg / m2 carfilz o mi b t hr o ug h a n I V o ver 3 0 
mi n utes o n Days 1, 2, 8, 9, 1 5 a n d 1 6 of all cycles. Y o u will recei ve 4 0 mg dexa met has o ne 
orally o n Days 1, 8 a n d 1 5 of all cycles a n d 1 5 mg r u x oliti ni b orally wit h or wit h o ut f o o d 
t wice daily f or 28 days.  
 
T he f oll o wi ng tests a n d / or pr oce d ures will be d o ne w he n y o u c o me t o t he cli nic f or treat me nt:  
•  P hysical e xa m ( Day 1 of eac h cycle)  
•  Vital sig ns  ( pri or t o eac h i nf usi o n of carfilz o mi b) 
•  E C O G perf or ma nce stat us ( Day 1 of eac h cycle)  
•  Bl o o d dra w t o c hec k bl o o d cell c o u nts, bl o o d c he mistries, bl o o d cl otti ng a bilities, car diac 
bi o mar kers (e val uates heart f u ncti o n),  a n d disease res p o nse ( Day 1 of eac h cycle). Bl o o d 
dra w t o c hec k cell c o u nts pri or t o eac h carfilz o mi b as i nf usi o n as well as Day 2 2 a n d bl o o d 
c he mistries o n Days 1, 8, 1 5 a n d 2 2 of eac h cycle.  
•  E C H O , M U G A  or car diac M RI  (Day 1 of e very 2 cycles) 
•  B o ne marr o w as pirate f or researc h p ur p oses ( Cycle 1 bet wee n Day 2 0-2 7 of r u x oliti ni b  
treat me nt a n d at disease rela pse or pr ogressi o n after r u x oliti ni b has bee n starte d) a n d 
a d diti o nally if cli nically i n dicate d 
•  Bl o o d dra w f or researc h p ur p oses ( Day 8 a n d bet wee n Day 2 0 - 2 7 of Cycle 1 of r u x oliti ni b 
treat me nt a n d at disease rela pse or pr ogre ssi o n after r u x oliti ni b has bee n starte d) 
•  U ri ne c ollecti o n sa m ple f or disease e val uati o n ( Day 1 of all cycles u ntil disease pr ogressi o n)  
 
T he p hase I p orti o n of t he st u dy is e x pecte d t o be n o l o nger t ha n 1 2 m o nt hs. 
 
 
P h as e II  
If y o u are partici pati ng i n t he p hase II p orti o n of t he st u dy: 
 
If y o u pre vi o usly recei ve d carfilz o mi b at a d ose greater t ha n or e q ual t o 5 6 mg / m 2, y o u will  begi n 
2 8 -day treat me nt cycles wit h carfilz o mi b  (I V)/ de xa met has o ne ( by m o ut h)/r u x oliti ni b  (by m o ut h ) 
regi me n u ntil y o ur disease pr ogresses. R u x oliti ni b will be gi ve n at t he M T D le vel esta blis he d i n 
P hase 1 – eit her 5, 1 0 or 1 5 mg t wice daily. If y o u pre vi o usly recei ve d carfilz o mi b less t ha n 5 6 


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mg / m
2, y o u will begi n a 2 8 -day treat me nt cycle  ( Cycle 1) wit h 5 6 mg / m 2 carfilz o mi b t hr o ug h a n I V 
o ver 3 0 mi n utes o n Days 1, 2, 8, 9, 1 5 a n d 1 6 . Y o u will als o recei ve 4 0 mg de xa met has o ne orally ( by 
m o ut h) P O  o n Days 1, 8, a n d 1 5.  If y o u are 7 5 years of age or ol der a n d / or dia betic, y o u may 
recei ve 2 0 mg of de xa met has o ne i nstea d of 4 0 mg. 
 
If y o ur disease res p o n ds well t o t he carfilz o mi b / de xa met has o ne treat me nt after Cycle 1, y o u  will 
c o nti n ue o n 2 8-day cycles of carfilz o mi b / de xa met has o ne  as descri be d a b o ve u ntil disease 
pr ogressi o n, y o u deci de y o u n o l o nger wis h t o recei ve st u dy treat me nt, or y o ur st u dy d oct or deci des 
it is i n y o ur best i nterest t o st o p st u dy treat me nt. If y o ur disease pr ogresses o n t he 
carfilz o mi b / de xa met has o ne, y o u will be gi ve n t he o pti o n t o ha ve r u x oliti ni b (at t he M T D le vel 
esta blis he d i n P hase I- eit her 5, 1 0, or 1 5 mg ta ke n orally t wice a day) a d de d t o t he 
carfilz o mi b / de xa met has o ne treat me nt regi me n. If y o u c h o ose t o a d d r u x oliti ni b t o t he 
carfilz o mi b / de xa met has o ne, y o u will c o nti n ue t his regi me n u ntil disease pr ogressi o n, y o u deci de 
y o u n o l o nger wis h t o recei ve st u dy treat me nt, or y o ur st u dy d oct or deci des it is i n y o ur best i nterest 
t o st o p st u dy treat me nt. 
 
If y o ur disease d oes n ot res p o n d well t o t he treat me nt after Cycle 1, y o u will t he n ha ve r u x oliti ni b  
(at t he M T D le vel esta blis he d i n P hase 1 – eit her 5, 1 0 or 1 5 mg P O  t wice daily) a d de d t o t he 
carfilz o mi b / de xa met has o ne treat me nt regi me n a n d will c o nti n ue t his treat me nt regi me n u ntil 
disease pr ogressi o n or y o ur st u dy d oct or deci des it is i n y o ur best i n terest t o st o p st u dy treat me nt. 
 
T he f oll o wi ng tests a n d / or pr oce d ures will be d o ne w he n y o u c o me t o t he cli nic f or treat me nt:  
 
•  P hysical e xa m ( Day 1 of eac h cycle)  
•  Vital sig ns  
•  E C O G perf or ma nce stat us ( Day 1 of eac h cycle)  
•  Bl o o d dra w t o c hec k bl o o d cell c o u nts, bl o o d c he mistries, bl o o d cl otti ng a bilities, car diac 
bi o mar kers (e val uates heart f u ncti o n), a n d disease res p o nse ( Day 1 of eac h cycle). Bl o o d 
dra w t o c hec k cell c o u nts pri or t o eac h carfilz o mi b as i nf usi o n as well as Day 2 2 a n d bl o o d 
c he mistries o n Days 1, 8, 1 5 a n d 2 2 of eac h cycle.  
•  E C H O , M U G A  or car diac M RI  (Day 1 of e very 2 cycles) 
•  B o ne marr o w as pirate f or researc h p ur p oses ( Cycle 1 bet wee n Day 2 0-2 7 of r u x oliti ni b  
treat me nt a n d at disease rela pse or pr ogressi o n after r u x oliti ni b has bee n starte d) a n d 
a d diti o nally if cli nically i n dicate d 
•  Bl o o d dra w f or researc h p ur p oses ( Day 8 a n d bet wee n Day 2 0 - 2 7 of Cycle 1 of r u x oliti ni b 
treat me nt a n d at disease rela pse or pr ogressi o n after r u x oliti ni b has bee n starte d) 
•  U ri ne c ollecti o n sa m ple f or disease e val uati o n ( Day 1 of all cycles u ntil disease pr ogressi o n) 
 
T he f oll o wi ng tests may be d o ne at a ny ti me w hile y o u are recei vi ng st u dy treat me nt (eit her P hase I 
or P hase II) o nly if cli nically i n dicate d as deter mi ne d by y o ur st u dy d oct or: 
 
 


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•  B o ne s keletal s ur vey  
•  B o ne marr o w bi o psy /as pirate (sa m ple) f or disease e val uati o n  
•  P E T / C T sca n or M RI  
•  B o ne marr o w as pirate f or disease e val uati o n  
•  Uri ne c ollecti o n sa m ple t o c hec k disease res p o nse  
 
T he p hase II p orti o n of t he st u dy is e x pecte d t o be n o l o nger t ha n 2 4 m o nt hs. 
 
Aft er y o u c o m pl et e t h e i nt er v e nti o n  ( eit h er P h as e I or  P h as e II ): 
 
A n e n d of treat me nt visit will be d o ne w he n y o u st o p st u dy treat me nt f or a ny reas o n. D uri ng t his 
visit, t he f oll o wi ng pr oce d ures a n d tests will be d o ne: 
 
•  P hysical e xa m  
•  Vital sig ns  
•  E C O G perf or ma nce stat us  
•  Preg na ncy test ( uri ne or bl o o d) f or fe males of c hil d beari ng p ote ntial 
•  E C H O , M U G A  or car diac M RI  
•  Bl o o d dra w t o c hec k bl o o d cell c o u nts, bl o o d c he mistries a n d disease res p o nse 
•  Uri ne c ollecti o n sa m ple t o c hec k disease res p o nse (if cli nically i n dicate d)  
•  B o ne s keletal s ur vey (if cli nically i n dicate d)  
•  B o ne marr o w bi o psy / as pirate f or disease e val uati o n (if cli nically i n dicate d) 
 
T hr o u g h o ut t h e st u d y:  
 
T he f oll o wi ng test will be d o ne w hile y o u are recei vi ng st u dy treat me nt  ( Cycle 1 Day 2 0 – Day 2 7) or 
d uri ng f oll o w- u p if y o ur disease rela pses (ret ur ns) or has pr ogresse d (g otte n w orse) after y o u ha ve 
beg u n treat me nt wit h r u x olit i ni b: 
 
•  B o ne marr o w bi o psy /as pirate f or c orrelati ve st u dies  
 
 
F oll o w- u p:  
 
If y o u recei ve d r u x oliti ni b i n t he st u dy a n d y o u st o p st u dy treat me nt f or a ny reas o n ot her t ha n 
disease pr ogressi o n, y o u s h o ul d c o nti n ue t o ha ve m o nt hly disease assess me nts at y o ur st u dy d oct or’s 
discreti o n  d o ne u ntil y o ur disease w orse ns or y o u start a n ot her ca ncer t hera py. Y o u will be f oll o we d 
f or at least 3 years fr o m t he day y o u starte d r u x oliti ni b a n d p ossi bly l o nger u ntil Le vi ne Ca ncer 
I nstit ute deter mi nes f oll o w- u p is n o l o nger re q uire d.  Y o u will be c o ntacte d by p h o ne o nce e very 3 
m o nt hs if y o u are n ot see n i n t he cli nic. Y o u will be n otifie d w he n f oll o w- u p is n o l o nger re q uire d. 
 


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If y o u d o n ot recei ve r u x oliti ni b o n t he st u dy, y o u will be f oll o we d f or si de effects f or at least 3 0 
days after y o ur last d ose of st u dy treat me nt. After t his safety m o nit ori ng peri o d has e n de d, y o ur 
partici pati o n o n t he st u dy will be c o m plete.  
 
Y O U R R O L E I N T H E S T U D Y  
 
Ta ki ng part i n a researc h st u dy ca n be a n i nc o n ve nie nce t o y o ur daily life.  Please c o nsi der t he st u dy 
ti me c o m mit me nts a n d res p o nsi bilities as a researc h s u bject w he n y o u are deci di ng t o ta ke part.  
Y o ur res p o nsi bilities as a st u dy s u bject i ncl u de t he f oll o wi ng: 
 
•  Tell t he tr ut h a b o ut y o ur me dical hist ory a n d c urre nt c o n diti o ns. 
•  Tell t he st u dy d oct or if y o u ha ve bee n i n a researc h st u dy i n t he last 3 0 days or are i n 
a n ot her researc h st u dy n o w. 
•  Tell t he st u dy d oct or a b o ut a ny pr o ble ms y o u ha ve d uri ng t he st u dy. 
•  Ta ke t he st u dy dr ug as directe d by t he st u dy d oct or a n d st u dy staff.  
•  D o n ot s hare t he st u dy dr ug wit h a ny o ne else.  Kee p t he st u dy dr ug o ut of t he reac h of 
c hil dre n a n d pers o ns of li mite d ca pacity t o rea d or u n dersta n d. 
•  T he st u dy d oct or or st u dy staff will tal k t o y o u a b o ut a ny f o o d or me dici nes t hat y o u s h o ul d 
n ot ta ke w hile i n t his st u dy.  
•  Use care w he n dri vi ng or usi ng mac hi nery w hile y o u are ta ki ng t he st u dy dr ug.  
 
RI S K S  O F T H E S T U D Y 
 
Y o u may ha ve si de effects w hile y o u are o n t his st u dy. E very o ne ta ki ng part i n t he st u dy will be 
caref ully watc he d f or si de effects. H o we ver, si de effects may occ ur t hat are n ot yet k n o w n.  
 
Si de effects ca n be mil d or very seri o us. Y o ur healt hcare tea m may  gi ve y o u me dici nes t o lesse n si de 
effects. Ma ny si de effects g o a way after y o u st o p ta ki ng t he st u dy dr ugs. I n s o me cases, si de effects 
ca n be seri o us i n t hat t hey ca n be l o ng lasti ng, may ne ver g o a way, may res ult i n h os pitalizati o n, or 
may res ult i n deat h.  
 
Y o u s h o ul d tal k t o y o ur st u dy d oct or a b o ut a ny si de effects t hat y o u ha ve w hile ta ki ng part i n t he 
st u dy. 
 
C arfil z o mi b  Si d e Eff e cts : 
 
Y o u will be t ol d a b o ut t he k n o w n ris ks, w hic h are t he si de effects re p orte d pre vi o usly by ot hers w h o 
t o o k carfilz o mi b. H o we ver, y o ur st u dy d oct ors d o n ot k n o w all t he si de effects t hat y o u may 
e x perie nce. As wit h all i n vestigati o nal dr ugs, all ris ks may n ot ha ve bee n i de ntifie d at t his ti me. T here 
may be seri o us u ne x pecte d or u nf oresee n ris ks w hile ta ki ng carfilz o mi b, i n cl u di ng deat h. It is k n o w n 
t hat nearly e very o ne w h o ta kes carfilz o mi b will ha ve s o me si de effects w hile o n t he st u dy dr ug. 
Ma ny of t hese si de effects may be mil d b ut s o me si de effects ca n be seri o us a n d e ve n fatal.  


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Bef ore y o u ta ke carfilz o mi b, y o ur st u dy d oct or nee ds t o k n o w if y o u ha ve a ny:  
•  Heart pr o ble ms, i ncl u di ng a hist ory or c hest pai n, heart attac k, heart fail ure, 
hig h bl o o d press ure, irreg ular heart beat, or if y o u ha ve e ver ta ke n a me dici ne 
f or y o ur heart 
•  L u ng pr o ble ms, i ncl u di ng a hist ory of s h ort ness of breat h at rest or wit h acti vity  
•  Ki d ney pr o ble ms, i ncl u di ng ki d ney fail ure or if y o u ha ve e ver recei ve d dialysis  
•  Li ver pr o ble ms, i ncl u di ng a hist ory of he patitis; partic ularly pre vi o us he patitis B 
vir us i nfecti o n, fatty li ver, or if y o u ha ve e v er bee n t ol d y o ur li ver is n ot 
w or ki ng pr o perly 
•  U n us ual blee di ng, i ncl u di ng easy br uisi ng, blee di ng fr o m a n i nj ury, s uc h as a c ut 
t hat d oes n ot st o p blee di n g i n a n or mal a m o u nt of ti me, or i nter nal blee di ng, 
w hic h ca n i n dicate y o u ha ve l o w platelets  
•  Bl o o d cl ots i n y o ur vei ns 
•  A ny ot her maj or disease f or w hic h y o u were h os pitalize d or recei ve d me dicati o n  
 
Please n otify y o ur st u dy d oct or as s o o n as p ossi ble if y o u e x perie nce bl urre d or d o u ble visi o n, visi o n 
l oss, diffic ulty s pea ki ng, wea k ness i n a n ar m or a leg, a c ha nge i n t he way y o u wal k, pr o ble ms wit h 
y o ur bala nce, persiste nt n u m b ness, decrease d se nsati o n or l oss of se nsati o n, decrease d alert ness, 
me m ory l oss or c o nf usi o n w hic h may be sy m pt o ms of a ce ntral ner v o us syste m i nfecti o n k n o w n as 
Pr ogressi ve M ulti f ocal Le u k oe nce p hal o pat hy ( P M L). 
 
Very C o m m o n  ( may affect m ore t ha n 1 i n 1 0 pe o ple): 
•  L o w re d bl o o d cell c o u nt, w hic h may ca use tire d ness 
•  L o w platelets, w hic h may ca use easy br uisi ng or pr ol o nge d blee di ng  
•  L o w w hite bl o o d cell c o u nt, w hic h may decrease y o ur a bility t o fig ht i nfecti o n  
•  S h ort ness of breat h 
•  C o ug h, c o ug h wit h p hleg m 
•  Diarr hea  
•  Q ueasy /feeli ng li ke y o u nee d t o t hr o w u p ( na usea)  
•  C o nsti pati o n 
•  V o miti ng  
•  Tire d ness (fatig ue)  
•  Fe ver  
•  S welli ng of t he ha n ds, feet or a n kles 
•  Ge neral wea k ness  
•  Res pirat ory tract i nfecti o n  
•  L u ng i nfecti o n ( p ne u m o nia)  
•  I nfecti o n of t he t u bes of t he l u ngs ( br o nc hitis)  
•  I nfla m mati o n of t he n ose a n d t hr oat 


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•  Decrease d a p petite  
•  Bac k pai n, j oi nt pai n, pai n i n li m bs, ha n ds or feet 
•  M uscle s pas ms 
•  Hea dac he  
•  Dizzi ness  
•  N u m b ness 
•  I ns o m nia ( diffic ulty slee pi ng) 
•  C ha nges t o bl o o d tests ( decrease d bl o o d le vels of p otassi u m, i ncrease d bl o o d le vels of 
creati ni ne) 
•  Hig h bl o o d press ure ( hy perte nsi o n) 
 
Less C o m m o n ( may affect u p t o 1 i n 1 0 pe o ple): 
•  Fe ver ass ociate d wit h l o w w hite bl o o d cell c o u nt  
•  Heart fail ure , a n d heart pr o ble ms i ncl u di ng ra pi d, str o ng or irreg ular heart beat. T he ris k of 
de vel o pi ng heart fail ure w he n recei vi ng carfilz o mi b is hig her if y o u are 7 5 years of age or 
ol der. T his ris k is als o hig her if y o u are Asia n 
•  Heart attac k  
•  Bl o o d cl ot i n t he l u ngs  
•  Fl ui d i n t he l u ngs 
•  N ose blee d  
•  C ha nge i n v oice or h oarse ness 
•  Pai n i n  t hr oat 
•  W heezi ng 
•  P ul m o nary hy perte nsi o n, sy m pt o ms i ncl u de s h ort ness of breat h wit h  e very day acti vities or at 
rest, irreg ular heart beat, raci ng p ulse, tire d ness, dizzi ness, a n d fai nti ng s pells 
•  Bl urre d visi o n  
•  Cataract (cl o u di ng of t he le ns of t he eye)  
•  St o mac h pai n  
•  I n digesti o n 
•  
T o ot hac he  
•  C hills, pai n, feeli ng u n well  
•  I nf usi o n site reacti o ns s uc h as pai n, s welli ng, irritati o n or disc o mf ort w here y o u recei ve d t he 
st u dy dr ug i njecti o n i nt o y o ur vei n 
•  Li ver pr o ble ms i ncl u di ng a n a b n or mal i ncrease i n y o ur li ver e nzy mes i n t he bl o o d 
•  R u n ny n ose or nasal c o ngesti o n 
•  Uri nary tract i nfecti o n  
•  Fl u -li ke sy m pt o ms (i nfl ue nza) 
•  Seri o us i nfecti o n i n t he bl o o d (se psis) 


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•  Viral i nfecti o n  
•  I nfecti o n a n d / or irritati o n of y o ur st o mac h a n d b o wels 
•  L u ng i nfecti o n  
•  De hy drati o n (lac k of fl ui ds)  
•  B o ne a n d m uscle pai n  
•  C hest pai n  
•  M uscle wea k ness  
•  Ac hi ng m uscles 
•  A b n or mal se nsati o n s uc h as ti ngli ng or decrease d se nsati o n i n ar ms a n d / or legs 
•  A n xiety  
•  Ki d ney pr o ble ms, i ncl u di ng decrease d a bility t o ma ke uri ne,  i ncrease d creati ni ne i n t he 
bl o o d, a n d ki d ney fail ure nee di ng dialysis  
•  Ras h, itc hy s ki n, re d ness of t he s ki n 
•  I ncrease d s weati ng 
•  C ha nges t o bl o o d tests ( decrease d bl o o d le vels of s o di u m, mag nesi u m,  pr otei n, calci u m or 
p h os p hate, i ncrease d bl o o d le vels of s ugars, calci u m, uric aci d, p otassi u m bilir u bi n, or c-
reacti ve pr otei n) 
•  L o w bl o o d press ure ( hy p ote nsi o n) 
•  Leg pai n ( w hic h c o ul d be a sy m pt o m of bl o o d cl ots i n t he dee p vei ns of t he leg), c hest pai n 
or s h ort ness of breat h ( w hic h may be a sy m pt o m of bl o o d cl ots i n t he l u ngs)  
•  Fl us hi ng (s ki n or face bec o me re d a n d h ot) 
•  Ri ngi ng i n t he ears  
•  A reacti o n t o carfilz o mi b i nf usi o n, w hic h ca n i ncl u de t he f oll o wi ng sy m pt o ms: fe ver, c hills 
or s ha ki ng, j oi nt pai n, m uscle pai n, facial re d, h ot s ki n or s welli ng, s welli ng of t he t hr oat, 
wea k ness, s h ort ness of breat h, l o w bl o o d press ure, fai nti ng, c hest tig ht ness, or c hest pai n.  
 
U nc o m m o n  ( may affect u p t o 1 i n 1 0 0 pe o ple): 
•  Blee di ng, br uisi ng, wea k ness, c o nf usi o n, fe ver, na usea, v o miti ng a n d diarr hea, a n d ac ute 
ki d ney fail ure, w hic h may be sig ns of a bl o o d c o n diti o n k n o w n as T hr o m b otic 
Micr oa ngi o pat hy (i ncl u di ng T hr o m b otic T hr o m b ocyt o pe nic P ur p ura [ T T P]) 
•  S u d de n l oss of heart f u ncti o n 
•  Re d uce d bl o o d fl o w t o t he heart  
•  A b n or mal a m o u nt of fl ui d bet wee n t he heart a n d t he li ni ng ar o u n d t he heart  
•  Heart m uscle disease w hic h may ca use s h ort ness of breat h a n d tire d ness 
•  S welli ng a n d irritati o n of t he li ni ng ar o u n d t he heart  
•  L u ng pr o ble ms, sy m pt o ms i ncl u de diffic ulty breat hi ng, i ncl u di ng s h ort ness of breat h  
( dys p nea) at rest or wit h acti vity or a c o ug h, ra pi d breat hi ng, feeli ng li ke y o u ca n't breat he i n 
e n o ug h air, w heezi ng, or c o ug h. 


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•  Blee di ng i n t he l u ngs 
•  Blee di ng i n t he st o mac h a n d b o wels  
•  Bl oc kage of t he i ntesti nes  
•  I nfla m mati o n of t he pa ncreas gla n d 
•  M ulti orga n  fail ure 
•  Yell o wi ng of y o ur s ki n a n d eyes, st o mac h pai n or s welli ng, q ueasy /feeli ng li ke y o u nee d t o 
t hr o w u p or v o miti ng, w hic h c o ul d be sig ns of li ver pr o ble ms, i ncl u di ng li ver fail ure. If y o u 
ha ve pre vi o usly ha d he patitis B vir us i nfecti o n, st u dy treat me nt wit h carfilz o mi b may ca use 
he patitis B vir us i nfecti o n t o bec o me acti ve agai n  
•  Li ver fail ure  
•  Itc hy s ki n, yell o w s ki n, very dar k uri ne a n d very pale st o ols w hic h may be ca use d by a 
bl oc kage i n t he fl o w of bile fr o m t he li ver  (c h olestasis) 
•  Se vere i nfecti o n of t he bl o o d ca usi ng l o w bl o o d press ure a n d l o w bl o o d fl o w t o t he differe nt 
orga ns 
•  Irreg ular heart beat, ki d ney fail ure or a b n or mal bl o o d test res ults w hic h may be ass ociate d 
wit h T u m or Lysis Sy n dr o me, a c o n diti o n t hat ca n occ ur after treat me nt of a fast -gr o wi ng 
ca ncer. As t u m or cells die, t hey brea k a part a n d release t heir c o nte nts i nt o t he bl o o d. T his 
ca uses a c ha nge i n certai n c he micals i n t he bl o o d, w hic h may ca use da mage t o orga ns, 
i ncl u di ng t he ki d neys, heart, a n d li ver  
•  Blee di ng i n t he brai n 
•  Hea dac hes, c o nf usi o n, seiz ures, bli n d ness, a n d hig h bl o o d press ure ( hy perte nsi o n), w hic h 
may be sy m pt o ms of a ne ur ol ogic c o n diti o n k n o w n as P osteri or Re versi ble E nce p hal o pat hy 
Sy n dr o me ( P R E S)  
•  Allergy t o  carfilz o mi b 
•  Str o ke  
•  Blee di ng 
•  E xtre mely hi g h bl o o d press ure, se vere c hest pai n, se vere hea dac he, c o nf usi o n, bl urre d visi o n, 
q ueasy /feeli ng li ke y o u nee d t o t hr o w u p a n d v o miti ng, or se vere a n xiety, ca n be sig ns f or a 
c o n diti o n k n o w n as hy perte nsi ve  crisis 
 
Rare  ( may affect u p t o 1 i n 1 0 0 0 pe o ple): 
•  He m olytic ure mic sy n dr o me ( H U S) (c o n diti o n t hat ca n occ ur w he n s mall bl o o d 
vessels i n y o ur ki d neys bec o me da ma ge d a n d i nfla me d w hic h ca n ca use cl ots t o 
f or m res ulti ng i n ki d ney fail ure, w hic h c o ul d be life-t hreate ni ng) 
•  S welli ng a n d irritati o n of t he li ni ng ar o u n d t he heart 
•  S welli ng of t he t hr oat  
•  H ole i n t he st o mac h, s mall i ntesti ne, or large b o wel  
•  I nfecti o n of t he bac k of t he eye (cyt o megal o vir us) 
 


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Ot her ris ks  i ncl u de fai nti ng, blee di ng, s welli ng, or (rarely) i nfecti o n. If carfilz o mi b s h o ul d 
acci de ntally be i njecte d u n der y o ur s ki n d uri ng a d mi nistrati o n, a l ocal s ki n reacti o n may occ ur (f or 
e xa m ple, re d ness, s welli ng, te n der ness, stiff ness). 
 
T he f oll o wi ng si de effects ha ve bee n see n i n pe o ple w h o recei ve d carfilz o mi b. It is u n k n o w n if t hey 
were ca use d by carfilz o mi b, y o u may or may n ot e x perie nce t hese si de effects:  
 
•  Tire d ness, i nfecti o n, a n d easy br uisi ng or blee di ng w hic h may be sy m pt o ms of a bl o o d 
c o n diti o n k n o w n as Myel o dys plastic sy n dr o me / Ac ute Myel oi d Le u ke mia ( M D S / A M L).  
•  Te n der ness or pai n i n t he a b d o me n t hat gets m ore i nte nse wit h m oti o n or t o uc h, a b d o mi nal 
bl oati ng or diste nti o n, q ueasy /feeli ng li ke y o u nee d t o t hr o w u p a n d v o miti ng, diarr h ea, 
c o nsti pati o n or t he i na bility t o pass gas w hic h may be sy m pt o ms of s welli ng of t he t hi n 
tiss ue t hat li nes t he i n ner wall of t he a b d o me n a n d c o vers m ost of t he a b d o mi nal orga ns.  
 
Dri vi ng a n d Usi ng Mac hi nes  
Y o u may e x perie nce tire d ness, dizzi ness, fai n ti ng, a n d / or a dr o p i n bl o o d press ure after st u dy 
treat me nt wit h carfilz o mi b. T his may i m pair y o ur a bility t o dri ve or o perate mac hi nery. If y o u ha ve 
t hese sy m pt o ms, y o u s h o ul d n ot dri ve a car or o perate mac hi nery.  
 
Hy drati o n Ris ks  
T here may be ris ks ass ociate d wit h o ver hy drati ng ( ha vi ng t o o m uc h fl ui d i n y o ur b o dy) s o it is 
i m p orta nt t o f oll o w y o ur st u dy d oct or’s i nstr ucti o ns regar di ng h o w m uc h water or ot her fl ui ds y o u 
s h o ul d dri n k. O ver hy drati o n ca n ca use si de effect t o y o ur heart, l u ngs, a n d ki d neys. 
 
D e x a m et h as o n e  Si d e Eff e cts : 
 
Li k el y ( o c c urri n g i n gr e at er t h a n or e q u al t o 3 0 % of  s u bj e cts): 
•  Diffic ulty slee pi ng  
•  Fatig ue (feeli ng tire d)  
 
L ess Li k el y ( o c c urri n g i n 1 0 % -2 9 % of  s u bj e cts): 
•  L o w re d bl o o d cells or platelets  
•  Bl urre d visi o n  
•  C o nsti pati o n or diarr hea  
•  U pset st o mac h , heart b ur n, or ulcer 
•  Fe ver  
•  S welli ng of t he ar ms or  legs 
•  U p per res pirat ory tract  i nfecti o n 
•  Weig ht gai n  
•  Hig h bl o o d s ugar 
•  Hig h bl o o d press ure  


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•  I ncrease d a p petite 
•  M uscle cra m ps 
•  B o ne pai n or bac k  
•  J oi nt pai n 
•  M uscle wea k ness or m uscle ac hes 
•  Hea dac he  
•  Dizzi ness  
•  Ti ngli ng i n t he ha n ds or feet 
•  M o o d c ha nges ( de pressi o n, or a b n or mal feeli ngs of well- bei ng a n d e xcite me nt)  
•  S ki n c ha nges lea di ng t o t hi n ni ng a n d easy br uisi ng 
•  Gra d ual c ha nges t o b o nes t hat may i ncrease t heir ris k of brea ki ng  
 
I nfr e q u e nt b ut S eri o us ( o c c urr e d i n l ess t h a n 1 0 % of s u bj e cts): 
•  L o w w hite bl o o d cell  c o u nts 
•  V o miti ng  
•  A b d o mi nal pai n  
•  P ne u m o nia 
•  L o w bl o o d p otassi u m 
•  Pai n i n t he ar ms or  legs 
•  Tre m or  
•  Altere d taste  se nsati o n 
•  N u m b ness i n t he ha n ds or feet 
•  Br o nc hitis 
•  I nfla m mati o n of t he n ose or t hr oat 
•  Gra d ual de vel o p me nt of cataracts  
•  If use d f or a pr ol o nge d peri o d of ti me, ster oi ds ca n s u p press t he f u ncti o n of t he 
n or mal gla n ds t hat ma ke ster oi ds (a dre nal gla n ds) lea di ng t o t he nee d f or 
c o nti n ue d re place me nt wit h ster oi d me dicati o n 
•  Gla uc o ma, w hic h mea ns ha vi ng hig h press ure wit hi n t he eye ball p ossi bly lea di ng 
t o bli n d ness. May re q uire me dical i nter ve nti o n t o pre ve nt vis ual i m pair me nt. 
•  Pa ncreatitis, w hic h is a n i nfla m mati o n of t he pa ncreas ca usi ng p ai n i n t he u p per 
a b d o me n. T his c o ul d bec o me se vere a n d ca use na usea a n d v o miti ng, fe ver a n d 
ra pi d heart rate. T his c o ul d re q uire h os pitalizati o n a n d may be life t hreate ni ng. 
 
R u x oliti ni b Si d e Eff e cts:  
 
T he ris ks ( p ossi ble si de effects) of ta ki ng r u x oliti ni b are n ot yet f ully k n o w n a n d may vary de pe n di ng 
o n t he diseases or c o n diti o ns y o u are bei ng treate d f or. Ma ny si de effects g o a way after r u x oliti ni b is 
st o p pe d, b ut i n rare cases a ny of t he descri be d si de effects may be seri o us, l o ng lasti ng, a n d / or 


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per ma ne nt, a n d may e ve n ca use deat h. If y o u e x perie nce a ny of t he si de effects liste d bel o w or ha ve 
a ny ot her pr o ble ms, y o u s h o ul d i m me diately tell t he st u dy staff or t he st u dy d oct or. If y o u feel t hat 
t hese sy m pt o ms or si de effects are life t hreate ni ng, see k me dical assista nce i m me diately. 
 
R u x oliti ni b may ca use l o w bl o o d cell c o u nts ( w hite bl o o d cells, re d bl o o d cells a n d platelets). If y o ur 
w hite bl o o d cell c o u nt bec o mes l o w w hile y o u ta ke r u x oliti ni b, t his mea ns y o u may ha ve a n 
i ncrease d c ha nce of getti ng a n i nfecti o n, i ncl u di ng uri nary tract i nfecti o ns a n d viral i nfecti o ns. Y o u 
will be c hec ke d f or a ny sig ns of i nfecti o n bef ore starti ng r u x oliti ni b. A ny seri o us i nfecti o ns s h o ul d 
be treate d bef ore y o u begi n ta ki ng r u x oliti ni b. Y o ur st u dy d oct or will c hec k y o u caref ully f or sig ns 
of i nfecti o n w hile y o u are bei ng treate d. 
 
Y o u als o may bec o me a ne mic (l o w re d bl o o d cell c o u nt) w hile y o u ta ke t he dr ug, a n d t hat may ca use 
y o u t o feel fatig ue d or s h ort of breat h. If y o ur platelet c o u nt bec o mes l o w w hile y o u ta ke t he dr ug, it 
may lea d t o blee di ng a n d / or br uisi ng.  
 
I n s o me pe o ple ta ki ng r u x oliti ni b, t he decreases i n bl o o d cell c o u nts ha ve bee n se vere. I n m ost 
cases, l o w bl o o d cell c o u nts ca n be re verse d by st o p pi ng t he dr ug te m p orarily or re d uci ng t he d ose; 
y o u will be c hec ke d ofte n f or t his si de effect w hile taki ng t he me dicati o n. If y o ur bl o o d cell c o u nts 
d o n ot rec o ver q uic kly, y o ur dr ug d ose may be st o p pe d f or a l o nger d urati o n t o all o w t he bl o o d cell 
c o u nts t o rec o ver. 
 
T he m ost fre q ue ntly re p orte d si de effects i n s u bjects wit h M F ( myel ofi br osis) a n d / or P V 
( p olycyt he mia vera) w h o ha ve bee n treate d wit h r u x oliti ni b are: 
 
 
Very C o m m o n  (at least 1 0 % of s u bjects) 
 
•  A ne mia (l o w re d bl o o d cells) 
•  T hr o m b ocyt o pe nia (l o w platelets)  
•  Br uisi ng 
•  Blee di ng 
•  T hr o m b osis ( bl o o d cl ot) 
•  Ne utr o pe nia (l o w w hite bl o o d cells)  
•  I nfecti o ns 
•  Viral I nfecti o ns  
•  Tire d ness 
•  Diarr hea  
•  S welli ng  
•  Ras h 
•  Dizzi ness  
•  Hea dac he  


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•  S h ort ness of Breat h 
•  M uscle S pas ms  
 
C o m m o n ( m ore t ha n 1 % b ut less t ha n 1 0 % of s u bjects) 
 
•  Q ueasy /feeli ng li ke y o u nee d t o t hr o w u p  
•  Weig ht gai n  
•  Flat ule nce (gas)  
•  C o nsti pati o n 
•  P ne u m o nia (i nfecti o n of t he l u ngs) 
•  Raise d A L T a n d A S T ( bl o o d pr otei ns t hat may i n dicate mil d li ver da mage)  
•  Hy perc h olester ole mia (i ncrease d c h olester ol)  
•  Hy pertriglyceri de mia (i ncrease d triglyceri des)  
•  Her pes Z oster (s hi ngles) 
•  Uri nary tract i nfecti o ns  
•  Hy perte nsi o n ( hig h bl o o d press ure) 
 
Rare b ut Seri o us (less t ha n or e q ual t o 1 % of s u bjects) 
 
•  T u berc ul osis has occ urre d i n a s mall n u m ber of s u bjects (less t ha n 1 %) wit h M F w h o were 
treate d wit h r u x oliti ni b, b ut it is n ot k n o w n w het her t his was d ue t o M F, r u x oliti ni b, or ot her 
fact ors t hat are k n o w n t o i ncrease t he ris k of t u berc ul osis (s uc h as dia betes, br o nc hitis, 
ast h ma, s m o ki ng, e m p hyse ma, or ster oi d use). Tell t he st u dy d oct or if y o u ha ve bee n treate d 
f or T B i n t he past or ha ve e ver ha d a p ositi ve s ki n test f or T B. A d diti o nally, y o u s h o ul d tell 
t he st u dy d oct or i m me diately if y o u ha ve a ny of t he f oll o wi ng sy m pt o ms w hile ta ki ng 
r u x oliti ni b: c hr o nic c o ug h wit h s pit t hat has bl o o d i n it, fe ver, nig ht s weats, a n d weig ht l oss. 
•  A rare disease calle d pr ogressi ve m ultif ocal le u k oe nce p hal o pat hy ( P M L) has bee n re p orte d 
d uri ng r u x oliti ni b treat me nt. P M L c o mes fr o m a viral i nfecti o n t hat ca uses brai n da mage a n d 
ca n be fatal. It is u n k n o w n w het her t his was d ue t o r u x oliti ni b treat me nt si nce P M L has 
occ urre d i n s u bjects wit h bl o o d ca ncers, i ncl u di ng M F, w h o were n ot tre ate d wit h 
r u x oliti ni b. Tell t he st u dy d oct or i m me diately if y o u ha ve a ny of t he f oll o wi ng sy m pt o ms or 
if a ny o ne cl ose t o y o u n otices t hat y o u ha ve a ny of t hese sy m pt o ms: c o nf usi o n or pr o ble ms 
t hi n ki ng, l oss of bala nce or pr o ble ms wal ki ng, cl u msi ness, diffic ulty s pea ki n g, decrease d 
stre ngt h or wea k ness o n o ne si de of y o ur b o dy, a n d bl urre d a n d / or l oss of visi o n. 
•  N o n -mela n o ma s ki n ca ncers, i ncl u di ng basal cell, s q ua m o us cell, a n d a rare a n d aggressi ve 
ty pe of s ki n ca ncer calle d Mer kel Cell Carci n o ma ha ve bee n re p orte d i n s u bjects w h o t o o k 
r u x oliti ni b. It is u n k n o w n w het her t his was d ue t o r u x oliti ni b treat me nt, as ma ny of t hese 
s u bjects ha d bee n eit her diag n ose d wit h n o n-mela n o ma s ki n ca ncer i n t he past or ha d 
pre vi o usly bee n treate d wit h hy dr o xy urea w hic h is ass ociate d wit h m ulti ple ty pes of s ki n 
ca ncers. Peri o dic s ki n e xa mi nati o n is rec o m me n de d f or s u bjects w h o are at i ncrease d ris k of 
s ki n ca ncer. 


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•  Pa ncyt o pe nia is a c o n diti o n w he n a s u bject has l o w c o u nts of all t hree ty pes of bl o o d cells: 
re d bl o o d cells, w hite bl o o d cells, a n d platelets. It has occ urre d i n a s mall pr o p orti o n of 
s u bjects (less t ha n 0. 5 %) w h o were treate d wit h r u x oliti ni b.  
 
T he effect of r u x oliti ni b o n viral re plicati o n i n s u bjects wit h c hr o nic he patitis B vir us is u n k n o w n. 
Y o u s h o ul d tell t he st u dy d oct or if y o u ha ve c hr o nic viral he patitis or ha d viral he patitis i n t he past.  
 
Treat me nt wit h r u x oliti ni b was ass ociate d wit h i ncreases i n bl o o d li pi ds i ncl u di ng t otal c h olester ol, 
hig h- de nsity li p o pr otei n ( H D L), l o w- de nsity li p o pr otei n c h olester ol ( L D L) a n d triglyceri des.  
 
I n s o me s u bjects w h o st o p pe d ta ki ng r u x oliti ni b, sy m pt o ms of t heir M F or P V ret ur ne d ra pi dly (als o 
calle d “ wit h dra wal effect”). D o n ot st o p ta ki ng r u x oliti ni b wit h o ut tal ki ng t o y o ur st u dy d oct or. 
 
 
Ot h er Ris ks:  
 
B o n e M arr o w Bi o ps y  Ris ks : y o u may e x perie nce pai n a n d / or disc o mf ort at t he site of t he nee dle 
i nserti o n.  T he a m o u nt of pai n a n d / or disc o mf ort will de pe n d o n y o ur pai n t olera nce, w hic h differs 
fr o m pers o n t o pers o n.  S o me pe o ple descri be a s har p pai n i n t he b o ne w here t he nee dle is i nserte d.  
Ot her patie nts descri be it as a l o ng, har d p u nc h or kic k.  T his pai n a n d / or disc o mf ort o nly lasts a 
fe w sec o n ds d uri ng t he act ual pr oce d ure.  Te n der ness o ver t he area may last f or a fe w days.  
Blee di ng fr o m t he site or i nfecti o n may occ ur b ut is rare.  
 
Y o u will be as ke d t o sig n a se parate pr oce d ure c o nse nt pri or t o u n derg oi ng a b o ne marr o w bi o psy, 
a n d a ny ot her ris ks ass ociate d wit h t hese pr oce d ures will be disc usse d wit h y o u by y o ur st u dy d oct or 
a n d / or cli nic staff.  Y o u  will be m o nit ore d caref ully d uri ng t hese pr oce d ures by s pecially trai ne d 
me dical staff.  
 
Bl o o d Dr a w /I V I ns erti o n  Ris ks : Y o u may ha ve pai n or br uisi ng at t he site w here t he bl o o d is 
dra w n or I V is i nserte d. Y o u may feel fai nt. A n i nfecti o n at t he site of t he bl o o d dra w or I V 
i nserti o n is p ossi ble. If y o u feel fai nt, y o u s h o ul d i m me diately lie d o w n t o a v oi d falli ng. 
 
R a di ol o gi c al E x a ms ( P E T / C T s c a ns a n d x -r a ys) Ris ks : P E T / C T sca ns a n d sta n dar d x-rays 
use x-ray ra diati o n. Ra diati o n has t he p ote ntial t o ca use ca ncer or har m a n u n b or n c hil d. T he 
a m o u nt of ra diati o n y o u will recei ve d uri ng a C T sca n is very l o w a n d m ost d oct ors agree t hat t he 
be nefits o ut weig h t he ris ks. S o me C T sca ns a n d P E T sca ns will re q uire y o u ta ke a “c o ntrast 
s ol uti o n” eit her by m o ut h, t hr o ug h t he rect u m or by i njecti o n i nt o a vei n. Y o u may e x perie nce 
disc o mf ort fr o m lyi ng still i n a n e ncl ose d s pace f or a pr ol o nge d peri o d of ti me. 
 
Alt h o ug h rare, t he c o ntrast s ol uti o n use d i n P E T / C T sca ns may ca use a n allergic reacti o n s uc h as 
na usea, v o miti ng, itc hi ng, s ki n ras h, o r i n very rare i nsta nces s welli ng of t he t hr oat a n d diffic ulty 
breat hi ng. If y o u feel a ny of t hese sy m pt o ms of a n allergic reacti o n y o u m ust tell t he cli nical staff 
i m me diately s o t hat y o u ca n be treate d q uic kly. 


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E c h o c ar di o gr a m or M U G A S c a n  Ris ks:  A n ec h ocar di ogra m ( heart ultras o u n d) d oes n ot ty pically 
ca use a ny disc o mf ort. A gel will be a p plie d t o y o ur c hest area, a n d t he n a wa n d-li ke i nstr u me nt is 
use d t o detect s o u n d wa ves. T here is a very l o w ris k of c o m plicati o ns. T he M U G A  sca n uses a dr ug 
[ra di oacti ve is ot o pe (tec h neti u m)] t hat is gi ve n wit h a n i njecti o n. T he nee dle p u nct ure f or i njecti ng 
of t he is ot o pe bef ore t he e xa m c o ul d be pai nf ul a n d c o ul d ca use blee di ng at t he site of t he i njecti o n, 
i nfla m mati o n (re d ness a n d s welli ng of t he vei n) a n d / or br uisi ng. Y o u will be e x p ose d t o a s mall 
a m o u nt of ra diati o n d uri ng t he e xa m. 
 
M RI Ris ks:  D uri ng M RI sca n ni ng, y o u may feel s o me heat a n d hear ba ngi ng n oises. S o me patie nts 
e x perie nce a “cl ose d-i n” se nsati o n or cla ustr o p h o bia w hile i nsi de t he M RI mac hi ne, a n d t his ca n be 
u nc o mf orta ble f or s o me i n di vi d uals. S o me M RI sca ns nee d pre parati o n bef ore ha n d; if t here are 
s pecial pre parati o ns y o u will be t ol d a b o ut t he m pri or t o t he day of y o ur sca n. Y o u may ha ve a n 
i njecti o n of a ty pe of dye j ust bef ore t he sca n t o hel p defi ne certai n orga ns m ore clearly. T he 
i njecti o n may ma ke y o u sic k t o y o ur st o mac h or ha ve pai n, war mt h, s welli ng, br uisi ng, a s mall bl o o d 
cl ot or i nfecti o n at t he i njecti o n site. Rarely, y o u may get a ras h or ot her sig ns of allergy fr o m t he 
i njecti o n. If y o u ha ve a hist ory of ki d ney pr o ble ms, y o u m ust i nf or m t he tec h n ol ogist or p hysicia n as 
y o u may n ot be a ble t o recei ve a n i njecti o n d uri ng t he M RI e xa m. Y o u will als o nee d t o i nf or m staff 
if y o u ha ve a ny metal i m pla nte d i n y o ur b o dy. F or exa m ple, s o me hi p re place me nts, heari ng ai ds, 
pace ma kers, b ullets, or je welry t hat ca n n ot be re m o ve d a n d t he staff nee ds t o k n o w bef ore ha n d 
beca use y o u may n ot ha ve a n M RI as t he sca n uses very p o werf ul mag nets.  
 
E C G ( El e ctr o c ar di o gr a m) Ris ks:  A n  E C G traces t he electrical acti vity of t he heart. Y o u may ha ve 
mil d irritati o n, slig ht re d ness, or itc hi ng at t he sites o n y o ur s ki n w here t he rec or di ng patc hes are 
place d.  
 
All er gi c R e a cti o n Ris ks: As wit h ta ki ng a ny dr ug, t here is a ris k of allergic reacti o n. If y o u ha ve a 
very seri o us allergic reacti o n, y o u may be at ris k of deat h. S o me sy m pt o ms of allergic reacti o ns are:  
 
•  Ras h 
•  W heezi ng a n d diffic ulty breat hi ng  
•  Dizzi ness a n d fai nti ng 
•  S welli ng ar o u n d t he m o ut h, t hr oat, or eyes  
•  A fast p ulse 
•  S weati ng  
 
Please see k treat me nt i m me diately a n d tell t he st u dy d oct or a n d st u dy staff if y o u ha ve a ny of t hese 
sy m pt o ms, or a ny ot her si de effects, d uri ng t he st u dy. 
 
 
 
 


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R e pr o d u cti v e Ris ks:   
 
W o m e n W h o C a n G et Pr e g n a nt or Ar e Br e astf e e di n g  
Y o u may n ot ta ke part i n t his st u dy if y o u are breastfee di ng, are preg na nt, t hi n k t hat y o u may be 
preg na nt, or are tryi ng t o get preg na nt.  If y o u are preg na nt or breastfee di ng, t here may be ris ks t o 
y o u a n d t he ba by t hat are n ot k n o w n at t his ti me.  W o me n w h o ca n get preg na nt will be teste d f or 
preg na ncy d uri ng t his st u dy.  Y o u will be as ke d t o ta ke a uri ne preg na ncy test wit hi n 3 days pri or t o 
t he first st u dy dr ug a d mi nistrati o n. 
 
Y o u m ust a v oi d getti ng preg na nt i n or der t o ta ke part i n t his researc h st u d y. Y o u s h o ul d n ot ha ve 
se x ual i nterc o urse or y o u s h o ul d use a met h o d of birt h c o ntr ol t hat is acce pta ble t o y o u, t he st u dy 
d oct or, a n d t he s p o ns or.  W o me n of c hil d beari ng p ote ntial m ust agree t o use t w o hig hly effecti ve 
birt h c o ntr ol (c o ntrace pti o n) met h o d s d uri ng t he st u dy a n d f or 6 m o nt hs after y o ur last d ose of 
st u dy dr ug.  Y o ur st u dy d oct or will tal k wit h y o u a b o ut t he best way t o pre ve nt preg na ncy w hile 
recei vi ng t he st u dy treat me nt. 
 
It is i m p orta nt f or y o u t o tell t he st u dy d oct or at o nce if y o u get preg na nt or t hi n k t hat y o u mig ht be 
preg na nt w hile y o u i n t he researc h st u dy.  If t his ha p pe ns, t he st u dy d oct or will disc uss wit h y o u 
w hat y o u s h o ul d d o.  If y o u get preg na nt, y o u will be as ke d t o st o p ta ki ng part i n t he st u dy.  Y o u 
may als o be as ke d q ues ti o ns a b o ut y o ur preg na ncy a n d t he ba by. 
 
M e n  
T he effect of t he st u dy dr ug o n s per m is u n k n o w n.  Male s u bjects m ust n ot d o nate s per m d uri ng 
a n d f or at least 9 0 days after st u dy treat me nt. 
 
Y o u s h o ul d n ot ha ve se x ual i nterc o urse or y o u s h o ul d use a met h o d of birt h c o ntr ol t hat is 
acce pta ble t o y o u, t he st u dy d oct or, a n d t he s p o ns or.  If y o u t hi n k t hat y o u ha ve g otte n a w o ma n 
preg na nt, y o u m ust tell t he st u dy d oct or at o nce.  If y o ur part ner gets preg na nt d uri ng t he st u dy, y o u 
may be as ke d q uesti o ns a b o ut t he pre g na ncy a n d t he ba by. 
 
Se x ually acti ve males m ust agree t o use t w o f or ms of hig hly effecti ve birt h c o ntr ol (c o ntrace pti o n) 
met h o ds t hr o ug h o ut t he st u dy a n d f or 9 0 days  after y o ur last d ose of st u dy dr ug.  Y o ur st u dy d oct or 
will tal k wit h y o u a b o ut t he best way t o pre ve nt preg na ncy w hile recei vi ng t he st u dy treat me nt.   If 
y o ur part ner gets preg na nt d uri ng t he st u dy or f or 9 0 days  after y o ur last d ose of st u dy dr ug, y o u 
may be as ke d q uesti o ns a b o ut t he pre g na ncy a n d t he ba by.  
 
U n k n o w n Ris ks  
Y o u mig ht ha ve si de effects or disc o mf orts t hat are n ot liste d i n t his f or m.  S o me si de effects may 
n ot be k n o w n yet.  Ne w o nes c o ul d ha p pe n t o y o u.  Tell t he st u dy d oct or or st u dy staff rig ht a way 
if y o u ha ve a ny pr o ble ms. 
 
 
 


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A L T E R N A TI V E S T O B EI N G I N T H E S T U D Y  
 
Y o u d o n ot nee d t o ta ke part i n t his researc h st u dy.  Y o u may c h o ose n ot t o partici pate i n t his 
st u dy a n d recei ve r o uti ne care treat me nt as rec o m me n de d by y o ur st u dy d oct or, s uc h as ot her 
c he m ot hera py or targete d t hera pies.  Y o ur st u dy d oct or ca n disc uss t he alter nati ves a n d t he ris ks 
a n d be nefits of t hese alter nati ves wit h y o u. 
 
 
P O T E N TI A L B E N E FI T S O F B EI N G I N T H E S T U D Y 
 
T he be nefits of treat me nt wit h carfilz o mi b, r u x oliti ni b, a n d l o w- d ose de xa met has o ne are n ot f ully 
k n o w n .  Y o u may or may n ot recei ve a ny be nefit fr o m bei ng i n t he st u dy. It is p ossi ble t hat y o u 
may get better, stay t he sa me, or get w orse.  If y o u ta ke part i n t his st u dy, ot her pe o ple wit h 
R R M M may be hel pe d.  
 
C O S T S O F B EI N G I N T H E S T U D Y  
 
If y o u c h o ose t o ta ke part i n t he st u dy, y o u a n d / or y o ur healt h pla n /i ns ura nce will nee d t o pay f or 
all y o ur r o uti ne care pr oce d ures. Y o u a n d / or y o ur i ns ura nce c o m pa ny will n ot be res p o nsi ble f or 
payi ng f or a ny pr oce d ures d o ne s olely f or researc h p ur p oses t hat w o ul d n ot ha ve bee n d o ne if y o u 
were n ot partici pati ng i n t he st u dy. T he st u dy dr ugs carfilz o mi b a n d r u x oliti ni b will be c o vere d by 
t he st u dy. 
 
Y o u may wis h t o disc uss c o verage wit h y o ur i ns ura nce c o m pa ny bef ore agreei ng t o partici pate i n 
t his research st u dy.  
 
F or m ore i nf or mati o n o n cli nical trials a n d i ns ura nce c o verage, y o u ca n visit t he Nati o nal Ca ncer 
I nstit ute’s we b site at htt p: / /ca ncer.g o v /cli nicaltrials / u n dersta n di ng /i ns ura nce- c o verage   Y o u ca n 
pri nt a c o py of t he “ Cli nical Trials a n d I ns ura nce C o verage” i nf or mati o n fr o m t his we b site.  
A n ot he r way t o get t he i nf or mati o n is t o call 1-8 0 0 - 4-C A N C E R ( 1 -8 0 0 -4 2 2 -6 2 3 7) a n d as k t he m t o 
se n d y o u a free c o py.  
 
Y O U R P A Y M E N T F O R B EI N G I N T H E S T U D Y  
 
Y o u will n ot be pai d f or bei ng i n t his st u dy. 
 
S T U D Y S T A F F P A Y M E N T / FI N A N CI A L DI S C L O S U R E 
 
N o ne of t he d oct or s as ki ng y o u t o partici pate i n t his st u dy has recei ve d or will recei ve m o ney or 
ot her be nefits f or pers o nal use fr o m t he c o m pa nies ( A mge n a n d I ncyte) t hat de vel o pe d s o me of t he 
dr ugs use d i n t his st u dy. 
 


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C O M P E N S A TI O N F O R I NJ U R Y  
 
I n t he e ve nt t hat y o u are i nj ure d as a res ult of y o ur partici pati o n i n t his st u dy, we will pr o vi de or 
arra nge f or treat me nt as necessary.  T his treat me nt, as well as ot her me dical e x pe nses, will be bille d 
t o y o u or y o ur i ns ura nce c o m pa ny i n t he us ual ma n ner.  Y o u may  be res p o nsi ble f or de d ucti bles, c o-
pay me nts, a n d c o -i ns ura nce. T here are n o pla ns t o pay or gi ve y o u ot her c o m pe nsati o n f or t he 
i nj ury. Y o u d o n ot wai ve a ny legal rig hts by sig ni ng t his c o nse nt f or m. 
 
If y o u bec o me ill or are h urt w hile y o u are i n t he st u dy, get t he me dical care t hat y o u nee d rig ht 
a way. 
 
F or i ns ura nce or ot her pay me nt re p orti ng p ur p oses, we may nee d t o k n o w s o me i nf or mati o n a b o ut 
y o u li ke y o ur na me, date of birt h, a n d Me dicare Be neficiary I de ntifier ( M BI). T his is beca use we may 
ha ve t o c hec k t o see if y o u recei ve Me dicare a n d if y o u d o, re p ort t he pay me nt we ma ke t o 
Me dicare.  
 
I n n o way d oes sig ni ng t his c o nse nt f or m wai ve y o ur legal rig hts n or d oes it relie ve t he i n vestigat ors, 
S p o ns or or i n v ol ve d i nstit uti o ns fr o m t heir legal a n d pr ofessi o nal res p o nsi bilities. 
 
C O N FI D E N TI A LI T Y  
 
T he rec or ds of t his st u dy will be ke pt pri vate.  I n a ny s ort of re p ort we mig ht p u blis h, we will n ot 
i ncl u de a ny i nf or mati o n t hat will ma ke it p ossi ble t o i de ntify a patie nt.  Y o ur rec or d f or t his st u dy 
may, h o we ver, be re vie we d a n d / or p h ot oc o pie d by Le vi ne Ca ncer I nstit ute, by Atri u m Healt h, or by 
re prese ntati ves of t he F o o d a n d Dr ug A d mi nistrati o n or ot her g o ver n me nt age ncies.  T o t hat e xte nt, 
c o nfi de ntiality is n ot a bs ol ute. 
 
T o e ns ure t hat y o ur i nf or mati o n c ollecte d f or t his st u dy will be ke pt pri vate, y o ur na me will n ot be 
use d w he ne ver p ossi ble.  A c o de will be use d i nstea d of y o ur na me.  All of y o ur st u dy data will be 
ke pt i n a sec ure l ocati o n.  
 
Y o ur sa m ples may be use d t o deter mi ne t he se q ue nce of s o me or all of y o ur ge nes ( D N A – traits 
passe d i n fa milies). H o we ver, t his st u dy is n ot i nte n de d t o i de ntify disease ca usi ng m utati o ns t hat 
ca n affect t he healt h of cl ose fa mily me m bers (s uc h as y o ur pa re nts, si bli ngs, or c hil dre n). Y o u will 
n ot recei ve a ny res ults fr o m a ny a nalyses perf or me d o n bl o o d a n d / or b o ne marr o w c ollecte d f or 
researc h p ur p oses. 
 


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A U T H O RI Z A TI O N T O U S E A N D DI S C L O S E Y O U R P R O T E C T E D H E A L T H 
I N F O R M A TI O N  
 
If y o u wis h t o partici pate  i n t his researc h st u dy, y o u  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pri nte d Na me of Researc h S u bject  
 
m ust sig n t his A ut h orizati o n. By sig ni ng t his A ut h orizati o n, y o u gi ve all healt hcare pr o vi ders, 
i ncl u di ng Atri u m Healt h, per missi o n t o use or discl ose (release) y o ur pr otecte d healt h i nf or mati o n, 
b ot h past a n d prese nt, f or t he researc h st u dy descri be d here:  
 
L CI - H E M-M Y E -C R D -0 0 4 : P h as e I /II St u d y of C arfil z o mi b, R u x oliti ni b  a n d L o w -D os e 
D e x a m et h as o n e f or C arfil z o mi b -R efr a ct or y M ulti pl e M y el o m a  
 
T he pr otecte d healt h i nf or mati o n t hat we may use or discl ose (release) f or t his researc h may i ncl u de 
all i nf or mati o n i n y o ur me dical rec or d, s uc h as res ults of p hysical e xa mi nati o ns, me dical hist ory, la b 
tests, or certai n healt h i nf or mati o n i n dicati ng or relati ng t o a partic ular c o n diti o n. 
 
T he healt h i nf or mati o n liste d a b o ve may be use d by a n d / or discl ose d (release d) t o :  
•  St u dy i n vestigat or a n d researc h staff  
•  St u dy s p o ns or a n d / or its ass ociate d c o m pa nies, i ncl u di ng A mge n a n d I ncyte 
•  Reg ulat ory or ot her g o ver n me ntal a ut h orities of t he U nite d States or ot her c o u ntries base d 
o n t his st u dy 
•  Ot her pers o ns or age nts a ut h orize d by t he st u dy s p o ns or 
•  Atri u m Healt h e m pl oyees  
•  Ot her pers o ns or age ncies as re q uire d by la w or all o we d by fe deral reg ulati o ns  
•  A d varra I nstit uti o nal Re vie w B oar d ( A d varra I R B) or Data Safety a n d M o nit ori ng B oar ds.  
 
Atri u m Healt h is re q uire d by la w t o pr otect y o ur pr otecte d healt h i nf or mati o n. By sig ni ng t his 
A ut h orizati o n, y o u a ut h orize Atri u m Healt h t o use a n d / or discl ose (release) y o ur pr otecte d healt h 
i nf or mati o n f or t his researc h st u dy. T h ose pers o ns w h o recei ve y o ur pr otecte d healt h i nf or mati o n 
may n ot be re q uire d by Fe deral pri vacy la ws (s uc h as t he Pri vacy R ule) t o pr otect it a n d may s hare 
y o ur pr otecte d healt h i nf or mati o n wit h ot hers wit h o ut y o ur per missi o n, if per mitte d by la ws 
g o ver ni ng t he m. Y o ur pr otecte d healt h i nf or mati o n may t he n n o l o nger be pr otecte d by t he Pri vacy 
R ule.  
 
Please n ote t hat y o u d o n ot ha ve t o si g n t his A ut h orizati o n, b ut if y o u d o n ot, y o u may n ot recei ve 
researc h-relate d treat me nt t hr o ug h t his st u dy. H o we ver, Atri u m Healt h may n ot c o n diti o n ( wit h h ol d 
or ref use) y o ur ot her Atri u m Healt h pr o vi ders treati ng y o u o n w het her y o u sig n t his A ut h orizati o n. 
Y o u may c ha nge y o ur mi n d a n d wit h dra w (ta ke bac k) t his A ut h orizati o n at a ny ti me, e xce pt t o t he 


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e xte nt t hat Atri u m Healt h or t he S p o ns or has alrea dy use d or discl ose d y o ur pr otecte d healt h 
i nf or mati o n base d o n t his A ut h orizati o n. T o wit h dra w t his A ut h orizati o n, y o u m ust write t o t he 
St u dy D oct or at t he a d dress liste d o n t he first page of t his f or m . 
 
N o p u blicati o n or p u blic prese ntati o n a b o ut t he researc h descri be d a b o ve will re veal y o ur i de ntity 
wit h o ut a n ot her A ut h orizati o n fr o m y o u. If all pr otecte d healt h i nf or mati o n t hat d oes or ca n 
i de ntify y o u is re m o ve d, t he re mai ni ng i nf or mati o n will n o l o nger be s u bject t o t his A ut h orizati o n or 
fe deral r ules (s uc h as t he Pri vacy R ule) a n d may be use d or discl ose d f or ot her p ur p oses. 
 
W he n t he researc h f or w hic h t he use or discl os u re is ma de i n v ol ves treat me nt a n d is c o n d ucte d by 
Atri u m Healt h: T o mai ntai n t he i ntegrity of t his researc h st u dy, y o u ge nerally will n ot ha ve access t o 
y o ur pers o nal healt h i nf or mati o n relate d t o t his researc h u ntil t he st u dy is c o m plete.  
 
At t he c o ncl usi o n of t he researc h st u dy a n d at y o ur re q uest, y o u ge nerally will ha ve access t o y o ur 
pr otecte d healt h i nf or mati o n. Access t o y o ur pr otecte d healt h i nf or mati o n i n a me dical rec or d is 
descri be d i n t he N otice of Pri vacy Practices pr o vi de d t o y o u by Atri u m Healt h.  
 
W he n c o n d ucti ng researc h, t he data a n d res ults may be use d or discl ose d f or f urt her treat me nt 
o utc o mes researc h or t o researc h a sec o n dary res ult. T his A ut h orizati o n will re mai n i n effect after 
t he e n d of t he c urre nt st u dy, a n d a ny f ut ure relate d sec o n dary st u dy u nless it is re v o ke d by y o u i n 
writi ng as descri be d a b o ve.  
 
 
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Sig nat ure of Researc h S u bject or Researc h S u bject’s Legally A ut h orize d Re prese ntati ve  
 
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Pri nte d na me of Researc h S u bject or Researc h S u bject’s Legally A ut h orize d Re prese ntati ve  
 
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Date  
 
 
W H O M T O C O N T A C T A B O U T T HI S S T U D Y  
 
D uri ng t his st u dy, if y o u e x perie nce a ny me dical pr o ble ms, s uffer a researc h -relate d i nj ury, or ha ve 
q uesti o ns, c o ncer ns or c o m plai nts a b o ut t he st u dy, please c o ntact t he I n vesti gat or at t he tele p h o ne 
n u m ber liste d o n t he first page of t his c o nse nt d oc u me nt.  If y o u see k e merge ncy care, or 
h os pit alizati o n is re q uire d, alert t he treati ng p hysicia n t hat y o u are partici pati ng i n t his researc h 
st u dy. 
 




Levi ne C a ncer I nstit ute / Pr ot oc ol N u m ber L CI -H E M -M Y E -C R D -0 0 4  
P a ge 2 4  of 2 5  
 
S he bli Atr as h, M D, M S  
A dv arr a I R B A p pr ove d Versi o n 2 2 N ov 2 0 2 2  
 
Revise d 2 2 N ov 2 0 2 2  
 
 
 
 
 
 
If y o u st o p ta ki ng part i n t his st u dy, a ny s peci me ns w hic h may ha ve alrea dy bee n c ollecte d a n d 
pr ocesse d will re mai n de -i de ntifie d a n d part of t he st u dy.  A ny s peci me ns w hic h may ha ve bee n 
c ollecte d b ut ha ve n ot yet bee n pr ocesse d may be destr oye d u p o n y o ur writte n re q uest.  N o 
s peci me ns will be ret ur ne d t o y o u. 
 
N E W I N F O R M A TI O N A B O U T T H E S T U D Y  
 
Y o u will be t ol d a b o ut a ny ne w i nf or mati o n f o u n d d uri ng t he st u dy t hat may affect w het her y o u 
wa nt t o c o nti n ue t o ta ke part.  
 
S T A T E M E N T O F C O N S E N T    
 
I ha ve rea d t his f or m a n d its c o nte nts were e x plai ne d t o me.  I agree t o be i n t his researc h st u dy f or 
t he p ur p oses liste d a b o ve.  All of my q uesti o ns were a ns were d t o my satisfacti o n.  I will recei ve a 
sig ne d a n d date d c o py of t his f or m f or my rec or ds.  I a m n ot gi vi ng u p a ny of my legal rig hts by 
sig ni ng t his f or m. 
 
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Sig nat ure of Researc h S u bject  
 
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Pri nte d Na me of Researc h S u bject  
 
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Sig nat ure of Legally A ut h orize d Re prese ntati ve (if a p plica ble)                 Date              Ti me                                          
 
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Pri nte d Na me of Legal ly A ut h orize d Re prese ntati ve (if a p plica ble)    
 
 
      
S T A T E M E N T O F I M P A R TI A L WI T N E S S  ( A S A P P LI C A B L E) 
 
I ha ve wit nesse d t he acc urate rea di ng of t his c o nse nt f or m t o t he p ote ntial researc h s u bject, a n d t he 
s u bject ha d t he o p p ort u nity t o as k q uesti o ns.  I c o nfir m t hat t he researc h s u bject has freely pr o vi de d 
his / her c o nse nt t o partici pate i n t his st u dy. 
 
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Sig nat ure of I m partial Wit ness    
  
  
  
    
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Ti me  
 
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Pri nte d Na me of I m partial Wit ness  
 


Levi ne C a ncer I nstit ute / Pr ot oc ol N u m ber L CI -H E M -M Y E -C R D -0 0 4  
P a ge 2 5  of 2 5  
 
S he bli Atr as h, M D, M S  
A dv arr a I R B A p pr ove d Versi o n 2 2 N ov 2 0 2 2  
 
Revise d 2 2 N ov 2 0 2 2  
 
 
 
 
 
 
 
S T A T E M E N T O F P E R S O N E X P L AI NI N G C O N S E N T  
 
I ha ve caref ully e x plai ne d t o t he s u bject or t he s u bject’s legally a ut h orize d re prese ntati ve  t he nat ure 
a n d p ur p ose of t he a b o ve st u dy.  T here has bee n a n o p p ort u nity f or t he s u bject or t he s u bject’s 
legally a ut h orize d re prese ntati ve t o as k q uesti o ns a b o ut t his researc h st u dy.  I ha ve bee n a vaila ble t o 
a ns wer a ny q uesti o ns t hat t he s u bject or t he s u bject’s legally a ut h orize d re prese ntati ve  has a b o ut t his 
st u dy. 
 
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Sig nat ure of Pers o n E x plai ni ng C o nse nt 
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Pri nte d Na me of Pers o n E x plai ni ng C o nse nt