Phase 2 Study of the Initial and Post-Transplant Treatment With Carfilzomib, Lenalidomide and Low Dose Dexamethasone (CRd) in Transplant Candidates With Newly Diagnosed, Multiple Myeloma Requiring Systemic Chemotherapy
Phase: PHASE2
Conditions: Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma
Sponsor: University of Chicago

 
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CLINICAL STUDY PROTOCOL 
NCT number: NCT01816971 
PROTOCOL INFORMATION 
 
Protocol Number: MMRC-043, University of Chicago IRB #12-1725 
 
Study Title: Open-label, Single-arm, Phase 2 Study of the Initial and Post-Transplant 
Treatment with Carfilzomib, Lenalidomide and Low dose Dexamethasone (CRd) in 
Transplant Candidates with Newly Diagnosed, Multiple Myeloma Requiring Systemic 
Chemotherapy 
 
 
Lead Institution Name: 
University of Chicago Medical Center 
 
Lead Principal Investigator Information: 
Andrzej Jakubowiak, MD, PhD 
Professor of Medicine 
Director, Myeloma Program 
Section of Hematology/Oncology 
The University of Chicago Medical Center 
5841 S. Maryland Ave, MC 2115 
Chicago, IL 60637-6613 
Phone: 773-702-4005  
Fax: 773-702-0963  
ajakubowiak@medicine.bsd.uchicago.edu 
 
A Multi-institutional Study Done In Collaboration with The Multiple Myeloma Research 
Consortium.  Participating sites include institutional members of the University of Chicago 
Personalized Cancer Care Consortium. 
 
 
Statistician: Kent Griffith, MPH, MS 
 
Investigational Products: 
Drug Company Supplied: Carfilzomib (Onyx) IND# 105821 
Commercial Agents: Dexamethasone, Revlimid 
 

 
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Original Version 
Version 1.0 
Version 2.0 
Version 3.0 
Version 4.0 
Version 5.0 
Version 5.1 
Version 5.2 
Version 6 
Version 6.1 
Version 6.2 
Version 7 
August 31, 2012 
September 26, 2012 
November 19, 2012 
March 19, 2013 
January 31, 2014 
July 15, 2014 
October 15, 2014 
May 20, 2015 
July 28, 2015 
October 21, 2015 
July 6, 2016 
October 5, 2016 
PROTOCOL SYNOPSIS 
Title: 
 
Open-Label, Single-arm, Phase 2 Study of the Initial and 
Post-Transplant Treatment with Carfilzomib, Lenalidomide 
and Low dose Dexamethasone (CRd) in Transplant 
Candidates with Newly Diagnosed Multiple Myeloma (MM) 
Requiring Systemic Chemotherapy  
 
Objectives: 
Primary Objectives: 
To determine the rate of stringent CR (sCR) after 8 cycles of CRd 
(4 cycles of induction + ASCT + 4 cycles of CRd consolidation). 
 
Secondary Objectives:  
Overall response rate defined as partial response or better (>PR) 
including the rate of VGPR or better (>VGPR) and near 
complete response or better (sCR/CR/nCR) across entire 
treatment in high risk and low risk patients 
 
Duration of response (DOR), Progression free survival (PFS), 
Time to progression (TTP), and Overall Survival (OS) 
 
Exploratory Objectives: 
Determination of the rate of minimal residual disease in patients 
who achieved CR 
 
Prospective evaluation of candidate markers of response to CRd 
established in the completed CRd trial 
 
Evaluation of markers of response and duration of response to 
treatment strategy using CRd with or without transplant 
 
 

 
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Study Design: 
This is a multi-center, open-label, Phase 2 study in which 
transplant candidates with newly diagnosed MM requiring 
systemic chemotherapy will receive initial induction with CRd 
followed by autologous stem cell transplant (ASCT) followed 
by CRd consolidation followed by CRd maintenance. The study 
will determine the efficacy of the treatment strategy by 
determining the rate of sCR after completion of a total 8 cycles 
of CRd (4 cycles of induction, followed by ASCT followed by 
4 cycles of CRd consolidation). Carfilzomib will be 
administered at 20 mg/m2 as an IV infusion on Days 1, 2 and 
then at 36 mg/m2 on Days 8, 9, 15, and 16 in cycle 1 of a 28-
day cycle and at 36 mg/m2 for the remaining cycles. Cycles 1 - 
4 represent induction. Lenalidomide will be administered PO at 
25 mg per dose on Days 1- 21 of the 28-day cycle for pre-
ASCT induction Cycles 1 – 4 and Dexamethasone will be 
administered PO or IV between 30 minutes and 4 hours 
preceding the carfilzomib dose at 40 mg per dose on Days 1, 8, 
15, and 22 in cycle 1-4. After Cycle 4, subjects will proceed 
into stem cell harvest (SCC) with use of growth factors or as 
per current standards of care and then to single ASCT. In the 
CRd consolidation phase, which will be initiated after 3 months 
post-ASCT evaluation (days 70-90 but not more than day 120), 
Carfilzomib will be used IV at the last tolerated dose on Days 1, 
2, 8, 9, 15, and 16 of a 28-day cycle for CRd consolidation 
cycles (overall CRd Cycles 5-8) and in the CRd maintenance 
phase at last tolerated dose as an IV infusion on Days 1, 2, 15, 
and 16 of a 28-day cycle for CRd maintenance (overall Cycles 
9-18). Lenalidomide will be used at the last tolerated dose but 
not higher than 15 mg per dose as initial dose in the CRd 
consolidation phase and at the last tolerated dose in the CRd 
maintenance phase on days 1-21 in 28 day cycles. In discussion 
with the Lead Principal Investigator and on a case-by-case 
basis, provisions may be made to start at a lower than 15 mg 
dose of lenalidomide for participants with adequate 
hematologic parameters following ASCT and/or to escalate 
lenalidomide dose up to 25 mg per dose after completion of 1 
cycle of CRd consolidation for participants with adequate 
hematologic parameters. Dexamethasone will be administered 
PO or IV between 30 minutes and 4 hours preceding the 
carfilzomib dose at 20 mg per dose on Days 1, 8, 15, and 22 in 
the consolidation phase at last tolerated dose in CRd Cycles 5-
8, and at 20 mg (or last tolerated dose) per dose on days 1, 8, 
15, and 22 in the CRd maintenance phase (overall CRd cycle 9-
18).  

 
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Study Population: 
 
Newly diagnosed multiple myeloma, autologous stem cell 
transplant candidates  
 
Inclusion Criteria: 
 
Disease-related: 
1. Newly diagnosed, myeloma requiring systemic chemotherapy 
as per IMWG uniform criteria (see Appendix B) 
• Prior treatment of hypercalcemia or spinal cord 
compression or active and/or aggressively progressing 
myeloma with corticosteroids or lenalidomide or 
bortezomib-based regimens does not disqualify the 
patient (the treatment dose should not exceed the 
equivalent of 160 mg of dexamethasone in a 4 week 
period or not more than 1 cycle) 
• Bisphosphonates are permitted 
 
2.  Suitable and interested to proceed to ASCT. (Refer to 6.4) 
 
3. Measurable disease, prior to initial treatment as indicated by 
one or more of the following: 
• Serum M-protein ≥ 0.5 g/dL  
• Urine M-protein ≥ 200 mg/24 hours 
• If serum protein electrophoresis is felt to be unreliable for 
routine M-protein measurement, then quantitative 
immunoglobulin levels are acceptable 
 
Demographic 
4. Males and females ≥ 18 years of age 
5. Life expectancy of more than 3 months 
6. Eastern Cooperative Oncology Group (ECOG) performance 
status 0-2 (See Appendix C) 
 
Laboratory 
7. Adequate hepatic function, with bilirubin < 1.5 times the 
upper limit of normal (ULN), and aspartate aminotransferase 
(AST) and alanine aminotransferase (ALT) < 2.5 times ULN 
8. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L, hemoglobin 
≥ 8 g/dL, platelet count ≥ 75 x 109/L.  Subjects may receive 
RBC transfusions or platelet transfusions, if clinically 
indicated in accordance with institutional guidelines.  
However, screening platelet count should be independent of 
platelet transfusions for at least 2 weeks.  
9. Calculated or measured creatinine clearance of ≥ 50 
mL/minute, calculated using the following formula of 
Cockcroft and Gault: 

 
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(140 – age) x mass (kg)      x 0.85 (if female) 
72 x creatinine (mg/dL) 
 
Or creatinine below 2 g/dl 
 
Ethical/Other 
10. Written informed consent in accordance with federal, local, 
and institutional guidelines  
11. Females of childbearing potential (FCBP) [defined as 
sexually mature females who: 1) have not undergone a 
hysterectomy or bilateral oophorectomy; or 2) have not been 
naturally postmenopausal for at least 24 consecutive months 
(ie, has had menses at any time in the preceding 24 
consecutive months)] must agree to ongoing pregnancy 
testing. 
12. FCBP must have 2 negative pregnancy tests (sensitivity of 
at least 50 mIU/mL) prior to initiating lenalidomide.  The 
first pregnancy test must be performed within 10-14 days 
before Day 1 Cycle 1 and the second pregnancy test must be 
performed within 24 hours of Day 1 Cycle 1.  The subject 
may not receive lenalidomide until the Treating Investigator 
has verified that the results of these pregnancy tests are 
negative, and must agree to ongoing pregnancy tests as 
outlined in the protocol. For patients already on Revlimid, 
continuation of current testing schedule is permitted as long 
as it is not interrupted during the transition to CRd therapy. 
13. FCBP must agree to use 2 reliable forms of contraception 
simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods 
related to this study: 1) for at least 28 days before starting 
lenalidomide; 2) while participating in the study; and 3) for 
at least 28 days after discontinuation from the study. The 2 
methods of reliable contraception must include a highly 
effective method (ie, intrauterine device (IUD), hormonal 
[birth control pills, injections, or implants], tubal ligation, 
partner’s vasectomy) and an additional effective (barrier) 
method (ie, latex condom, diaphragm, cervical cap).  FCBP 
must be referred to a qualified provider of contraceptive 
methods if needed. 
14. Male subjects must agree to use a latex condom during 
sexual contact with females of childbearing potential while 
participating in the study and for at least 28 days following 
discontinuation from the study even if he has undergone a 
successful vasectomy. 

 
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15. Male subjects must agree to inform his physician if he has 
had unprotected sexual contact with a female who can 
become pregnant or if he thinks for any reason that his 
sexual partner may be pregnant.   
16. Male subjects must agree not to donate semen or sperm 
while taking lenalidomide and/or carfilzomib and 28 days 
after the last Lenalidomide/Carfilzomib dose. 
17. All study participants must be registered into the mandatory 
Revlimid REMS® program and be willing and able to 
comply with the requirements of Revlimid REMS®. 
18. The ability to take aspirin or other appropriate VTE 
prophylaxis     
19. Subjects must agree to adhere to all study requirements, 
including birth control measures and pregnancy testing, visit 
schedule, outpatient treatment, required concomitant 
medications, and laboratory monitoring 
 
Exclusion Criteria: 
Disease-related 
1. Non-secretory or hyposecretory multiple myeloma, prior 
to initial treatment defined as <0.5 g/dL M-protein in 
serum, <200 mg/24 hr urine M-protein, or disease only 
measured by serum free light chain   
2. POEMS syndrome (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes)   
3. Waldenström’s macroglobulinemia or IgM myeloma 
4. Radiotherapy to multiple sites or immunotherapy within 
4 weeks before start of protocol treatment (localized 
radiotherapy to a single site at least 1 week before start is 
permissible) 
5. Participation in an investigational therapeutic study for 
other reasons than symptomatic myeloma within 3 weeks 
or within 5 drug half-lives (t1/2) prior to first dose, 
whichever time is greater  
6. Participation in another clinical trial unless approved by 
the Lead Principal Investigator 
 
 
Concurrent Conditions 
7. Pregnant or lactating females 
8. History of allergy to mannitol 
9. Major surgery within 3 weeks prior to first dose 
10. Myocardial infarction within 6 months prior to 
enrollment,  NYHA Class III or IV heart failure, 
uncontrolled angina, severe uncontrolled ventricular 
arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities 

 
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11. Uncontrolled hypertension or diabetes 
12. Acute active infection requiring systemic antibiotics, 
antivirals, or antifungals within two weeks prior to first 
dose 
13. Known or suspected HIV infection, known HIV 
seropositivity 
14. Active hepatitis A, B, or C infection 
15. Non-hematologic malignancy within the past 3 years 
except  a) adequately treated basal cell, squamous cell 
skin cancer, thyroid cancer, carcinoma in situ of the 
cervix, or prostate cancer < Gleason Grade 6 with stable 
prostate specific antigen levels  or cancer considered 
cured by surgical resection alone 
16. Any clinically significant medical disease or condition 
that, in the Treating Investigator’s opinion, may interfere 
with protocol adherence or a subject’s ability to give 
informed consent  
17. Significant neuropathy (Grades 3-4, or Grade 2 with 
pain) at the time of the first dose and/or within 14 days 
before enrollment 
18. Contraindication to any of the required concomitant 
drugs, 
including 
proton-pump 
inhibitor 
(eg, 
lansoprazole), enteric-coated aspirin, allopurinol or if a 
history of prior thrombotic disease, warfarin or low 
molecular weight heparin 
19. Subjects in whom the required program of PO and IV 
fluid hydration is contraindicated, eg, due to pre-existing 
pulmonary, cardiac, or renal impairment 
20. Subjects with known or suspected amyloidosis of any 
organ 
21. Subjects with pleural effusions requiring thoracentesis or 
ascites requiring paracentesis. 
22. No coverage or not-acceptable by patient co-pay for 
Lenalidomide. 
 
 
Study Treatment: 
 
Subjects will receive carfilzomib, lenalidomide, and 
dexamethasone. All subjects are planned to receive 4 cycles of 
CRd induction. After completion of induction, all eligible 
patients will proceed to stem cells harvest followed by ASCT. 
Patients who recover from ASCT toxicities will resume 
protocol treatment starting at 70-90 days post stem cell infusion 
(not later than 120) in the consolidation and the maintenance 
portion of the protocol. No toxicities will be recorded from the 
ASCT period.  
 

 
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An individual subject will be considered off-treatment 
following a 30-day safety follow-up period after the last cycle 
of CRd treatment.  Subjects who have not progressed upon 
completion or discontinuation of the study will be followed for 
up to 5 years from the safety follow-up visit for disease 
progression or the start of a new treatment regimen. 
Primary Endpoint: 
 
To determine the rate of stringent CR (sCR) after 8 cycles of CRd 
(4 cycles of induction + ASCT + 4 cycles of CRd consolidation). 
 
Secondary Endpoints: 
 
Overall response rate defined as partial response or better (>PR) 
including the rate of VGPR or better (>VGPR) and near 
complete response or better (sCR/CR/nCR) across entire 
treatment in high risk and low risk patients 
 
Duration of response (DOR), Progression free survival (PFS), 
Time to progression (TTP), and Overall Survival (OS) 
 
Exploratory Endpoints: 
Determination of the rate of minimal residual disease in patients 
who achieved CR 
 
Prospective evaluation of candidate markers of response to CRd 
established in the completed CRd trial 
 
Evaluation of markers of response and duration of response to 
treatment strategy using CRd with or without transplant 
Statistical Methods: 
 
A total of 70 patients will be enrolled in a single-stage Phase II 
design. Patients who decline transplant for other reasons than 
toxicities will be replaced. It is anticipated that most will resume 
post-transplant CRd at the consolidation phase but those who do 
not, will not be replaced. 
 
 
 

 
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SCHEMA 
 
Newly Diagnosed Symptomatic Myeloma 
 
CRd induction x 4 cycles 
 
Stem cell harvest 
 
ASCT                         
 
CRd consolidation x 4 cycles (CRd Cycles 5-8)  
 
CRd maintenance x 10 cycles (CRd cycles 9-18) 
   
 
Lenalidomide maintenance (Off protocol maintenance)                        

 
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CONFIDENTIALITY STATEMENT 
This document contains confidential information.  It is provided for the sole use of the 
Principal Investigator, Sub-investigators, Staff, Institutional Review Board or Independent 
Ethics Committee, and Regulatory Authorities.  By accepting this document, you agree to 
maintain the information as confidential and to use it only for the purpose of conducting 
the study. 
 
 
Open-label, Single-arm, Phase 2 Study of the Initial and Post-Transplant Treatment with 
Carfilzomib, Lenalidomide and Low dose Dexamethasone (CRd) in Transplant Candidates with 
Newly Diagnosed, Multiple Myeloma Requiring Systemic Chemotherapy 
 
 
Protocol Acceptance Form 
 
I have read this protocol and agree to conduct the study as outlined herein, in accordance with 
Good Clinical Practices (GCPs) and the Declaration of Helsinki, and complying with the 
obligations and requirements of clinical Investigators and all other requirements listed in 
21 CFR part 312. 
 
 
 
 
Investigator Signature 
 
                      Date 
 
 
 
 
 
Print Investigator Name and Title 
        
 
 Date 

 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL .........................................................................................1 
Original Version.........................................................................................................................2 
August 31, 2012 .........................................................................................................................2 
September 26, 2012 ...................................................................................................................2 
November 19, 2012 ....................................................................................................................2 
PROTOCOL SYNOPSIS ........................................................................................................2 
TABLE OF CONTENTS ......................................................................................................11 
1 INTRODUCTION............................................................................................................18 
1.1 Multiple Myeloma ..............................................................................................18 
1.2 Combinations of Proteasome Inhibitors and Immunomodulatory Agents .........18 
1.3 Carfilzomib Background .....................................................................................20 
1.3.1 CARFILZOMIB Toxicology STudies .................................................20 
1.3.2 Carfilzomib Preclinical Antitumor Activity ........................................21 
1.3.3 Phase 1 Experience with Carfilzomib as a Monotherapy ....................22 
1.3.4 Phase 2 Experience with Carfilzomib as a monotherapy.....................23 
1.4 Dose Rationale ....................................................................................................25 
1.5 Lenalidomide Background ..................................................................................27 
1.6 Experience with Carfilzomib in Combination with lenalidomide and 
dexamethasone .................................................................................................28 
1.7 Study Rationale ...................................................................................................32 
2 OBJECTIVES ..................................................................................................................34 
2.1 Primary Objective ...............................................................................................34 
2.2 Secondary Objectives..........................................................................................34 
2.3 Exploratory objectives ........................................................................................34 
3 EXPERIMENTAL PLAN ...............................................................................................34 
3.1 Study Design .......................................................................................................34 
3.2 Number of Centers ..............................................................................................36 
3.3 Number of Subjects.............................................................................................36 
3.4 Estimated Study Duration ...................................................................................37 
3.5 Treatment Schema ..............................................................................................37 
3.6 Inclusion Criteria ................................................................................................37 

 
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3.7 Exclusion Criteria ...............................................................................................40 
4 SUBJECT ENROLLMENT ............................................................................................41 
4.1 Patient Enrollment and Registration ...................................................................41 
5 TREATMENT ..................................................................................................................42 
5.1 General Procedures .............................................................................................42 
5.2 Drug Administration ...........................................................................................43 
5.2.1 Pretreatment Preparation ......................................................................43 
5.2.2 Dexamethasone ....................................................................................44 
5.2.3 Carfilzomib ..........................................................................................45 
5.2.4 Lenalidomide .......................................................................................46 
5.2.5 Treatment Compliance .........................................................................47 
5.3 Instructions for Initiation of a New Cycle ..........................................................48 
5.4 Dose Modification Guidelines ............................................................................48 
5.4.1 Hematologic Toxicity ..........................................................................50 
5.4.2 Non-hematologic Toxicity ...................................................................50 
5.4.3 Conditions Not Requiring Dose Reduction .........................................57 
5.4.4 Treatment Discontinuation...................................................................58 
5.5 Concomitant Medications ...................................................................................58 
5.5.1 Required Concomitant Medications ....................................................58 
5.5.2 Optional and Allowed Concomitant Medications ................................59 
5.5.3 Excluded Concomitant Medications ....................................................60 
5.6 Safety Guidance for Investigators .......................................................................60 
5.6.1 "First-dose Effect" ...............................................................................60 
5.6.2 Tumor Lysis Syndrome........................................................................61 
5.6.3 Renal Function .....................................................................................61 
5.6.4 Hydration .............................................................................................62 
6 STUDY TESTS AND OBSERVATIONS ......................................................................62 
6.1 Screening (Days -21 to -1) ..................................................................................62 
6.2 Treatment Cycles 1 through 4 (Induction), Cycles 5-8 (consolidation), and 
Cycles 9-18 (maintenance) ..............................................................................65 
6.3 End of Cycle 4 ....................................................................................................67 
6.4 stem cell collection and autologous stem cell transplant ....................................67 

 
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6.4.1 Mobilization and collection of autologous peripheral blood stem cells68 
6.4.2 autologous stem cell transplant procedure ...........................................68 
6.5 3 MONTHS POST TRANSPLANT ...................................................................68 
6.6 END OF CYCLE 8 (END of cycle 4 crd consolidation) ....................................69 
6.7 Long-Term follow-up .........................................................................................69 
6.8 Tumor Response Assessment .............................................................................70 
6.9 Optional Correlative studies ...............................................................................70 
7 STUDY DISCONTINUATION ......................................................................................72 
8 ADVERSE EVENTS .......................................................................................................73 
8.1 Adverse Events Definitions ................................................................................73 
8.2 Causality .............................................................................................................74 
8.3 Adverse Events Reporting Procedures ................................................................75 
8.4 Serious Adverse Events ......................................................................................76 
8.4.1 SERIOUS ADVERSE EVENT DEFINITION ....................................76 
8.4.2 Serious and Unexpected Suspected Adverse Reaction (SUSAR) .......77 
8.5 Serious Adverse Event Reporting and Documentation Requirements ...............78 
8.5.1 Expedited Reporting by Lead Principal Investigator to Onyx .............78 
8.5.2 investigator reporting responsibilites ...............................................................79 
8.5.3 FDA Reporting by the lead principal investigator ...............................80 
8.5.4 Adverse Event Updates/IND Safety Reports .......................................81 
8.6 Pregnancy ................................................................................................81 
9 STATISTICAL METHODS AND DATA ANALYSIS ................................................83 
9.1 Objectives ...........................................................................................................83 
9.1.1 Primary objectives ...............................................................................83 
9.1.2 Secondary Objectives...........................................................................83 
9.1.3 Exploratory Objectives ........................................................................83 
9.2 Population for analysis ........................................................................................84 
9.3 Study design and sample size .............................................................................84 
9.3.1 Primary objective .................................................................................85 
9.3.2 Secondary objectives ...........................................................................86 
9.3.3 Exploratory objectives .........................................................................86 
9.3.4 Safety analysis .....................................................................................86 

 
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10 INVESTIGATIONAL PRODUCT...............................................................................87 
10.1 Carfilzomib Description....................................................................................87 
10.1.1 Formulation ......................................................................................................87 
10.1.2 Storage .............................................................................................................88 
10.1.3 Accountability ..................................................................................................88 
10.1.4 Carfilzomib ordering ........................................................................................88 
10.2 Lenalidomide ....................................................................................................89 
10.2.1 Description .........................................................................................89 
10.2.2 Supply ................................................................................................89 
10.2.3 Storage conditions ..............................................................................89 
10.2.4 AccountAbility ...................................................................................90 
10.2.5 Prescribing information .....................................................................90 
10.2.6 Special handling instructions .............................................................90 
10.3 Dexamethasone .................................................................................................90 
Dexamethasone may be given IV or PO ..........................................................90 
10.3.1 Description .........................................................................................90 
10.3.2 Formulation ........................................................................................90 
10.3.3 Storage conditions ..............................................................................90 
10.3.4 Accountibility ....................................................................................90 
11 REGULATORY OBLIGATIONS ...............................................................................91 
11.1 Informed Consent..............................................................................................91 
11.2 Compliance with Laws and Regulations...........................................................91 
11.3 Pre-study Documentation Requirements ..........................................................92 
11.4 Subject Confidentiality .....................................................................................93 
12 ADMINISTRATIVE AND LEGAL OBLIGATIONS ...............................................93 
12.1 Protocol Amendments and Study Termination .................................................93 
12.2 Study Documentation and Archive ...................................................................94 
12.2.1 Source documents ..............................................................................94 
12.2.2 Case rerport form completion ............................................................94 
12.2.3 Archival of records ............................................................................95 
12.2.4 Clinical monitoring procedures..........................................................95 
12.2.5 Data safety and monitoring ................................................................96 

 
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12.2.6 Protocol deviations.............................................................................96 
12.2.7 Quality assurance and auditing ..........................................................97 
13 REFERENCES ...............................................................................................................98 
APPENDIX A.  SCHEDULE OF TESTS AND OBSERVATIONS ...............................102 
APPENDIX B. MULTIPLE MYELOMA STAGING ......................................................108 
APPENDIX C.  ECOG PERFORMANCE SCALE .........................................................110 
APPENDIX D.  NCI CTCAE VERSION 4.0 ....................................................................111 
APPENDIX E.  RESPONSE CRITERIA FOR MULTIPLE MYELOMA ...................112 
APPENDIX F. RISKS OF FETAL EXPOSURE, PREGNANCY TESTING ...............115 
APPENDIX G: COCKROFT-GAULT ESTIMATION OF CRCL ................................117 
APPENDIX H:    
FACT/GOG-NEUROTOXICITY QUESTIONNAIRE, 
VERSION 4.0 118 
APPENDIX I:    
IMWG CRITERIA FOR THE DIAGNOSIS OF MYELOMA119 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
°C 
degrees Centigrade 
°F 
degrees Fahrenheit 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time (also PTT) 
ASaT 
All Subjects as Treated 
ASCT 
AST 
Autologous Stem Cell Transplant 
aspartate aminotransferase 
bid 
twice daily 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CR 
complete response 
CrCl 
Creatinine Clearance 
CRF 
case report form(s) 
CRO 
clinical research organization 
CSR 
Clinical Study Report 

 
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CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DVT 
deep venous thrombosis 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
Full Analysis Set 
FCBP 
Females of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
FLC 
free light chain 
G-CSF 
granulocyte colony stimulating factor 
GCP 
Good Clinical Practice  
GLP 
Good Laboratory Practice  
GM-CSF 
granulocyte macrophage colony stimulating factor 
h 
hour(s) 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
kg 
kilogram(s) 
LDH 
lactate dehydrogenase 
mg 
milligram(s) 
min 
minute(s) 
mIU 
Milli International Units 
mL 
milliliter(s) 
MM 
multiple myeloma 
mm2 
millimeter(s) squared 
mm3 
millimeter cubed 
MR 
minimal response 
MRD 
MTD 
minimum residual disease 
maximum tolerated dose 
NCI 
National Cancer Institute 

 
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NHL 
non-Hodgkin’s lymphoma 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cells 
PCCC 
Personal Cancer Care Consortium (of the University of Chicago) 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PO 
per os (oral) 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QDx5 
daily dosing for five days 
QIU 
Qualified Investigator Undertaking Form 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
SCC 
Statistical Analysis Plan 
Stem Cell Collection 
sCR 
stringent complete response 
SD 
stable disease 
SEER 
Surveillance, Epidemiology, and End Results 
SPEP 
serum protein electrophoresis  
STD10 
severely toxic dose in 10% of animals 
TLS 
Tumor lysis syndrome 
TTP 
time to tumor progression 
UCM 
University of Chicago Medicine 
ULN 
upper limit of the normal range 
UPEP 
urine protein electrophoresis 
VGPR 
very good partial response 
WBC 
white blood count 
 

 
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1 
INTRODUCTION 
1.1 
MULTIPLE MYELOMA 
Multiple myeloma is a clonal neoplastic proliferation of plasma cells affecting 19,900 US patients 
each year.1 Multiple myeloma is characterized by anemia, bone destruction, monoclonal 
gammopathy, renal failure, hypercalcemia and increased susceptibility to infections. The disease 
is systemic, and chemotherapy is indicated for management of symptomatic myeloma.  Current 
treatments include combination chemotherapy with regimens using melphalan (Alkeran®), 
bortezomib (Velcade®), thalidomide (Thalomid®), and lenalidomide (Revlimid®) and their 
combinations with and without corticosteroids.  Younger patients are consolidated with high-dose 
therapy (ablative chemotherapy or radiation) with autologous stem cell transplantation (ASCT).  
Although improvements in progression free survival and overall survival have occurred in the past 
5 years, even with the best available approved agents, 10-30% of patients fail to respond to the 
primary therapy, and almost all subjects eventually relapse, with a median overall survival of 44.8 
months.2 
1.2 
COMBINATIONS OF PROTEASOME INHIBITORS AND 
IMMUNOMODULATORY AGENTS 
Proteasome inhibitors (bortezomib, carfilzomib) and immunomodulatory agents (thalidomide and 
lenalidomide) are both highly effective agents in multiple myeloma.  Lenalidomide is an 
immunomodulatory derivative of thalidomide and has both immunomodulatory and anti-
angiogenic properties which are considered to confer anti-tumor effects.  Two pivotal randomized 
Phase 3 trials established that lenalidomide in combination with high-dose dexamethasone 
produced a significant improvement in overall response rate and time to tumor progression (TTP) 
vs. high-dose dexamethasone alone in relapsed multiple myeloma patients with up to 3 prior 
therapies.3,4 
Preclinical studies show that lenalidomide sensitizes multiple myeloma to the proteasome inhibitor 
bortezomib, suggesting combination therapy may enhance clinical activity.  The combination of a 
proteasome inhibitor and immunomodulatory agent is attractive, as the expected overlapping 
toxicities would be manageable.  A Phase 1 dose-escalation study was conducted to determine the 
maximum tolerated dose (MTD) and activity of the bortezomib, lenalidomide, and dexamethasone 

 
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combination in subjects with heavily pre-treated relapsed and/or refractory multiple myeloma.5  
The MTD was established as lenalidomide 15 mg and bortezomib 1.0 mg/m2 with 20 to 40 mg 
dexamethasone.  In 36 evaluable subjects, the overall response rate (CR+PR+MR) was 58%, 
including 6% CR.  Although the regimen is active, the requirement for dose reductions of both 
agents to achieve a tolerable combination may have resulted in suboptimal complete response 
rates. 
A phase 2 study followed to evaluate the efficacy and safety of lenalidomide, bortezomib, 
dexamethasone (RVD) at the phase 1 MTD.17 In 63 response-evaluable patients, the overall 
response rate (CR/nCR+VGPR+ PR+ MR) is currently 86%, including 24% CR/nCR and 67% 
CR/nCR/VGPR/PR. Response rates according to baseline cytogenetics, disease stage, and prior 
therapies showed no significant differences according to adverse risk. Toxicities were manageable, 
consisting primarily of grade (G) 1-2 myelosuppression. Attributable non-hematologic toxicities 
included deep vein thrombosis (two patients; attributed to lenalidomide), and two episodes of atrial 
fibrillation (G3) prompting Dex dose reduction. G3 polyneuropathy was reported in one pt 
attributed to bortezomib and leading to treatment discontinuation despite bortezomib dose 
reduction. Dose reductions were required for: lenalidomide (13 pts); bortezomib (9 pts) and 
dexamethasone (26 pts). 
Lenalidomide and high-dose dexamethasone without a proteasome inhibitor has shown impressive 
activity in untreated disease.  In a Phase 2 study of 34 subjects with newly diagnosed myeloma, 
subjects received lenalidomide (25 mg Days 1 to 21 of a 28-day cycle) and high-dose 
dexamethasone (40 mg Days 1 to 4, 9 to 12, and 17-20).  The objective response rate was 91%, 
with 6% CR, 32% near CR plus VGPR, and 53% PR.12  However, when this regimen was 
compared with a more conventional delivery of dexamethasone (40 mg Days 1, 8, 15, and 22) in 
a 445-subject study, the more intensive dexamethasone schedule was associated with significantly 
shorter overall survival relative to the less intensive regimen (1-year survival rates 86% vs. 96.5%, 
respectively).13  The dexamethasone-intensive regimen was associated with higher incidences of 
thromboembolism, hyperglycemia, and higher incidences of Grades 3 and 4 toxicities overall.  
Clearly, better and safer combination regimens for newly diagnosed disease are warranted. 

 
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A recently completed phase 1/2 study of bortezomib in combination with lenalidomide and 
dexamethasone (RVD) in newly diagnosed subjects with multiple myeloma has yielded promising 
results.9,10 Patients (N=66) received median 10 cycles of combination treatment and achieved 39% 
and 67% across all dose levels had achieved a CR or VGPR, and at MTD  57% and 74%, 
respectively.  The regimen overall was well tolerated; however, dose reductions due to bortezomib 
were common and 80% of patients developed peripheral neuropathy. 
In summary, the combination of proteasome inhibitors and immunomodulatory agents seems to be 
very active and well tolerated in patients with relapsed and/or refractory MM, including patients 
who have received prior lenalidomide, bortezomib, thalidomide, and SCT.  Further investigations 
with combination therapy with these agents in newly diagnosed disease are warranted. 
1.3 
CARFILZOMIB BACKGROUND 
Carfilzomib (PR-171) is a tetrapeptideketoepoxide-based inhibitor specific for the chymotrypsin-
like active site of the 20S proteasome.  Carfilzomib is structurally and mechanistically distinct 
from the dipeptide boronic acid proteasome inhibitor bortezomib (Velcade®).  In addition, when 
measured against a broad panel of proteases including metallo, aspartyl, and serine proteases, 
carfilzomib demonstrated less reactivity against non-proteasomal proteases when compared to 
bortezomib.11,12 
1.3.1 
CARFILZOMIB TOXICOLOGY STUDIES 
In the initial Good Laboratory Practice (GLP)-compliant toxicity studies done by the drug maker, 
Onyx, carfilzomib was administered to rats and monkeys as two complete two-week cycles of 
QDx5 for five days with nine days rest13 Administration to rats at 12 mg/m2, the severely toxic 
dose in 10% of animals (STD10), caused > 90% proteasome inhibition in red blood cells one hour 
after dosing.  Overall, stronger inhibition of the proteasome and longer duration of inhibition was 
tolerated with carfilzomib compared with bortezomib.  Daily administration of bortezomib at anti-
tumor doses is not tolerated in animals, and therefore daily bortezomib has not been given in the 
clinic.  A dose-dependent decrease in proteasome activity was demonstrated in animals, and 
equivalent levels of proteasome inhibition were achieved with administration of carfilzomib as 
either an intravenous (IV) push or an IV infusion.  The dose-limiting toxicities (DLTs) of 
carfilzomib in both the rat and monkey 28 day GLP toxicity studies included toxicity to the 

 
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gastrointestinal tract, bone marrow, pulmonary, and cardiovascular systems.  No behavioral or 
histopathological signs of neurotoxicity were observed, and carfilzomib does not cross the blood-
brain barrier. 
In 6-month rat and 9-month chronic toxicity studies, carfilzomib was administered on Days 1, 2, 
8, 9, 15, and 16 of a 28-day cycle, mimicking the active anti-tumor regimen being used in ongoing 
Phase II studies in myeloma and solid tumors.13 Tolerability was excellent, with no evidence of 
peripheral (or central) neurotoxicity, including neuropathology, observed, even at high doses.  This 
is in stark contrast to that observed with bortezomib.14,15  DLTs included effects on the 
gastrointestinal, renal, pulmonary, and cardiovascular systems and appeared to related to Cmax 
effects.  Of note, neutropenia was not observed; rather, transient neutrophilia was seen following 
acute dosing.  Renal, cardiovascular and gastrointestinal toxicities were similar to those observed 
with bortezomib.  Finally, cyclical thrombocytopenia, likely due to inhibition of platelet budding 
from megakaryocytes, was similar to that seen with bortezomib.  Proteasome inhibition in the 
blood in excess of 90% was achievable at well-tolerated doses, which contrasts with the ~70% 
proteasome inhibition achieveable with bortezomib at its maximum tolerated dose (MTD).  In 
summary, these animal toxicity studies support the tolerability of carfilzomib in clinical studies, 
even on intensive dosing schedules and at doses achieving proteasome inhibition in excess of what 
can be achieve with bortezomib at its MTD on a less intensive schedule. 
1.3.2 
CARFILZOMIB PRECLINICAL ANTITUMOR ACTIVITY 
Based upon the results of in vitro and in vivo studies, it is anticipated that the more intense and 
longer duration of proteasome inhibition that can be achieved with carfilzomib will result in 
enhanced anti-tumor activity relative to bortezomib.  Continuous (72 hr) exposure to carfilzomib 
is associated with potent cytotoxic and pro-apoptotic activity across a broad panel of tumor-derived 
cell lines in culture.11, 16  Incubation of hematologic tumor cell lines with carfilzomib for as little 
as one hour leads to rapid inhibition of proteasome activity followed by accumulation of 
polyubiquitinated proteins and induction of apoptotic cell death.  Carfilzomib has also been 
demonstrated to be cytotoxic in bortezomib-resistant tumor cell lines.11,16 
The anti-tumor efficacy of carfilzomib has been tested in immunocompromised mice implanted 
with a variety of tumor cell lines.  In a human colorectal adenocarcinoma model HT-29, 

 
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administration of carfilzomib on a twice-weekly Day 1, Day 2 schedule resulted in significant 
reduction in tumor size and was superior to a twice-weekly Day 1, Day 4 schedule using the same 
dose of carfilzomib, and a once-weekly dosing schedule using twice the dose level.  Bortezomib 
at its MTD has no activity in this xenograft model using the standard Day 1, Day 4 schedule.11 
1.3.3 
PHASE 1 EXPERIENCE WITH CARFILZOMIB AS A MONOTHERAPY 
A Phase 1 clinical trial, PX-171-002, testing carfilzomib in subjects with relapsed/refractory 
hematologic malignancies, is being completed.17  During the dose escalation portion of the trial, 
36 subjects received carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.  Subjects with 
Multiple 
Myeloma 
(MM), 
Non-Hodgkin’s 
Lymphoma 
(NHL), 
Waldenström’s 
Macroglobulinemia, and Hodgkin’s Lymphoma (HL) were enrolled on the study.   
No dose limiting toxicities (DLTs) were observed in the initial seven cohorts (doses ranged from 
1.2 to 15 mg/m2) of three subjects each.  At the 20 mg/m2 dose level, one of eight patients had a 
Grade 3 renal failure at Cycle 1, Day 2 which was considered possibly related to study drug and 
lasted for six days.  The patient continued on study for the remainder of Cycle 1 before having 
disease progression.   At the 27 mg/m2 dose level, one of six subjects experienced a DLT during 
Cycle 1, consisting of severe hypoxia with pulmonary infiltrates following Day 2 of dosing.  In 
subjects where the 27 mg/m2 dose was efficacious, a “first dose effect” was seen that included a 
constellation of findings that appeared to be the clinical sequelae of rapid tumor lysis syndrome 
(TLS) and/or cytokine release.  This effect was notable for fever, chills, and/or rigors occurring 
during the evening following the first day of infusion.  On the second day, three of five subjects 
with multiple myeloma experienced an increase in creatinine to Grade 2 (including the subject 
with the DLT).  This elevation was rapidly reversible and all three subjects were rechallenged with 
carfilzomib without recurrence of the events.  Interestingly, all three subjects had a rapid decline 
in serum and/or urine M-protein levels; two subjects achieved a PR and the third subject achieved 
a minimal response (MR).  There were no consistent changes in potassium, calcium, phosphorous, 
or uric acid levels although some increases in LDH and other markers of tumor lysis were noted.  
Because of the possible TLS and reversible creatinine elevations, hydration and very-low dose 
dexamethasone prophylaxis were instituted in subsequent studies and have essentially eliminated 
clinically significant TLS/creatinine elevations and the other “first-dose” effects.   

 
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Hematologic toxicities were primarily mild or moderate.  The thrombocytopenia reported with 
carfilzomib is cyclical and similar to that reported with bortezomib.  The cause and kinetics of the 
thrombocytopenia following treatment are different from those of standard cytotoxic agents.  To 
maximize the likely benefit of carfilzomib, subjects with thrombocytopenia should be supported 
as clinically indicated rather than having treatment reduced due to thrombocytopenia. 
Of the 36 evaluable patients enrolled in PX-171-002, 20 had MM.17  Four MM patients achieved 
a partial response (PR), one of two at the 15 mg/m2 dose, one of six at the 20 mg/m2 dose, and two 
of five at the 27 mg/m2 dose.  The responses have been rapid in onset, beginning in some subjects 
after 1-2 doses.  The duration of response (DOR) ranged from 134 to 392 days. The minimal 
effective dose was 15 mg/m2 wherein >80% proteasome inhibition in peripheral blood and 
mononuclear cells was observed one hour after dosing.  The median number of prior therapies for 
subjects on this trial was five, and responses were seen in subjects who had relapsed from 
(including some refractory to) bortezomib and/or immunomodulatory agents.  Stable disease also 
occurred in four NHL and five MM subjects, with subjects on therapy for up to 409 days.  Such 
prolonged therapy, at “full” twice-weekly doses, is not possible with bortezomib.  These results 
led to the initiation of two Phase 2 studies. 
1.3.4 
PHASE 2 EXPERIENCE WITH CARFILZOMIB AS A MONOTHERAPY 
Two Phase 2 clinical studies are ongoing with carfilzomib in MM patients, PX-171-003-A0 
(N=46) in relapsed and refractory MM and PX-171-004 (N=39) in relapsed MM.  In both studies, 
patients were dosed with 20 mg/m2 on Days 1, 2, 8, 9, 15, and 16 on a 28 day schedule.  In these 
studies there were four cases of suspected or documented TLS prior to institution of the 
prophylaxis guidelines.  Since these guidelines were implemented, no further cases of TLS have 
been reported including in >350 additional patients with relapsed or refractory MM treated in 
ongoing Phase II studies.  In both studies, the most common adverse events were fatigue, anemia, 
thrombocytopenia (primarily cyclical), gastrointestinal, and dyspnea.  Almost all were Grades 1 
or 2.  There were reported cases of increased in serum creatinine that were primarily < Grade 2 
and were transient, rapidly reversible, and non-cumulative.  A very low rate of treatment-emergent 
peripheral neuropathy, 2.2% Grade 3/4, was observed in PX-171-003-A0 despite the fact that 78% 
of patients had Grade 1/2 neuropathy upon study entry8.   

 
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The response rate in PX-171-003-A0 was 18% PR, 7% MR and 41% SD in these patients that 
entered the study with progressive disease and were refractory to their most recent therapy, often 
including bortezomib and/or an immunomodulatory drug (usually lenalidomide).  The median time 
to progression on the PX-171-003-A0 study was 5.1 months with a DOR of 7.4 months (mean 
follow up of 7.6 months).18   
A “stepped up” dosing schedule, referred to as 20/27 mg/m2, has subsequently been incorporated 
into the PX-171-003 study (referred to as PX-171-003-A1) in order to maximize the clinical 
benefit of carfilzomib.  Patients receive 20 mg/m2 for the first cycle and 27 mg/m2 thereafter.  The 
study completed enrollment of 266 patients by the end of 2009 and may form the basis for an 
accelerated approval NDA filing by the end of 2010.  To date, this dosing schedule has been well 
tolerated.17 An independent Safety Oversight Group (SOG) evaluated the safety data from the 40 
of 250 patients to be enrolled on the 20/27 schedule and agreed that the trial should proceed without 
modification.  No cases of TLS were observed and rates of BUN and creatinine elevation dropped 
sharply, with Grade 3/4 renal impairment dropping to 2.2% in A1( from 15% in A0), most likely 
due to hydration and very low dose dexamethasone.  The other most common adverse events were 
similar to the A0 portion of the study.  Treatment-emergent peripheral neuropathy remains low on 
this portion of the study with 15% Grade 1/2 and one (0.7%) Grade 3/4 event reported to date on 
PX-171-003-A1.18 In addition, anemia rates in the PX-171-003-A1 (higher dose) were lower than 
those reported in the PX-171-003–A0 portion of the study, possibly indicating that the higher dose 
of carfilzomib is achieving better clearing of neoplastic cells in the bone marrow allowing superior 
normal marrow reconstitution.  Rates of thrombocytopenia and neutropenia were similar in the 
two cohorts, with Grade 3 neutropenia in ~5% without any Grade 4 neutropenia to date.18 
In PX-171-004, a first cohort of patients received 20 mg/m2.  The subset of patients (N=54) that 
had not seen bortezomib had an ORR of 46% (2% CR, 9% VGPR and 35% PR), while the 
bortezomib treated patients (N=33) had an ORR of 18% (3% CR, 3% VGPR and 12% PR).19, 20 
The median TTP was 7.6 and 5.3 months in these two groups, respectively.  Thus, carfilzomib can 
induce very high levels of response in patients who have not previously been treated with 
bortezomib and, even in bortezomib-treated patients, substantial anti-tumor activity is observed.  
Of note, disease control (PR + MR + SD) was achieved in ~65% of patients with progressive MM 
entering the study.  Patients on these studies have been treated for >12 cycles with good tolerability 

 
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and no cumulative toxicity (e.g., bone marrow, severe fatigue, or neuropathy) have not been 
observed.  
The protocol was amended to allow patients to increase to 27 mg/m2 in Cycle 2 or later based on 
tolerability, similar to that used in PX-171-003 – A1.   
Further information about the Phase 2 studies is presented in the Investigator’s Brochure. 
1.4 
DOSE RATIONALE 
Preliminary data suggest that carfilzomib as a single agent can produce substantial response rates 
in myeloma subjects across a variety of dosing cohorts.  Responses were seen over a wide 
therapeutic window, from 15 to 27 mg/m2.  Maximum proteasome inhibition was seen at doses 11 
mg/m2 and higher in whole blood samples taken 1 hour after the first dose.  The final analysis of 
the human pharmacokinetic (PK) data is ongoing but appears to be rapid and similar to the results 
from the animal studies.  Carfilzomib is rapidly cleared from plasma with an elimination half-life 
of < 60 minutes at the 20 mg/m2 dose.  Large, single arm studies of the 27 mg/m2 dose are ongoing 
and suggest that this dose is very well tolerated with patients being treated for >10 cycles without 
cumulative toxicities. 
 
By the end of 2009, 269 patients with relapsed and refractory multiple myeloma have been enrolled 
in the PX-171-003-A1 study. The goal of dose escalating to 27 mg/m2 beginning with Cycle 2 is 
to improve ORR, DOR, and TTP. 
In multiple preclinical studies, the tolerability of carfilzomib in rats has been shown to be 
significantly higher when administered as a 30 min infusion as compared to a rapid IV 
bolus.  Toxicities observed with IV bolus injection of carfilzomib above the MTD at a dose of 48 
mg/m2 include evidence of prerenal azotemia (transient increases in BUN > creatinine) as well as 
lethargy, piloerection, dyspnea, and gastrointestinal bleeding. Notably, death occurred in ~50% of 
animals at 48 mg/m2 when carfilzomib was given as a bolus. Administration of the same dose (48 
mg/m2) as a 30 min continuous infusion was well tolerated, with no changes in BUN and creatinine 
and substantially reduced signs of lethargy, piloerection, or dyspnea.  Moreover, all animals in the 
infusion treatment groups survived.  The only toxicity observed following infusion of carfilzomib 

 
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for 30 min was gastrointestinal bleeding.  The reduced toxicity seen with dosing by infusion may 
reflect the reduced Cmax of carfilzomib vs that with bolus dosing.  Inhibition of the 
pharmacologicaltarget of carfilzomib (the chymotrypsin-like activity of the proteasome) was 
equivalent in the bolus and infusion treatment groups.   
In the clinic, the MTD of carfilzomib has not been reached in the multiple myeloma (MM) setting, 
particularly when administered as a 30’ infusion.  27mg/m2 of carfilzomib (bolus administration 
over 2-10’) is well tolerated in MM patients overall and can be tolerated for >12 cycles in late 
stage MM patients with substantial comorbidities.  
A phase 1 dose escalation study (PX-171-007) of single agent carfilzomib administered is ongoing 
and as of 10 July 2009, over 65 patients with solid tumors had started treatment in the initial Phase 
2 portion of the study at 36 mg/m2 (bolus administration over 2-10’). A review of the tolerability 
of 36 mg/m2 carfilzomib in these patients  indicates that this regimen was very well tolerated with 
only one DLT (fatigue) and an overall adverse event profile similar to that seen with the 27mg/m2 
carfilzomib experience with bolus dosing (see IB for details). Three patients completed > 12 cycles 
of therapy at 36 mg/m2 with no evidence of cumulative toxicity.  There were no significant DLTs 
observed; the majority of discontinuations on the study were due to progressive disease. Because 
of the long-term tolerability carfilzomib, the Phase 1b portion of this study was reopened, and a 
separate arm for multiple myeloma was added.  
In the PX-171-007 trial, more recently patients have been treated with carfilzomib given as a 30-
minute infusion in order to potentially minimize Cmax-related infusion events. The protocol was 
amended and does of 20/36 (20 mg/m2 given on Days 1 and 2 of cycle 1 only; followed by 36 
mg/m2 for all subsequent doses), 20/45, 20/56 mg/m2 and so forth are being investigated.  Doses 
of 20/56 mg/m2 are currently being given in two separate cohorts of patients with advanced MM 
and advanced solid tumors; the lower doses were well tolerated.  Preliminary tolerability 
information at this dose level (20/56 mg/m2) indicated that it is reasonably well tolerated, with 
minimal infusion reactions.  In some cases at 20/56mg/m2, dexamethasone was increased from 
4mg/dose to 8mg with the 56mg/m2 doses in order to reduce fevers and hypotension.  As of March 
20, 2010, seven patients have received 20/56mg/m2 and are tolerating it.  Patients with advanced, 
refractory MM being treated at 36mg/m2 and 45mg/m2 have shown very good tolerability (>6 

 
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months in some cases) with documented minimal and partial responses in these heavily pretreated 
patients. These data indicate that carfilzomib 30-minute infusion can be given at very high levels, 
with >95% inhibition of blood proteasome levels achievable and with (at least) acute tolerability.  
All protocols using ≥36mg/m2 carfilzomib are now administering the drug as a 30-minute 
infusion. 
In addition to the above observations, a phase I study of carfilzomib in patients with relapsed and 
refractory multiple myeloma was reported in abstract form at the 2009 American Society of 
Hematology meeting which demonstrated that carfilzomib can be safely administered to patients 
with substantial renal impairment (CrCl< 30, including patients on dialysis) without dose 
adjustment.21 These data indicate that carfilzomib does not exacerbate underlying renal 
dysfunction, and confirm the “pre-renal” etiology of the BUN/creatinine elevations observed with 
IV bolus carfilzomib. 
1.5 
LENALIDOMIDE BACKGROUND 
 
Lenalidomide (Revlimid®) is a proprietary IMiD® compound of Celgene Corporation.  IMiD® 
compounds have both immunomodulatory and anti-angiogenic properties which could confer 
antitumor and antimetastatic effects.  Lenalidomide has been demonstrated to possess anti-
angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell 
migration, due at least in part to inhibition of Akt phosphorylation response to bFGF.22 In addition, 
lenalidomide has a variety of immunomodulatory effects.  Lenalidomide stimulates T cell 
proliferation, and the production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and 
modulates IL-12 production.22 Upregulation of T cell derived IL-2 production is achieved at least 
in part through increased AP-1 activity.23  
Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of 
mechanisms are postulated to be responsible for lenalidomide’s activity against multiple myeloma.  
Lenalidomide has been shown to increase T cell proliferation, which leads to an increase in IL-2 
and IFN-gamma secretion.  The increased level of these circulating cytokines augment natural 
killer cell number and function, and enhance natural killer cell activity to yield an increase in 
multiple myeloma cell lysis.24  In addition, lenalidomide has direct activity against multiple 

 
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myeloma and induces apoptosis or G1growth arrest in multiple myeloma cell lines and in multiple 
myeloma cells of patients resistant to melphalan, doxorubicin and dexamethasone.25 
Indications and Usage: Revlimid® (lenalidomide) is indicated for the treatment of patients with 
transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes 
associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic 
abnormalities.  Revlimid® is also approved in combination with dexamethasone for the treatment 
of patients with multiple myeloma that have received at least one prior therapy. 
Adverse Events: Most frequently reported adverse events reported during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of presumed relationship to 
study medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal 
pain, nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, 
Upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, chest 
pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, generalized 
pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural effusion, pulmonary 
embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord compression, syncope, 
disease progression, death not specified and fractures. 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters. 
1.6 
EXPERIENCE WITH CARFILZOMIB IN COMBINATION WITH 
LENALIDOMIDE AND DEXAMETHASONE 
PX-171-006 is an ongoing Phase 1b study in patients with relapsed multiple myeloma in which 
carfilzomib is administered in combination with lenalidomide (Revlimid®) and dexamethasone.  
“Low-dose” dexamethasone 40 mg/day is given on Days 1, 8, 15, and 22 in all cases.  Carfilzomib 
is administered IV on Days 1, 2, 7, 8, 15, and 16; lenalidomide is administered PO on Days 1 
through 21.   
Enrollment has closed in this study, and no MTD was reached.  The maximum per protocol doses 
of carfilzomib (27mg/m2) with lenalidomide 25mg and low dose dexamethasone are being used.26 
After 8 patients tolerated these doses well, an additional 44 patients were enrolled in an 

 
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“expansion” cohort at this level, and this regimen is being taken into Phase III in study PX-171-
009. 
To date, 40 patients were treated in cohorts 1-6 and 44 in the cohort 6 expansion. 27/32 patients in 
cohorts 1–5 are evaluable for safety and 29/32 for response. Patients were heavily pre-treated; 72% 
received prior BTZ and 87.5% received prior LEN or thalidomide (Thal). 47% of patients were 
refractory to their last therapy (typically lenalidomide + high dose dexamethasone; > 84% of 
patients had a history of neuropathy with 67% BTZ- or Thal-related. No treatment emergent 
fatigue, neuropathy, or thrombotic events ≥ Grade (G) 3 were observed. Hematological AEs ≥G3 
(thrombocytopenia [n=6], anemia [n=4], and neutropenia [n=6]) were reversible. 4 patients had 
drug-related SAEs as follows: transient G3 sinus bradycardia, G3 upper respiratory tract infection, 
febrile neutropenia, and G3 diarrhea + G3 urinary infection. ORR and CBR for the 29 evaluable 
patients are 59% and 72%, respectively. Response data is shown in the table below. Initial 
responses improved with continued therapy, (up to 18 cycles). Median duration of response has 
not been reached (median follow-up 5.2 months). No dose-limiting toxicities or deaths attributed 
to study treatment have been observed. Several patients have completed the study (in the lower 
dose cohorts) after 18 cycles and are continuing in an extension study.  Updated efficacy data are 
presented in the following table: 
 
 
CRd: Cohorts 1–5 
(CFZ: 15 to 20 mg/m2; LEN: 10 to 25 mg)  
Response 
Relapsed (n=16) 
Refractory 
(n=13) 
Overall  
(n=29) 
   ≥ CR/nCR 
5 (31) 
1 (8) 
6 (21) 
   ≥ VGPR 
7 (44) 
4 (31) 
11 (38) 
   ≥ PR 
9 (56) 
8 (62) 
17 (59) 
   ≥ MR 
11 (67) 
10 (77) 
21 (72) 
 
In the Investigator Initiated CRd study in newly diagnosed MM, the regimen was well tolerated in 
phase I portion of the study up to maximum planned dose (MPD) of carfilzomib 36 mg/m2, 
lenalidomide 25 mg and dexamethasone 40 mg without reaching MTD, and highly active with 
>PR 96%, >VGPR 70%, and 55% CR/nCR as best response for all dose levels.27 Furthermore, the 

 
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lack of overlapping toxicity have allowed for the use of these agents at full doses and for extended 
periods and the study proceeded to Phase II at MPD and completed enrollment (total 53 patients). 
On both phase I and II, patients receive 8 initial 28-day cycles, with carfilzomib at 20 mg/m2, 27 
mg/m2 (Phase I), and 36 mg/m2 (Phase I and II, given IV on days 1, 2, 8, 9, 15, and 16, lenalidomide 
at 25 mg PO (days 1–21), and dexamethasone at 40/20 mg PO weekly (cycles 1–4/5-8). Patients 
achieving ≥PR could proceed to stem cell collection (SCC) and autologous stem cell transplant 
(ASCT) after 4 cycles. Per protocol design, ASCT candidates were offered the option to continue 
CRd treatment after SCC. After 8 cycles, pts received 28-day maintenance cycles of carfilzomib 
(days 1, 2 15, 16), lenalidomide days 1–21, and dexamethasone weekly at the doses tolerated at 
the end of 8 cycles. Responses are assessed by IMWG criteria with the addition of nCR. In the 
phase I, 4 patients were enrolled at carfilzomib 20 mg/m2, 13 at carflizomib 27 mg/m2 and 36 at 
CFZ 36 mg/m2 (18 in Phase I and 18 in Phase II). Median age was 59 years (range 35-81; including 
23 patients 65 or older), 74% were men, 60% ISS stage II/III, 33% of 49 with available data any 
of del 13 or hypodiploidy by metaphase, or t(4;14), t (14;16), del17 by FISH. As of cut-off date 
(June 30, 2011), 51 evaluable pts received a median of 8 cycles. Toxicity data (cycles 1-8) were 
available for 51 pt who have completed at least the first cycle. Hematologic toxicities were 
reversible and included Grade (G) 3/4 neutropenia in 10%, G3/4 thrombocytopenia in 10%, and 
G3/4 anemia in 9%. The most common non-hematologic toxicities (all grades) were 
hyperglycemia (76%), hypophosphatemia (61%), and infection (53 %). G3/4 non-hematologic 
AEs included DVT/PE while on ASA prophylaxis (10%), mood alteration (2%) and glucose 
elevations (24%); the last 2 AEs were related to Dexamethasone. Peripheral neuropathy was 
limited to G1/2 sensory (24%) Forty-five pts continue treatment (2 proceeded to transplant, 1 
discontinued for toxicities, 3 for events not related to treatment or per pt wish), and 22 pts continue 
on treatment in the maintenance phase. The majority of pts did not require any dose modifications, 
neither in the initial nor in the maintenance phase (31% and 25%, respectively). Responses were 
rapid with 42 of 49 pts achieving at least PR after 1 cycle. After a median of 8 cycles for all pts 
(range 1–20), the best response rates per IMWG criteria in 49 evaluable pts who completed at least 
1 cycle are shown in Table. Response rates improved with the duration of treatment and reached 
PR 100%, >VGPR 100%, and CR/nCR 79%. Responses were deep even at lowest dose levels with 
the majority of pts at level 3 still early in treatment.  Responses by ISS stage or cytogenetic status 
were similar in specific subgroups to overall response results. 24 patients proceeded to stem cell 

 
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collection after a median of 5 cycles of CRd (range 4-9), using growth factors only in 23 patients 
and cyclophosphamide and growth factors in 1 pt, with a median 6.55 x 106 CD34+ cells/kg 
collected (range 3.75-9.6); all resumed CRd treatment. After a median of 9.5 months of follow-up, 
only 1 evaluable patient has progressed, and all are alive. More recent analysis, showed continued 
improvement of the depth of response with the duration of treatment (median 13 months) and an 
unprecedented rate of stringent responses (sCR) which at the completion of 8 cycles reached 43% 
28 
 
 
ORR (%) 
CR/nCR (%) 
VGPR(%) 
Tx cycles 
 
 
 
1+ (n=49) 
94 
53 
65 
4+ (n=35) 
100 
71 
89 
8+ (n=28) 
100 
75 
89 
12+ (n=19) 
100 
79 
100 
CFZ dose, mg/m2 
 
 
 
20 (n=4) 
100 
75 
100 
27 (n=13) 
100 
85 
100 
36 (n=32) 
91 
38 
47 
ISS stage 
 
 
 
I (n=20) 
90 
50 
65 
II (n=16) 
94 
44 
56 
III (n=13) 
100 
69 
77 
Cytogenetics n=49 
 
 
 
Normal/favorable (n=33) 
91 
52 
61 
Unfavorable (n=16) 
100 
56 
75 
 
It was concluded that CRd is highly active and well tolerated allowing the use of full doses for an 
extended time in patients with newly-diagnosed MM with limited need for dose modification. 
Responses are rapid and improve over time reaching 100% >VGPR. Efficacy results were 
comparable across ISS stage and cytogenetic status and early time-to-event data are very 
encouraging. This study is the first to report the frontline treatment of myeloma with CRd to date, 
and provides additional support for the ongoing phase 3 ASPIRE trial of CRd vs. Rd in patients 
with relapsed and/or refractory MM.29  
Together, these results suggest that carfilzomib, lenalidomide, and low-dose dexamethasone 
(CRd) in combination are active and well tolerated and that there are no significant overlapping 

 
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toxicities (in the dose ranges tested). Importantly, lenalidomide-associated neutropenia and 
thrombocytopenia do not appear to be exacerbated by concurrent treatment with carfilzomib, 
suggesting that carfilzomib will combine well with other anti-cancer agents. 
1.7 
STUDY RATIONALE 
Considering that autologous stem cell transplant (ASCT) improves the depth of response of even 
the most active regimens and that post ASCT consolidation further improves this effect,3,4, the 
current study will investigate whether a combination of initial treatment with 4 cycles of CRd (pre-
ASCT induction) followed by ASCT followed by 4 cycles of CRd consolidation improves the rate 
of sCR compared to the historical rate of sCR determined in the recently completed frontline CRd 
study with delayed transplant, with comparisons made at the completion of the equivalent duration 
of treatment without transplant, i.e. after 8 cycles of CRd without transplant.28,30 In addition, the 
study design will provide an estimate of an impact of ASCT on an overall response, DOR, PFS, 
and OS in comparison to treatment with CRd induction and CRd maintenance of similar patient 
population but without transplant. Therefore, this study’s results help to answer whether or not we 
can build upon the already established high activity of the CRd regimen adding of the most active 
treatment in myeloma, i.e. high dose of melphalan and ASCT to the CRd treatment strategy and 
further improve sCR rate.  
The CRd combination shows very high activity without transplant in new myeloma (100% PR 
rate, up to 82% VGPR, and 67% CR/nCR rate)1 and is well tolerated in both new myeloma1 as 
well is in relapsed myeloma.2 At the completion of 8 cycles of CRd, 67% of patients achieved 
nCR/CR and 43% sCR. While the role of autologous stem cell transplant (ASCT) in the era of 
novel active therapies is currently being evaluated, ASCT remains a standard of care for transplant 
candidates and still commonly used.  Initial therapy with active novel regimens (ie RVD, RVDD, 
VDT) followed by autotransplant produced excellent post-ASCT response rates with evidence that 
transplant improves further pre-transplant level of disease cytoerduction.3,4   We hypothesized that 
given the superior activity seen in the CRd combination, this combination will likely improve the 
depth of response achieved with other regimens prior to transplant, and therefore subsequently at 
3 months post-ASCT. Using similar strategy, pre-ASCT and at 3 months post-ASCT patients 
initially treated with VDT achieved 31% and 52% nCR/CR, respectively (sCR not reported).31 

 
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Since at least VGPR (including CR/nCR) prior to ASCT and post-ASCT improves progression 
free survival and overall survival,5,6 we will use information gained from this study to evaluate if 
ASCT incorporated into the CRd treatment is a better treatment strategy for initial therapy of 
patients starting treatment with CRd than an extended treatment with CRd without transplant. 
Therefore, this study can influence the design of future randomized studies with CRd as initial 
treatment of newly diagnosed myeloma. The study population for the current protocol, i.e. newly 
diagnosed multiple myeloma subjects, is expected to have similar characteristics as the study 
population enrolled in the recently completed CRd study and is expected to tolerate therapy very 
well, based on our frontline CRd experience, as detailed in Section 1.5 above. Since we established 
tolerable CRd doses in the recently completed frontline CRd trial, there is no need for Phase 1b 
study.  This study will allow for an assessment of the role of ASCT for patients initially induced 
with CRd as the results from this study could be compared to the results from the recently 
completed clinical trial in which all patients, including ASCT candidates continue CRd treatment 
with a deferred transplant for later. The current standard of care for patients who completed ASCT 
is lenalidomide maintenance based on the results of 2 randomized studies, which showed superior 
PFS versus placebo for all patient groups including patient in CR post ASCT (Attal et al ASH 
2010, McCarthy et al. ASH 2010), and superior OS (McCarthy et al., IMW 2011). But there is also 
evidence of benefit of bortezomib-based consolidation (Cavo et al, ASH 2010 and ASH 2011) and 
maintenance with proteasome inhibitor (bortezomib, the first approved proteasome inhibitor; 
Sonnefeld et al, ASH 2011) and appearance of superior maintenance when both IMiD and 
bortezomib are combined (Palumbo et al, ASH 2010, Mateos et al, Lancet Oncology 2011). Based 
on excellent tolerance of CRd for extended periods of time in the recently completed frontline CRd 
study (Jakubowiak et al, ASH 2011) we hypothesized that a course of post-ASCT CRd 
consolidation and CRd maintenance will improve depth of response and progression-free survival 
in post transplant setting compared to post-ASCT lenalidomide alone. Therefore, PFS from this 
study—which is one of the study secondary endpoints—will provide an estimate whether this 
strategy is superior to the initial therapy with any regimen followed by transplant followed by 
lenalidomide maintenance reported earlier (Attal et al ASH 2010, McCarthy et al. ASH 2010), 
therefore further enhancing our ability to design future randomized studies with CRd in transplant 
candidates.  

 
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2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To determine the rate of stringent CR (sCR) after 8 cycles of CRd (4 cycles of induction 
+ ASCT + 4 cycles of CRd consolidation). 
2.2 
SECONDARY OBJECTIVES 
Secondary objectives include characterization of additional efficacy variables: 
• Overall response rate defined as partial response or better (>PR) including the 
rate of VGPR or better (>VGPR) and near complete response or better 
(sCR/CR/nCR) across entire treatment in high risk and low risk patients 
• Duration of response (DOR), Progression free survival (PFS), Time to 
progression (TTP), and Overall Survival (OS) 
2.3 
EXPLORATORY OBJECTIVES 
Exploratory objective include characterization of following variables: 
• To determine the rate of minimal residual disease by multiparameter-flow 
cytometry  in patients who achieved CR after 4 cycles, transplant, 8 cycles and 
end of treatment 
• Evaluation of MRD by gene sequencing method using the Sequenta platform 
(LymphoSIGHT®) in parallel with multi-parameter flow cytometry (MFC) 
• Prospective evaluation of candidate markers of response to CRd established in 
the completed CRd trial 
• Evaluation of markers of response and duration of response to treatment strategy 
using CRd with or without transplant 
3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This study is a multi-center, open-label, Phase 2 study in which transplant candidates with newly 
diagnosed MM requiring systemic chemotherapy will receive induction treatment with 

 
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carfilzomib, lenalidomide, and dexamethasone and post autologous stem cell transplant CRd 
consolidation/maintenance therapy.   
The study will determine the efficacy of the treatment strategy.  The primary endpoint is to 
determine the response rate (sCR) after completion of a total of 8 cycles of CRd (4 cycles of CRd 
induction followed by ASCT followed by 4 cycles of CRd consolidation).  Definitions of these 
primary endpoints plus a list of secondary endpoints are given in Section 2.1.  Protocol treatment 
(CRd) will last for a total of 18 cycles (4 cycles prior to ASCT + 4 cycles post ASCT consolidation 
+ 10 cycles of maintenance).   
This study will enroll 70 patients in the pre-ASCT induction portion of the study and anticipate 
that most of these will resume protocol treatment at the consolidation/maintenance therapy post 
ASCT. Patients who complete the CRd induction but who become not eligible for ASCT can be 
considered to continue protocol treatment after discussion with the Lead Principal Investigator 
with an additional 4 cycles of CRd as in consolidation regimen followed by 10 cycles of CRd 
maintenance as in CRd maintenance regimen. Patients who decline transplant for reasons other 
than toxicities will be replaced. After completion of CRd treatment, it will be recommended that 
patients continue single-agent lenalidomide maintenance therapy off protocol at the last tolerated 
dose of lenalidomide, provided the dose is tolerated and there is no evidence of progressive disease. 
Carfilzomib will be administered at 20 mg/m2 as an IV infusion on Days 1 and 2 of Cycle 1 
followed by 36 mg/m2 as an IV infusion on Days 8, 9, 15, and 16 for the remainder of Cycle 1 and 
on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle for the remaining Cycles 2-4 (Cycles 1- 4 represent 
induction) and at dose last tolerated prior to ASCT on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle 
for Cycles 5-8 (CRd consolidation). During CRd maintenance (Cycles 9-18), carfilzomib will be 
administered at the last tolerated dose as an IV infusion on Days 1, 2, 15, and 16 of a 28-day cycle. 
Lenalidomide will be administered PO daily at 25 mg on Days 1-21 of the 28 day cycle for pre-
ASCT induction Cycles 1-4 (induction) and at the last tolerated dose prior to ASCT on Days 1-21 
of the 28 day cycle for Cycles 5-8 (CRd consolidation) and Cycles 9-18 (CRd maintenance). The 
first cycle of consolidation post-transplant must start at a lenalidomide dose no higher than 15 mg. 
In discussion with the Lead Principal Investigator and on a case-by-case basis, provisions may be 
made to start CRd consolidation with a lower than 15 mg dose of lenalidomide for participants 

 
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with inadequate hematologic parameters at 70-90 days following stem cell reinfusion (not later 
than 120) and/or to escalate lenalidomide dose up to 25 mg per dose after completion of 1 cycle 
of CRd consolidation for participants with adequate hematologic parameters. Patients that do not 
complete ASCT but continue on CRd maintenance will follow the same CRd consolidation 
treatment for 4 cycles followed by 10 cycles of CRd maintenance. 
Dexamethasone will be administered PO or IV between 30 minutes and 4 hours preceding 
carfilzomib infusion as follows: 
• Cycles 1-4 (induction): 40 mg per dose on Days 1, 8, 15, and 22 
• Cycles 5-8 (CRd consolidation): 20 mg (or last tolerated dose) per dose on days 1, 8, 15, and 
22 
• Cycles 9-18 (CRd maintenance): 20 mg (or last tolerated dose) on days 1, 8, 15 and 22 
Individual subjects should receive 4 cycles of pre-ASCT CRd induction treatment.  After cycle 4, 
subjects will proceed to stem cell harvest with the use of growth factors or as per current standards 
of care as described in section 6.4. Patients who achieve confirmed CR/nCR prior to completion 
of 4 cycles of CRd can proceed to stem cell collection (SCC) earlier but then resume treatment for 
a total of 4 induction CRd cycles. Patients who achieve less than optimal response (≤PR) may be 
eligible to receive up to two more cycles of induction CRd prior to transplant after approval from 
the Lead Principle Investigator. The number of post-transplant consolidation cycles will be 
adjusted accordingly so that the total number of cycles (induction + consolidation) remains at 8. 
3.2 
NUMBER OF CENTERS 
A total of 5 MMRC centers will participate in this study.  
3.3 
NUMBER OF SUBJECTS 
This study will enroll 70 patients in the induction portion of the study. Those who do not have 
ASCT will be replaced.  

 
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3.4 
ESTIMATED STUDY DURATION 
The total study enrollment period is expected to be 18-24 months.  A subject is considered to have 
completed the treatment phase of the study 4 weeks (28 days) after the end of the last treatment 
cycle.  Excluding long-term follow-up, the treatment phase of the study will be completed once 
the last subject completes the 28-day safety follow-up visit (30 days for resolution of toxicity).  
Subjects who have not progressed will be followed for progression for up to 5 years from the 
completion of the safety follow-up visit. All subjects will be followed for survival and 
development of new cancers at least every 3 months for 5 years. 
3.5 
TREATMENT SCHEMA 
 
Newly Diagnosed Symptomatic Myeloma 
 
CRd induction X 4 cycles 
 
Stem cell Harvest 
 
ASCT 
 
CRd consolidation X 4 cycles 
 
CRd maintenance X 10 cycles 
 
Lenalidomide maintenance 
(recommended off protocol maintenance therapy) 
 
3.6 
INCLUSION CRITERIA 
Disease-related: 
1. Newly diagnosed, myeloma requiring systemic chemotherapy as per IMWG uniform 
criteria (see Appendix B): 
• 
Prior treatment of hypercalcemia or spinal cord compression or active and/or 
aggressively progressing myeloma with corticosteroids or lenalidomide or bortezomib-

 
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based regimens does not disqualify the patient (the treatment dose should not exceed 
the equivalent of 160 mg of dexamethasone in a 4 week period or not more than 1 
cycle) 
• 
Bisphosphonates are permitted 
2. Suitable and interested to proceed to ASCT. (Refer to section 6.4) 
3. Measurable disease, prior to initial treatment as indicated by one or more of the following: 
• 
Serum M-protein ≥ 0.5 g/dL  
• 
Urine M-protein ≥ 200 mg/24 hours 
• 
If serum protein electrophoresis is felt to be unreliable for routine M-protein 
measurement, then quantitative immunoglobulin levels are acceptable 
Demographic:   
4. Males and females ≥ 18 years of age 
5. Life expectancy of more than 3 months 
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix C) 
Laboratory 
7. Adequate hepatic function, with bilirubin < 1.5 times the upper limit of normal (ULN), and 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times ULN 
8. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L, hemoglobin ≥ 8 g/dL, platelet count ≥ 75 
x 109/L.  Screening platelet count should be independent of platelet transfusions for at least 
2 weeks.   
9. Calculated or measured creatinine clearance of ≥ 50 mL/minute, calculated using the 
following formula of Cockcroft and Gault:  
(140 – age) x mass (kg)      x 0.85 (if female) 
72 x creatinine (mg/dL) 
Or creatinine below 2 g/dl 
Ethical/Other 
10. Written informed consent in accordance with federal, local, and institutional guidelines  
11. Females of childbearing potential (FCBP) [defined as sexually mature females who: 1) 
have not undergone a hysterectomy or bilateral oophorectomy; or 2) have not been 

 
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naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any 
time in the preceding 24 consecutive months)] must agree to ongoing pregnancy testing. 
12. FCBP must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
initiating lenalidomide.  The first pregnancy test must be performed within 10-14 days 
before Day 1 Cycle 1 and the second pregnancy test must be performed within 24 hours of 
Day 1 Cycle 1.  The subject may not receive lenalidomide until the Treating Investigator 
has verified that the results of these pregnancy tests are negative, and must agree to ongoing 
pregnancy tests as outlined in the protocol. For patients already on Revlimid, continuation 
of current testing schedule is permitted as long as it is not interrupted during the transition 
to CRd therapy. 
13. FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice 
complete abstinence from heterosexual intercourse during the following time periods 
related to this study: 1) for at least 28 days before starting lenalidomide; 2) while 
participating in the study; and 3) for at least 28 days after discontinuation from the study. 
The 2 methods of reliable contraception must include a highly effective method (ie, 
intrauterine device (IUD), hormonal [birth control pills, injections, or implants], tubal 
ligation, partner’s vasectomy) and an additional effective (barrier) method (ie, latex 
condom, diaphragm, cervical cap).  FCBP must be referred to a qualified provider of 
contraceptive methods if needed.   
14. Male subjects must agree to use a latex condom during sexual contact with females of 
childbearing potential while participating in the study and for at least 28 days following 
discontinuation from the study even if he has undergone a successful vasectomy.   
15. Male subjects must agree to inform his physician if he has had unprotected sexual contact 
with a female who can become pregnant or if he thinks for any reason that his sexual partner 
may be pregnant.   
16. Male subjects must agree not to donate semen or sperm while taking lenalidomide and/or 
carfilzomib and 28 days after the last Lenalidomide/Carfilzomib dose.   
17. All study participants enrolled in the United States must be registered into the mandatory 
REVLIMID Rems ® program and be willing and able to comply with the requirements of 
REVLIMID Rems®.      
18. The ability to take aspirin or other appropriate VTE prophylaxis 

 
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19. Subjects must agree to adhere to all study requirements, including birth control measures 
and pregnancy testing, visit schedule, outpatient treatment, required concomitant 
medications, and laboratory monitoring. 
3.7 
EXCLUSION CRITERIA 
Disease-related 
1. Non-secretory or hyposecretory multiple myeloma, prior to initial treatment defined as 
<0.5 g/dL M-protein in serum, <200 mg/24 hr urine M-protein, or disease only measured 
by serum free light chain   
2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, 
and skin changes)   
3. Waldenström’s macroglobulinemia or IgM myeloma 
4. Radiotherapy to multiple sites or immunotherapy within 4 weeks before start of protocol 
treatment (localized radiotherapy to a single site at least 1 week before start is permissible) 
5. Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-
lives (t1/2) prior to first dose, whichever time is greater 
6. Participation in another clinical trial unless approved by the Lead Principal Investigator 
Concurrent Conditions 
7. Pregnant or lactating females 
8. History of allergy to mannitol 
9. Major surgery within 3 weeks prior to first dose 
10. Myocardial infarction within 6 months prior to enrollment,  NYHA Class III or IV heart 
failure, 
uncontrolled 
angina, 
severe 
uncontrolled 
ventricular 
arrhythmias, or 
electrocardiographic evidence of acute ischemia or active conduction system abnormalities 
11. Uncontrolled hypertension or diabetes 
12. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two 
weeks prior to first dose 
13. Known or suspected HIV infection, known HIV seropositivity 
14. Active hepatitis A, B, or C infection 

 
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15. Non-hematologic malignancy within the past 3 years except  a) adequately treated basal 
cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate 
cancer < Gleason Grade 6 with stable prostate specific antigen levels  or cancer considered 
cured by surgical resection alone 
16. Any clinically significant medical disease or condition that, in the Treating Investigator’s 
opinion, may interfere with protocol adherence or a subject’s ability to give informed 
consent  
17. Significant neuropathy (Grades 3-4, or Grade 2 with pain) at the time of the first dose 
and/or within 14 days before enrollment 
18. Contraindication to any of the required concomitant drugs, including proton-pump 
inhibitor (eg, lansoprazole), enteric-coated aspirin, allopurinol or if a history of prior 
thrombotic disease, warfarin or low molecular weight heparin 
19. Subjects in whom the required program of PO and IV fluid hydration is contraindicated, 
eg, due to pre-existing pulmonary, cardiac, or renal impairment 
20. Subjects with known or suspected amyloidosis of any organ 
21. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis. 
22. For subjects enrolled in the United States, no coverage or not-acceptable by patient co-pay 
for Lenalidomide. 
4 
SUBJECT ENROLLMENT 
4.1 
PATIENT ENROLLMENT AND REGISTRATION 
Patient registration for this trial will be centrally managed by the designated University of Chicago 
Clinical Research Associate (CRA). A potential study subject who has been screened for the trial 
and who has signed the Informed Consent document will be initially documented by the 
participating site on the Screening and Enrollment Log provided by the University of Chicago. 
It is the responsibility of the site Treating Investigator to determine patient eligibility prior to 
submitting a patient registration request to the lead site. After patient eligibility has been 
determined, a copy of the completed Eligibility Worksheet together with all the pertinent source 
documents will be submitted by the requesting site to the University of Chicago CRA, either by 
fax or by email between the hours of 9 am and 5 pm CST. 

 
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The University of Chicago CRA, who acts as the registrar, will review the submitted documents 
and process the registration.  Sites should inform the CRA of a potential registration by 5 p.m. 
Central Time at least 72 hours prior to the anticipated Cycle 1 Day 1.  Same day registrations 
cannot be guaranteed. 
Subsequently, an email will be sent by the University of Chicago CRA to the requesting site 
registrar to confirm patient registration and to provide the study identification number that has 
been assigned to the patient. In addition, a copy of the completed eligibility worksheet signed and 
dated by the registrar, will be faxed back to the requesting site registrar. 
Following completion of the induction therapy, patients proceeding to ASCT will be considered 
“off study.” Prior to beginning consolidation, subjects must meet treatment  parameters including 
ANC ≥ 1.0 x 109/L, Platelet count ≥ 50 x 109/L, serum uric acid and creatinine levels returned to 
baseline and resolution of all transplant-related toxicities (Section 5.3). 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 
5 
TREATMENT 
5.1 
GENERAL PROCEDURES 
Individual Subject Treatment 
After screening, eligibility determination, and enrollment, subjects will receive carfilzomib, 
lenalidomide, and dexamethasone.  All subjects are planned to receive 4 cycles of CRd induction. 
Patients who achieve confirmed CR/nCR prior to completion of 4 cycles can proceed to SCC 
earlier but then resume treatment for a total of 4 induction cycles. After completion of induction, 
all patients will proceed to stem cells harvest followed by ASCT.   
Following ASCT (3 months post-AST; 70-90 days but not more than 120), subjects will continue 
with CRd consolidation (cycles 5-8). Of note, 30 days following the last dose of CRd, (i.e. Cycle 
4 Day 22), or at the start of stem cell collection (whichever occurs first), and during ASCT period, 
patients will be considered to be off-study so no toxicities will be recorded for this period unless 

 
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considered directly related to treatment with CRd. The CRd maintenance phase will commence at 
the start of cycle 9 and continue through cycle 18. 
For patients enrolled into CRd induction, consolidation, and maintenance the protocol treatment 
will last for a total of 18 cycles (4 cycles prior to ASCT + 4 cycles post ASCT consolidation + 10 
cycles of CRd maintenance).  After completion of CRd treatment, patients will then move to a 
recommended single-agent lenalidomide maintenance therapy off protocol, as long as it is tolerated 
and there is no evidence of progressive disease.   
An individual subject will be considered off-treatment following a 30-day safety follow-up period 
after the last CRd cycle of treatment.  Subjects who have not progressed upon completion or 
discontinuation of the study will be followed for up to 5 years from the safety follow-up visit for 
disease progression. All subjects will be followed for survival and development of new cancers at 
least every 3 months. 
5.2 
DRUG ADMINISTRATION 
5.2.1 
PRETREATMENT PREPARATION 
Two days before Day 1 of Cycle 1, the following required concomitant medication should be 
started: 
• Oral hydration 30 mL/kg/day (approximately 6 to 8 cups of liquid per day) and 
before each dose of carfilzomib.  Compliance must be assessed before initiating 
treatment; treatment is to be delayed if PO hydration is not adequate. 
The following required treatments will be started on Cycle 1 Day 1 or up to 24 hours prior to 
Cycle 1 Day 1: 
• Valacyclovir 500 mg PO QD or equivalent HZV prophylaxis, continuing for the 
duration of treatment.  Additional prophylaxis is at the Treating Investigator's 
discretion. 
• Aspirin (enteric-coated) 325 mg PO QD for the duration of treatment.  (Subjects 
with known high thrombotic risk, eg, prior thrombosis, DVT, etc) should receive 
full anticoagulation at the Treating Investigator's discretion.) 
The following may be given at Treating Investigator’s discretion 

 
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• Lansoprazole (Prevacid ) 15 mg PO QD, or other PO proton-pump inhibitor or H1 
blocker to prevent peptic disease for the duration of treatment 
• Mycostatin or Nystatinto prevent oral thrush  
Serum chemistries and hematology must be obtained and reviewed prior to carfilzomib dosing on 
Days 1, 8, 15 during Cycle 1-8 and on Days 1 and 15 of Cycles 9-18.  Clinically significant 
electrolyte abnormalities (ie, ≥ Grade 2) should be corrected before carfilzomib dosing. Serum 
chemistries on Day 2, 9, 16 are optional if Tumor Lysis Syndrome is suspected or at the discretion 
of the treating investigator. 
• On Day 1: 
o Dexamethasone (IV or PO) is given between 30 minutes and 4 hours before 
carfilzomib.   
o IV hydration will be given immediately before each carfilzomib dose during Cycle 
1.  This will consist of 125 to 500 mL normal saline or other appropriate IV fluid.  If 
LDH or uric acid is elevated (and/or in subjects considered still at risk for tumor lysis 
syndrome) at Cycle 2, Day 1, then the recommended IV hydration should be given 
additionally before each dose in Cycle 2.  The goal of the hydration program is to 
maintain robust urine output (comparable to fluid intake).  Subjects should be 
monitored closely during this period for evidence of fluid overload and diuretics 
should be used if patients have positive fluid balance of more than 1litre or weight 
gain of more than 1 kg. 
o Subjects should have a dedicated line for carfilzomib administration.  Before and 
after administration, the line must be flushed with 20 mL of normal saline.  If a 
dedicated line is not possible, the existing line must be flushed with a minimum of 
20 mL of normal saline before and after drug administration. 
5.2.2 
DEXAMETHASONE 
Dexamethasone will be administered between 30 minutes and 4 hours preceding the carfilzomib 
(on days that they coincide), as follows:  
• Cycles 1 – 4 (induction):  40 mg PO or IV per dose Days 1, 8, 15 and 22 

 
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• Cycles 5 – 8 (consolidation): 20 mg (or last tolerated dose) PO or IV per dose Days 1, 8, 15 and 
22 
• Cycles 9 – 18 (maintenance): 20 mg (or last tolerated dose) PO or IV per dose Days 1, 8, 15 and 
22 
During Cycle 1, dexamethasone may administered as a split schedule PO or IV pre-Carfilzomib 
on days 1, 2, 8, 9, 15, 16 as well as Day 22, 23 in patients with high tumor burden or risk for 
cytokine release syndrome. This means that a patient assigned 40mg dexamethasone on days 1, 8, 
15, 22 may receive 20 mg on days 1,2, 8, 9, 15, 16, 22, 23 (20/20) or 36 mg on Day 1, 8, 15, 22 
and 4 mg on Days 2, 9, 16, 23 (36/4). It is recommended that patients should return to one dose of 
40mg/week in Cycle 2+ however a split schedule may be implemented after discussion with the 
Lead Principle Investigator.  
Dexamethasone given on days without carfilzomib (on Days 22 of Cycles 1-8) may be self-
administered by the subject on an outpatient basis.  
Missed doses of dexamethasone will not be made up. Procedures for dose reductions and delays 
are summarized in Section 5.4 (Table 5.3)  
5.2.3 
CARFILZOMIB 
Carfilzomib will be administered after dexamethasone as follows: 
• 
Cycle 1 Days 1 and 2: 20 mg/m2 IV over 10 minutes but may be administered over 30 
minutes according to institutional guidelines 
o For patients at high risk for Tumor Lysis Syndrome, step-up dosing to 27 mg/m2 on 
Day 8, 9 and to 36 mg/m2 on Days 15, 16 may be used. 
• 
Induction Cycles 1-4 (starting with Cycle 1 Day 8) 36 mg/m2 IV as a 30 minute infusion 
Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle  
• 
CRd Consolidation Cycles 5-8: Last tolerated dose prior to ASCT as IV infusion Days 1, 
2, 8, 9, 15, and 16 of a 28-day cycle 

 
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• 
CRd Maintenance Cycles 9-18: Last tolerated dose as IV infusion Days 1, 2, 15, and 16 of 
a 28-day cycle 
The dose will be calculated using the subject’s actual body surface area (BSA) at baseline.  
Subjects with a BSA > 2.2 m2 will receive a dose based upon a 2.2 m2 BSA. For weight changes 
>10%, carfilzomib dose should be recalculated. 
Carfilzomib for Injection will be given as an IV infusion.  The dose will be administered at a 
facility capable of managing hypersensitivity reactions.  Subjects will remain at the clinic for at 
least 1 hour following each dose of carfilzomib for clinical observation during each dose in Cycle 
1 and for Day 1 of Cycle 2.     
Doses of carfilzomib may be rescheduled by up to 2 days, In the event that there is a one day break 
in between Carfilzomib dosing (i.e. Carfilzomib administered on Day 1 and 3, for example, due to 
a holiday) then 4mg of dexamethasone should be administered prior to the second day of dosing. 
Anticipated delays of carfilzomib dosing should be discussed with the Lead Principal Investigator. 
Missed doses will not be replaced during a cycle. 
Procedures for carfilzomib dose reductions and delays are summarized in Section 5.4, along with 
the criteria that must be met for re-treatment with study drug. 
Carfilzomib for Injection is supplied both as a lyophilized parenteral product in single-use vials; 
the lyophilized product is supplied in 25-mg and 60-mg vials.  Prior to use, the lyophilized product 
is reconstituted with Water for Injection. See Section 10.1 for details on carfilzomib description, 
formulation, preparation, storage, and accountability. 
5.2.4 
LENALIDOMIDE 
Subjects will receive lenalidomide as follows: 
• Induction Cycles 1-4: Lenalidomide 25 mg PO once daily on Days 1-21 of each 28-day cycle. 
• CRd Consolidation Cycles 5-8 and CRd maintenance Cycles 9-18: Last tolerated dose prior to 
ASCT on Days 1-21 of each 28-day cycle. The first cycle of consolidation, Cycle 5, must start 
at last tolerated dose prior to ASCT but  not higher than 15 mg per dose. 

 
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In discussion with the Lead Principal Investigator and on a case-by-case basis, provisions may 
be made to start at a lower than 15 mg dose of lenalidomide for participants with inadequate 
hematologic parameters following ASCT. The dose of lenalidomide should be re-escalated up 
to 25 mg per dose (or best tolerated dose prior to transplant) after completion of 1 cycle of CRd 
consolidation for participants with adequate hematologic parameters. On days coinciding with 
carfilzomib administration, lenalidomide should be taken at least 4 hours after the carfilzomib 
dose and may be self-administered at home by the subject.  On days on which carfilzomib is not 
administered, lenalidomide should be taken at approximately the same time each day.  Missed 
doses of lenalidomide will not be made up.  Subjects should be instructed to never take 
lenalidomide past Day 21 of each cycle. 
Lenalidomide is taken with water on a full or empty stomach.  Subjects should not break, chew or 
open capsules.  Late doses of lenalidomide should if possible be taken on the assigned day but 
should not be made up the next day. Vomited doses will not be made up.  
No intra-subject dose escalation of lenalidomide will be permitted.   
For all subjects enrolled in the United States, Lenalidomide (Revlimid®) will be used as 
commercial drug covered by patients insurance in accordance with the Revlimid REMS® program 
of Celgene Corporation.  In accordance with Revlimid REMS® requirements, all participating 
investigators and subjects must be registered in and must comply with all requirements of the 
program.  Prescriptions must be filled within 7 days and will only be filled for one cycle at a time, 
for 21 days of treatment. All subjects and investigators must comply with lenalidomide prescribing 
requirements. 
Procedures for dose reductions and delays are summarized in Section 5.4.  Information on 
lenalidomide description, formulation, storage, and accountability may be found in Section 10.2. 
5.2.5 
TREATMENT COMPLIANCE 
Research center personnel will review the dosing instructions with subjects.  Subjects will be asked 
to maintain a diary to record drug administration.  Subjects will be asked to bring any unused drug 
and empty drug containers to the research center at their next visit.  Research personnel will count 
and record the number of used and unused drug at each visit and reconcile with the patient diary. 

 
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5.3 
INSTRUCTIONS FOR INITIATION OF A NEW CYCLE 
NOTE: to initiate consolidation therapy following ASCT, the patient must be recovered from all 
transplant-related toxicities as well as meet the treatment parameters described below:  
The following guidelines refer to a new course of treatment following cycle 1 induction or after 
the first consolidation cycle. Patients who do not proceed to ASCT and continue on CRd therapy 
may proceed as noted below. 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if all of the following 
are met: 
• ANC ≥ 1.0 x 109/L 
• Platelet count ≥ 50 x 109/L, unless attributed to myeloma involvement of > 50% in the bone 
marrow, in which case platelets must be > 30 x 109/L to initiate the next cycle 
• Any other study drug-related adverse event must have resolved to grades as specified in protocol 
(see Section 5.4) 
• Serum uric acid and creatinine levels must return to baseline prior to carfilzomib doses during 
Cycles 1 and 2 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly, and 
a new treatment cycle will not be initiated until the toxicity has resolved, as described above.   
If either lenalidomide or carfilzomib are held for the remainder of the previous cycle or the new 
cycle is delayed due to residual toxicity on the planned Day 1 of the next cycle, then the new cycle 
will be started at 1 dose decrement. (see Section 5.4) 
5.4 
DOSE MODIFICATION GUIDELINES 
The following sections and tables summarize dosing modifications of carfilzomib, lenalidomide, 
and dexamethasone to manage possible toxicity.  Dose modifications different from those stated 
in the protocol should be discussed with the Lead Principal Investigator.  Administration of 

 
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carfilzomib and lenalidomide will be discontinued in the event of any other toxicity that, in the 
opinion of the Lead or Treating Investigator, warrants discontinuation.   
Dose reduction levels of carfilzomib and lenalidomide for toxicity management of individual 
subjects are provided below:    
Table 5-1.  Dose Reductions for Carfilzomib 
Nominal 
Carfilzomib Dose 
Reduced Carfilzomib Doses 
Dose -1 
Dose -2 
Dose -3 
Dose -4 
36 mg/m2 
27 mg/m2 
20 mg/m2 
15 mg/m2 
11 mg/m2 
 
Table 5-2.  Dose Reductions for Lenalidomide 
Nominal 
Lenalidomide 
Dose 
Reduced Lenalidomide Doses 
Dose -1 
Dose -2 
Dose -3 
Dose -4 
25 mg 
20 mg 
15 mg 
10 mg 
5 mg 
In addition to dose reductions, administration of carfilzomib and lenalidomide will be held 
temporarily in the event of a treatment-related toxicity at the Treating Investigator's discretion.  
Study treatment may be reintroduced if resolution of the event to the baseline value or to ≤ Grade 
1 within 21 days; otherwise study drug will be permanently discontinued, unless approved by the 
Lead Principal Investigator.  
Two dose reduction levels of dexamethasone are defined for the 2 protocol-stipulated dose levels 
(40 mg for Cycles 1-4 and 20 mg for Cycles 5-18), as illustrated in Table 5-3. Dexamethasone 
delay should be performed as clinically indicated at the discretion of the treating investigator 
however the dexamethasone dose must be administered as part of the premedication for 
carfilzomib on Days 1, 8, 15.Refer to section 5.5.2 for further guidance on dexamethasone 
administration. 
Table 5-3.  Dose Reductions for Dexamethasone 
Nominal 
Dexamethasone 
Dose 
 Reduced Dexamethasone Doses 
Dose -1 
Dose -2 
Dose -3 
Dose -4 

 
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40 mg 
30 mg 
20 mg 
15 mg 
10 mg 
20 mg 
15 mg 
10 mg 
N/A 
N/A 
5.4.1 
HEMATOLOGIC TOXICITY 
Guidelines for the management of hematologic toxicities (thrombocytopenia and neutropenia) are 
summarized in Table 5-4. 
5.4.2 
NON-HEMATOLOGIC TOXICITY 
Guidelines for the management of non-hematologic toxicities are summarized in Table 5-5. 
Table 5-4.  Dose Reduction Guidelines for Hematologic Toxicity 
Thrombocytopenia1 
 
Recommended Action 
When Platelets: 
Lenalidomide 
Carfilzomib 
Fall to < 30 x 109/L 
Hold lenalidomide, follow CBC 
weekly.  Hold prophylactic ant-
coagulation until platelets return to 
30 x 109/L 
Hold carfilzomib, follow CBC 
weekly. Hold prophylactic anti-
coagulation until platelets return to 
30 x 109/L 
Return to ≥ 30 x 109/L 
Resume lenalidomide at full dose 
Resume carfilzomib at full dose. 
Subsequently drop to < 30 x 
109/L 
Hold lenalidomide and follow 
CBC weekly 
Hold carfilzomib and follow CBC 
weekly 
Return to ≥ 30 x 109/L 
Resume lenalidomide at 1 dose 
decrement 
Resume carfilzomib at one dose 
decrement if cyclical 
thrombocytopenia is still below 
levels considered safe by the 
Treating Investigator at one dose 
decrement (i.e., dose decrease only 
if Treating Investigator judgment is 
that Carfilzomib contributed to 
thrombocytopenia) 
1Platelet transfusions should also be considered for the management of thrombocytopenia as clinically indicated 
Neutropenia 
 
Recommended Action 
When ANC 
Lenalidomide 
Carfilzomib 
Falls to < 0.5 x 109/L or to < 
1.0 x 109/L with fever 
Hold lenalidomide,  
add filgrastim if Grade 3 with fever 
or Grade 4, follow CBC weekly 
Hold carfilzomib, add filgrastim if 
Grade 3 with fever or Grade 4, 
follow CBC weekly 

 
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Returns to 1.0 x 109/L  (if 
neutropenia was the only 
toxicity noted) 
Resume lenalidomide at full dose 
 
Resume carfilzomib at full dose 
Return to 1.0 x 109/L (if 
other toxicity noted) 
 
Resume lenalidomide at 1 dose 
decrement 
Resume carfilzomib at full dose  
unless marked cyclical 
thrombocytopenia is present, then 
reduce by 1 dose decrement 
Subsequently drops to < 0.5 x 
109/L or to < 1.0 x 109/L with 
fever 
Hold lenalidomide treatments 
Hold carfilzomib treatments 
Returns to 1.0 x 109/L 
Resume lenalidomide at 1 dose 
decrement 
Resume carfilzomib previous dose at 1 
dose decrement (dose decrease required 
only if treating investigator judgment is 
that Carfilzomib contributed to 
neutropenia) 
 
Table 5-5.  Dose Modifications for Non-hematologic Toxicity 
Toxicity 
Recommended Action 
Lenalidomide 
Carfilzomib 
Non-Blistering Rash 
 
 
Grade 3 
Hold lenalidomide dose; follow 
weekly 
If the toxicity resolves to ≤ Grade 
1 prior to Day 21 of the current 
cycle, restart at 1 dose decrement 
and continue the cycle until Day 
21 of the current cycle. 
Hold (if Treating Investigator’s 
opinion is possibly related to 
Carfilzomib) until ≤ Grade 1, 
reinstitute at current dose 
Grade 4 
Discontinue lenalidomide study 
drug. 
Hold until ≤ Grade 1, reinstitute at 
current dose. 
Desquamating (blistering) 
rash  
– any grade 
Discontinue lenalidomide study 
drug. 
Hold until ≤ Grade 1, reinstitute at 
current dose. 
Erythema multiforme ≥ 
Grade 3 
Discontinue lenalidomide study 
drug. 
Hold until ≤ Grade 1, reinstitute at 
current dose. 
Sinus bradycardia/ other 
cardiac arrhythmia 
 
 

 
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Table 5-5.  Dose Modifications for Non-hematologic Toxicity 
Toxicity 
Recommended Action 
Lenalidomide 
Carfilzomib 
≤ Grade 2 
Hold lenalidomide dose. Follow 
at least weekly. 
If the toxicity resolves to ≤ Grade 
1 prior to Day 21, restart at 1 dose 
decrement and continue the cycle 
until Day 21. 
Hold until ≤ Grade 1, reinstitute at 
current dose. 
≥ Grade 3 
Discontinue lenalidomide study 
drug 
Hold until ≤ Grade 1, reinstitute at 
current dose. 
Allergic 
reaction/hypersensitivity 
 
 
Grade 2 – 3 
Hold lenalidomide dose. Follow 
at least weekly. 
If the toxicity resolves to ≤ Grade 
1 prior to Day 21, restart at 1 dose 
decrement and continue the cycle 
until Day 21. 
Hold until ≤ Grade 1, reinstitute at 
current dose. 
Grade 4 
Discontinue 
Discontinue 
Tumor lysis syndrome 
(≥ 3 of the following: ≥ 50% 
increase in creatinine, 
uric acid, or phosphate;≥ 
30% increase in 
potassium;≥ 20% 
decrease in calcium; or ≥ 
2-fold increase in LDH 
Hold lenalidomide until all 
abnormalities in serum 
chemistries have resolved. 
Reinstitute at full doses. 
Hold carfilzomib until all 
abnormalities in serum chemistries 
have resolved. 
Reinstitute at full doses. 
Infection Grade 3 or 4 
Hold lenalidomide until systemic 
treatment for infection is 
completed. If no neutropenia, 
restart both drugs at full dose.  If 
neutropenic, follow neutropenic 
instructions. 
Hold carfilzomib until systemic 
treatment for infection is completed 
If no neutropenia, restart both drugs 
at full dose.  If neutropenic, follow 
neutropenic instructions. 
Herpes zoster or simplex of 
any grade 
Hold lenalidomide until lesions 
are dry. 
Reinstitute at full doses. 
Hold carfilzomib until lesions are 
dry. 
Reinstitute at full doses. 

 
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Table 5-5.  Dose Modifications for Non-hematologic Toxicity 
Toxicity 
Recommended Action 
Lenalidomide 
Carfilzomib 
Grade 2 neuropathy with 
pain or any Grade 3 
neuropathy 
Hold until ≤ Grade 2.  
Then restart lenalidomide at 1 
dose decrement 
Hold until resolved to ≤ Grade 2. 
Then restart carfilzomib at  1 dose 
decrement 
Grade 4 neuropathy 
Discontinue 
Discontinue 
Renal dysfunction 
 
 
Serum creatinine > 2 mg/dL 
Base dose reduction on calculated 
GFR (below) 
Base dose reduction on calculated 
GFR (below) 
CrCl>50 mL/min 
Full dose 
Full dose 
CrCl <50 mL/min 
> 30 mL/min 
Reduce lenalidomide to 10 mg 
every 24 h; may reinstate prior 
dose if, after 2 cycles, CrCl 
normalizes 
Full dose 
CrCl< 30 mL/min 
Reduce lenalidomide to 15 mg 
every 48 h 
Hold carfilzomib until CrCl> 30 
mL/min; restart at  1 dose decrement 
CrCl< 30 mL/min requiring 
dialysis 
5 mg. Once daily. On dialysis 
days the dose should be 
administered following dialysis. 
Hold until resolved to ≤ Grade 2. 
Then restart carfilzomib at  1 dose 
decrement 

 
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Table 5-5.  Dose Modifications for Non-hematologic Toxicity 
Toxicity 
Recommended Action 
Lenalidomide 
Carfilzomib 
Venous 
thrombosis/embolism 
≥ Grade 3 
Hold lenalidomide dose and 
adjust anticoagulation regimen; 
re-start at Treating Investigator’s 
discretion at full dose 
No adjustment required 
Hyperthyroidism or 
hypothyroidism 
Omit lenalidomide for remainder 
of cycle, evaluate, and initiate 
appropriate therapy. 
Restart lenalidomide next cycle at 
1 dose decrement 
No adjustment required 
Congestive heart failure 
(CHF) 
Any subject with symptoms of 
CHF, whether or not 
lenalidomide related, must have 
the dose held until resolution or 
return to baseline.  If CHF was 
felt to be lenalidomide related, 
reinstate by one dose decrement 
after return to baseline. If no 
resolution of CHF after 2 weeks, 
the subject will be withdrawn 
from the study. 
Any subject with symptoms of CHF, 
whether or not carfilzomib related, 
must have the dose held until 
resolution or return to baseline.  If 
CHF was felt to be carfilzomib 
related, reinstate by one dose 
decrement after return to baseline. If 
no resolution of CHF after 2 weeks, 
the subject will be withdrawn from 
the study. 
Hypertension including 
Hypertensive Crises 
NA 
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to ≤ Grade 2.  
Resume at one level dose reduction 
Heart problems, including 
rapid, strong, or irregular 
heartbeat 
Heart attack, reduced 
blood flow to the heart, 
abnormal amount of fluid 
between the heart and 
lining around the heart, 
and swelling/irritation of 
the lining around the heart 
NA 
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to ≤ Grade 1.  
Resume at one level dose reduction 
Pericardial Effusion 
NA 
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to Grade 1.  
Resume at one level dose reduction 
Pericarditis 
NA 
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to Grade 1.  
Resume at one level dose reduction 

 
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Table 5-5.  Dose Modifications for Non-hematologic Toxicity 
Toxicity 
Recommended Action 
Lenalidomide 
Carfilzomib 
Pulmonary Hypertension 
 
 
NA 
= Grade 2: Carfilzomib attribution, 
Reduce drug: one level dose 
reduction 
 
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to ≤Grade 2.  
Resume at one level dose reduction 
Pulmonary Toxicities: 
Interstitial Lung Disease 
(inc. pneumonitis), Acute 
Respiratory Failure, and 
Adult Respiratory Distress 
Syndrome (ARDS), cough 
and cough with phlegm 
 
 
NA 
≥ Grade 2 for Pneumonitis 
≥ Grade 3 for ARDS 
≥ Grade 4 for Respiratory Failure 
 
Carfilzomib attribution, hold drug 
until resolved to ≤Grade 1. Resume 
at one level dose reduction 
 
Blood clot in the lungs, 
fluid in the lungs, bleeding 
in the lungs 
NA 
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to ≤ Grade 1.  
Resume at one level dose reduction 
Gastrointestinal 
Perforation 
NA 
≥ Grade 3: Carfilzomib attribution, 
hold drug until resolved to Grade 1.  
Resume at one level dose reduction 
Hepatic Toxicities (≥ Grade 
3 elevation of AST or ALT, 
Bilirrubin, or other 
≥ Grade 3 liver 
abnormalities) 
Hold drug until resolved to 
≤Grade 1 or baseline. Resume at 
the same dose or reduced dose as 
appropriate. If tolerated, the 
reduced dose may be escalated to 
the previous dose at the discretion 
of the physician. Frequent 
monitoring of liver function 
should then be implemented. 
Hold drug until resolved to ≤Grade 1 
or baseline. Resume at the same dose 
or reduced dose as appropriate. If 
tolerated, the reduced dose may be 
escalated to the previous dose at the 
discretion of the physician. Frequent 
monitoring of liver function should 
then be implemented. 
Other non-hematologic 
toxicity assessed as 
lenalidomide-related 
≥ Grade 3 
Hold lenalidomide dose. Follow 
at least weekly. 
If the toxicity ≤ Grade 1 before 
Day 21 of the current cycle, 
restart at 1 dose decrement and 
continue until Day 21 of the 
current cycle 
Full dose 

 
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Table 5-5.  Dose Modifications for Non-hematologic Toxicity 
Toxicity 
Recommended Action 
Lenalidomide 
Carfilzomib 
Other non-hematologic 
toxicity assessed as 
carfilzomib-related 
≥ Grade 3 
Full dose 
Hold carfilzomib dose until toxicity 
resolves to ≤ Grade 1 or baseline. 
Restart at  1 dose decrement 
Other non-hematologic 
toxicity assessed as drug-
related ≥ Grade 3 
Hold treatment and restart at 1 
dose decrement when toxicity has 
resolved to ≤ Grade 1 or baseline 
Hold treatment and restart at 1 dose 
decrement when toxicity has resolved 
to ≤ Grade 1 or baseline 
 
 

 
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Table 5-6.  Treatment Guidelines 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 at 
1 dose decrement along with concurrent therapy with H2 blockers, 
sucralfate, or omeprazole.  If symptoms persist despite above 
measures, discontinue dexamethasone permanently. 
Gastrointestinal Acute pancreatitis 
Discontinue dexamethasone permanently.   
Cardiovascular 
Edema 
≥ Grade 3 (limiting function 
and unresponsive to therapy 
or anasarca) 
Diuretics as needed, and restart dexamethasone at  1 dose decrement; 
if edema persists despite above measures, decrease dose another level.  
Discontinue dexamethasone permanently 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 at 1 dose 
decrement.  If symptoms persist despite above measures, discontinue 
dexamethasone permanently. 
Musculoskeletal Muscle weakness > Grade 2 
(symptomatic and 
interfering with function +/- 
interfering with activities of 
daily living) 
Decrease dexamethasone by 1 dose level.  If weakness persists, 
decrease dose by 1 more dose level.  Discontinue dexamethasone 
permanently if symptoms persist. 
Metabolic 
Hyperglycemia ≥ Grade 3 
Treatment with insulin or PO hypoglycemic agents as needed.  If 
uncontrolled despite above measures, decrease dose by 1 dose level 
until levels are satisfactory. 
 
5.4.3 
CONDITIONS NOT REQUIRING DOSE REDUCTION 
The following conditions are exceptions to the above guidelines.  Carfilzomib does not need to be 
held in the following cases: 
• 
Grade 3 nausea, vomiting, or diarrhea (unless persisting more than 3 days with adequate 
treatment of antiemetics or antidiarrheal agents) 
• 
Grade 3 dexamethasone-related hyperglycemia 
• 
Grade 1-3 lenalidomide-induced rash 

 
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• 
Grade 3 fatigue (unless persisting for > 14 days) 
• 
Alopecia 
5.4.4 
TREATMENT DISCONTINUATION 
Administration of Carfilzomib, lenalidomide and dexamethasone can be discontinued permanently 
in the event of a treatment-related toxicity at the Treating Investigator's discretion. 
If a delay of starting a new cycle is greater than 21 days, the subject should be discontinued from 
treatment, unless continuing treatment is mutually agreed upon by the Treating Investigator and 
the Lead Principal Investigator.  
If either carfilzomib or lenalidomide requires permanent discontinuation before Cycle 4 induction, 
the subject’s treatment will be discontinued at the end of Cycle 4 induction.  If either carfilzomib 
or lenalidomide requires permanent discontinuation during consolidation or maintenance cycles, 
the subject may remain on study with the remaining drug(s).   
Dexamethasone may be discontinued without the subject discontinuing study treatment. 
5.5 
CONCOMITANT MEDICATIONS 
Concomitant medication is defined as any prescription or over-the-counter preparation, including 
vitamins and supplements.  All concomitant medications must be recorded on the concomitant 
medications case report form from 21 days before Day 1 through 30 days following the last dose 
of study drugs. 
5.5.1 
REQUIRED CONCOMITANT MEDICATIONS 
• Valacyclovir or similar anti-varicella (anti-herpes) agent HZV prophylaxis 
• Aspirin for VTE prophylaxis. 
Instructions for their administration are found in Section 5.2.1.   
Note:  If a subject is allergic to aspirin, low-molecular-weight heparin or clopidogrel may be used.  
In subjects with a prior history of venous thrombosis, low-molecular-weight heparin or therapeutic 
doses of warfarin (target INR 2-3) are required.  

 
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5.5.2 
OPTIONAL AND ALLOWED CONCOMITANT MEDICATIONS 
In view of emerging data that pneumocystis pneumonia (PCP) is unlikely in patients treated with 
low dose dexamethasone, the use of Pentamidine or Bactrim will be optional in CRd.  
Of these medications, use of Pentamidine is recommended as the PCP prophylaxis of choice for 
CRd patients.  
Use of Dapsone for PCP prophylaxis will require approval of the Lead Principal Investigator, in 
view of the potential for hemolysis in this subset of patients. 
Mycostatin and lansoprazole or other proton pump inhibitor or an H2 antagonist are recommended 
but NOT required and considered optional medications. 
Marketed bisphosphonates are allowed.   
Subjects may receive anti-emetics and antidiarrheal agents as necessary.   
Colony-stimulating factors may be used if neutropenia occurs but should not be given 
prophylactically. 
Subjects may receive RBC or platelet transfusions if clinically indicated in accordance with 
institutional guidelines, however screening platelet count must be independent of platelet 
transfusions for at least 2 weeks (Section 3.6).  Subjects who require repeated platelet transfusion 
support should be discussed with the Lead Principal Investigator. 
Allopurinol (for use only in subjects at risk for TLS due to high tumor burden) is optional and will 
be prescribed at the Treating Investigator’s discretion.  These subjects may receive allopurinol 300 
mg PO BID (Cycle 1 Day -2, Day -1), continuing for 2 days after Cycle 1 Day 1 (total of 4 days), 
then reduce dose to 300 mg PO QD, continuing through Day 17 of Cycle 1.  Allopurinol dose 
should be adjusted according to the package insert.  Subjects who do not tolerate allopurinol and 
are at risk for TLS should be discussed with the Lead Principal Investigator in order to discuss 
alternatives. 

 
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If signs of tumor flare are present, split dosing of dexamethasone may be implemented so that 
subjects may be given 4 mg dexamethasone PO or IV on Days 2, 9 and 16 in Cycles 1 and 2 prior 
to carfilzomib infusion. The total dose of dexamethasone prior to carfilzomib should not exceed 
40 mg weekly therefore it is recommended that the dose is split between days of carfilzomib 
administration, for example 36mg Day 1 and 4mg Day 2..  This will be prescribed at the Treating 
Investigator’s discretion. Subjects believed to be at high risk for bacterial infection may receive 
antibiotic prophylaxis as per institutional guidelines. 
Radiation therapy to a localized mass for subjects on CRd therapy is acceptable with prior approval 
of the Lead Principal Investigator.  
Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel disease) 
equivalent to a dexamethasone dose ≤ 4 mg/day or prednisone ≤ 20 mg/day are permitted 
5.5.3 
EXCLUDED CONCOMITANT MEDICATIONS 
Concurrent therapy with a marketed or investigational anticancer therapeutic is not allowed. 
Corticosteroids for non-malignant conditions (e.g., asthma, inflammatory bowel disease) 
equivalent to a dexamethasone dose > 4 mg/day or prednisone > 20 mg/day are not permitted.   
Other investigational agents are not to be used during the study.   
5.6 
SAFETY GUIDANCE FOR INVESTIGATORS 
5.6.1 
"FIRST-DOSE EFFECT" 
A “first dose” effect has been encountered early in carfilzomib treatment, characterized by 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, treatment with glucocorticoids is 
recommended.  In addition IV fluids, vasopressors, oxygen, bronchodilators, and acetaminophen 
should be available for immediate use and instituted as medically indicated. 

 
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5.6.2 
TUMOR LYSIS SYNDROME 
Tumor lysis syndrome, which may be associated with multi-organ failure, has been observed in 
Cycles 1 and 2 of some subjects with multiple myeloma treated with carfilzomib.  In addition, 
multiple myeloma subjects with high tumor burden (e.g., Durie-Salmon or ISS Stage II/III) or 
rapidly increasing M-protein or light chains or compromised renal function (GFR < 50 mL/min) 
should be considered to be at particularly high risk.  All such subjects should be identified at 
screening.       
During Cycles 1 and 2, serum electrolytes and chemistries are closely monitored as outlined in 
Section 7.2.  Subjects with laboratory abnormalities consistent with lysis of tumor cells (e.g., serum 
creatinine ≥ 50% increase, LDH ≥ 2-fold increase, uric acid ≥ 50% increase, phosphate ≥ 50% 
increase, potassium ≥ 30% increase, calcium ≥ 20% decrease) prior to dosing should not receive 
the scheduled dose.  Subjects with such abnormalities should be re-evaluated as clinically 
indicated.  The Lead Principal Investigator should be consulted if there are further delays.  
Subjects should be informed of signs and symptoms that may be indicative of tumor lysis 
syndrome, such as fevers, chills/rigors, nausea, vomiting, muscle tetany, weakness, or cramping, 
seizures, and decreased urine output; subjects should be instructed to report such symptoms 
immediately and seek medical attention.  
In the event tumor lysis syndrome manifests, cardiac rhythm, fluid, and serial laboratory 
monitoring should be instituted.  Correct electrolyte abnormalities, monitor renal function and 
fluid balance, and administer therapeutic and supportive care, including dialysis, as clinically 
indicated. 
All cases of tumor lysis syndrome must be reported to The University of Chicago as a Serious 
Adverse Event (SAE) as outlined in Section 8.5. 
5.6.3 
RENAL FUNCTION 
Carfilzomib has not been fully characterized in subjects with creatinine clearance < 30 mL/min.  
It is critical that the subject’s renal function is known at the time of dosing.  Renal function, serum 
creatinine, and serum uric acid should be monitored closely as outlined in Section 6.  See Section 

 
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5.4.2 and Table 5-5 for guidance regarding dose reduction in subjects with compromised renal 
function.    
5.6.4 
HYDRATION 
All subjects should be well-hydrated.  However, over-hydration without matching output should 
be avoided with use of diuretics as needed. Carfilzomib treatment can cause nausea, vomiting, 
diarrhea, or constipation sometimes requiring the use of antiemetics or antidiarrheal agents.  Fluid 
and electrolyte replacement should be administered as outlined in Section 5.2.1 
6 
STUDY TESTS AND OBSERVATIONS 
All protocol-required tests and observations along with their chronology are summarized in 
Appendix A. 
6.1 
SCREENING (DAYS -21 TO -1) 
Written informed consent must be obtained before any protocol-specific tests or procedures may 
be conducted.  The consent may be obtained within 30-days of Cycle 1 Day 1 however the 
following screening assessments will be performed between Days -21 and –1 unless otherwise 
stated: 
General 
• Medical history (review of systems, prior treatments for all significant conditions including 
neuropathy) 
• Complete physical examination (including vital signs [systolic and diastolic blood 
pressure, respiration, pulse, oral temperature], height, weight, calculation of body surface 
area [BSA], and ECOG score). Height outside of the 21-day window is acceptable. 
• Skeletal survey (lateral radiograph of the skull, anteroposterior and lateral views of the 
spine, and anteroposterior views of the pelvis, ribs, femora, and humeri).  May be within 
30 days of planned Day 1 of Cycle 1. Skeletal surveys performed outside of the 30 day 
window may be considered for inclusion. Please contact the Lead Principal Investigator on 
a case-by-case basis. 

 
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• 12-lead ECG, including QTc interval 
• Neurologic assessment, consisting of neurologic exam (to detect peripheral neuropathy 
and/or changes in pre-existing neuropathy) and completion of the neurologic questionnaire 
by the subject.  
• Record all concomitant medications starting 21 days before planned Day 1 of Cycle 1. 
Laboratory 
• Pregnancy test (FCBP must have a negative serum or urine pregnancy test, with a 
sensitivity of at least 50 mIU/mL, within 10-14 days before and again within 24 hours 
before lenalidomide is prescribed for Day 1 of Cycle 1).  See also Appendix F.  
• Urinalysis  
• Serum chemistries (see Section 6.2 for list of analytes).  Creatinine clearance calculated by 
Cockroft-Gault (See Appendix G) 
• Hematology (hemoglobin, hematocrit, WBC with complete differential, RBC, platelets) 
• Coagulation tests (prothrombin time, activated partial thromboplastin time, and 
international normalized ratio) 
Disease-related 
• M-protein determination using both of the following procedures: 
o Serum protein electrophoresis (SPEP) and serum protein immunofixation 
• Pre-treatment serum M-protein baseline level from outside institution must be well 
documented and recorded and required for eligibility 
o Urine protein electrophoresis (UPEP), urine protein immunofixation (using 24-hour urine 
collection above) and total protein in urine. SPEP will be used serially during the study if 
the baseline value for M-protein is > 0.5 g/dL.  UPEP will be used if the baseline value is 

 
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> 200 mg per 24 hours.  If both tests are positive at baseline, both will be performed at each 
required time point. 
• Pre-treatment urine M-protein baseline level from outside institution (light chain 
24 hr quantitation) must be well documented and recorded. If not available but the 
patient has pre-treatment measurable serum M-protein, lack of pre-treatment 24 hr 
urine results is not an exclusion 
• Plasmacytoma evaluation (either physical exam or imaging where applicable and at 
treating investigator’s discretion) 
• Serum quantitative immunoglobulins 
• Serum β2 microglobulin 
• Serum free light chains (SFLC) 
• Bone marrow aspirate and biopsy – quantify percent myeloma cell involvement, and obtain 
bone marrow aspirate for cytogenetics  [i.e. diploidy, del 13] and fluorescent in situ 
hybridization (FISH) studies [i.e. t(4:14); t(11:14); del 17p].  Cytogenetics is only required 
at screening.  
o All patients are required to have two samples for MRD analysis centrally (by Flow 
cytometry at the University of Chicago and by Next Generation Sequencing (NGS) 
at Adaptive Biotechnologies) collected at 1) Screening (for calibration for MRD by 
gene sequencing), 2) Pre-transplant (end of cycle 4), 3) Post-transplant (pre-
consolidation), 4) End of Cycle 8, 5) End of Treatment, 6) 1, 2, 3, and 5 years after 
EOT. In the event that a superfluous bone marrow aspirate (BMA) sample from 
screening was not available, slides of BMA smear or clot from a time prior to 
enrollment can be used. 
• CT-PET – Performed to confirm MRD-negative disease per Standard of Care, at every 
time-point when MRD is checked. 
• CRP levels 

 
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• If pre-treatment serum β2 microglobulin, serum free light chains (SFLC), and 
cytogenetics are missing, this is not an exclusion. 
6.2 
TREATMENT CYCLES 1 THROUGH 4 (INDUCTION), CYCLES 5-8 
(CONSOLIDATION), AND CYCLES 9-18 (MAINTENANCE) 
• Complete physical examination (including vital signs [systolic and diastolic blood 
pressure, respiration, pulse, oral temperature], weight, calculation of body surface area 
[BSA]) and ECOG score) on Day 1 of each cycle.  Abbreviated (i.e., symptom-directed) 
exams may be performed on Days 8 and 15 if indicated.  For Cycle 1, the screening physical 
may be used if it was within 7 days before Day 1. 
• Vital signs within 1 hour before the dose of carfilzomib on Days 1, 2, 8, 9, 15, and 16 
during Cycles 1-8 and on Days 1, 2, 15, and 16 during Cycles 9-18. 
• Hematology Days 1 and 15 of each cycle during Cycles 1-8 and on Day 8 of Cycles 1 and 
2 only. On cycles 9-18 hematology should be done on day 1 only. Results must be available 
before the dose of carfilzomib is given (hence may be performed the day before planned 
dosing).   
• Full serum chemistry panel on Days 1, 8, and 15 of Cycles 1 through 8 and on Day 1 of 
Cycles 9-18, plus abbreviated panel (see below) on Days 2, 9, and 16 of Cycles 1 and 2 
only and only if clinically indicated as per institutional standards of care (i.e., subject at 
risk for tumor lysis syndrome).   
Results must be available before the dose of carfilzomib is given (hence may be performed 
the day before planned dosing). Results must be consistent with eligibility criteria prior to 
dosing on Cycle 1 Day 1. 

 
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Full Chemistry Panel 
Abbreviated 
Chemistry Panel 
sodium 
potassium 
chloride 
bicarbonate 
BUN 
creatinine 
glucose 
uric acid 
total protein 
albumin 
calcium 
Phosphorus 
Magnesium 
total bilirubin 
alkaline 
phosphatase 
ALT 
AST 
LDH 
sodium 
potassium 
chloride 
bicarbonate 
BUN 
creatinine 
glucose 
uric acid 
• FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, at study 
discontinuation, and at day 28 following discontinuation from the study.  If menstrual 
cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then 
every 14 days while on study, at study discontinuation, and 14 and 28 days after 
discontinuation from the study. Patients already on lenalidomide at the initiation of CRd 
therapy, may continue with the regularly scheduled pregnancy testing schedule as long as 
there has been no interruption in the testing schedule and use of birth control measures, 
rather that repeating the cycle 1 weekly testing. 
In addition to the above, at each visit the Treating Investigator must confirm that FCBP are 
continuing to use 2 reliable methods of birth control.  Pregnancy testing and counseling 
must be performed if a subject misses her period or if her pregnancy test or her cycle is 
abnormal.  See also Appendix F.  
• Disease-related tests (M-protein by SPEP and/or UPEP [requires 24-hour urine 
collection] as appropriate, quantitative immunoglobulins, and plasmacytoma as 
appropriate) on Day 1 of each cycle.  For cycle 1, screening values may be used if within 
7 days of Day 1.  In Cycle 1 only, these tests are repeated on Day 15 to assess possible 
onset of early response.  

 
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• Neurologic assessment as before on Day 1 of every cycle.  This includes subject 
completion of the neurologic questionnaire. 
• All patients are required to have two samples for MRD analysis centrally (by Flow 
cytometry at the University of Chicago and by Next Generation Sequencing (NGS) at 
Adaptive Biotechnologies) collected at 1) Screening (for calibration for MRD by gene 
sequencing), 2) Pre-transplant (end of cycle 4), 3) Post-transplant (pre-consolidation), 4) 
End of Cycle 8, 5) End of Treatment, 6) 1, 2, 3, and 5 years after EOT. In the event that a 
superfluous bone marrow aspirate (BMA) sample from screening was not available, slides 
of BMA smear or clot from a time prior to enrollment can be used. 
• CT-PET – Performed to confirm MRD-negative disease per Standard of Care, at every 
time-point when MRD is checked. 
6.3 
END OF CYCLE 4 
After 4 cycles of induction treatment, disease status including bone marrow for pre-transplant 
assessment will be assessed as described in Section 6.8.Bone marrow biopsy and aspirate must 
include two research samples for MRD by flow and by NGS.  Also at this point of the study, 
subjects will proceed to stem cell collection and then ASCT. A CT-PET must be performed to 
confirm MRD-negative disease per Standard of Care, at every time-point when MRD is checked. 
6.4 
STEM CELL COLLECTION AND AUTOLOGOUS STEM CELL 
TRANSPLANT 
Thirty days after the last dose of CRd treatment, or at the start of stem cell collection (whichever 
occurs first), subjects will no longer be followed for adverse events and will be considered off-
treatment for the remainder of the transplant period. Treating Investigators should follow their 
institution’s standard practice for SCC and mobilization however section 6.4.1 should be 
referenced for guidance and recommendations. Section 6.4.2 should be followed for autologous 
stem cell transplant along with standard practice. 

 
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6.4.1 
MOBILIZATION AND COLLECTION OF AUTOLOGOUS PERIPHERAL BLOOD STEM 
CELLS 
Mobilization with G-CSF should start 2-4 weeks from the last dose of lenalidomide (i.e., 2-4 weeks 
after Cycle 4 Day 21). In general, scheduling of stem cell collection should assure as limited break 
as possible between the last dose of CRd treatment and ASCT, which should not exceed 6 weeks. 
Neupogen (G-CSF) should be used for stem cell mobilization according to standard practice. If G-
CSF alone is not sufficient for mobilization, the addition of plerixafor (Mozibil) should be used or 
as per the institution’s standard.  
During the apheresis procedure, correction of cytopenias and electrolyte abnormalities will be 
performed as per standard unit policy. 
6.4.2 
AUTOLOGOUS STEM CELL TRANSPLANT PROCEDURE 
Patients will be admitted to the inpatient stem cell transplant unit at the treating institution. 
Conditioning chemotherapy will consist of melphalan 200mg/m2 IV. If melphalan at 200mg/m2 
cannot be administered because it is not tolerated or it is against institutional guidelines for reasons 
such as the patient’s age, than the patient is not considered suitable for transplant per protocol and 
should not be enrolled to the trial. Sites should follow their standard protocol for hydration and 
antiemetic prophylaxis prior to melphalan infusion, antibiotic prophylaxis, platelet and packed red 
blood cell transfusions, and standard laboratory testing. Administration of autologous peripheral 
stem cells will take place on day 0 according to standard unit protocol. Patients will be monitored 
inpatient per standard protocol until criteria for discharge are met. 
6.5 
3 MONTHS POST TRANSPLANT 
After recovery from ASCT toxicities (day 70-90 but not more than 120 and prior to initiation of 
CRd consolidation), disease status will be assessed as described in section 6.8 and Appendix E and 
bone marrow biopsy and aspirate must include two samples for MRD by flow and by 
NGS. Patients who have established sCR earlier with negative MRD can have bone marrow biopsy 
waived after discussion with study Lead Principal Investigator. A CT-PET must be performed to 
confirm MRD-negative disease per Standard of Care, at every time-point when MRD is checked. 

 
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6.6 
END OF CYCLE 8 (END OF CYCLE 4 CRD CONSOLIDATION) 
After completion of 8 cycles, disease status will be assessed as described in section 6.8 and 
Appendix E and bone marrow biopsy and aspirate including two samples for MRD by flow and 
by NGS. Patients who have established sCR earlier with negative MRD can have bone marrow 
biopsy waived after discussion with study Lead Principal Investigator. A CT-PET must be 
performed to confirm MRD-negative disease per Standard of Care, at every time-point when MRD 
is checked. 
6.7 
LONG-TERM FOLLOW-UP 
Subjects who did not progress while on study, including subjects on lenalidomide maintenance, 
will be followed every 3 months for 5 years from the safety follow-up visit (28 days post last dose 
of study treatment) to document progression-free survival and development of any new cancers. 
Progression-free survival (PFS) and overall survival (OS) will be calculated every 6 months. When 
the median PFS/OS is reached, follow-up can be stopped. 
For subjects who are in CR or better at the end of 18 cycles (± 30 days), a repeat bone marrow 
aspirate and biopsy should be collected for Minimal Residual Disease (MRD) at the end of study 
treatment visit done in central labs. One sample will be analyzed by Flow cytometry at the 
University of Chicago and the other by Next Generation Sequencing (NGS) at Adaptive 
Biotechnologies). A bone marrow aspirate and biopsy with two aspirates for MRD analysis should 
be collected 1, 2, 3, and 5 years after EOT for central analysis at UC and at Adaptive 
Biotechnologies. 
Fresh Bone Marrow aspirate for MRD analysis by flow cytometry will be shipped at ambient 
temperature on the same day of the procedure directly to the University of Chicago Hematology 
lab. Please refer to the lab manual for shipping details. 
On the other hand, fresh Bone Marrow aspirate MRD analysis by NGS by Adaptive 
Biotechnologies, will be shipped at ambient temperature on the same day of the procedure directly 
to the University of Chicago Multiple Myeloma lab for processing and later batched shipping. 
Please refer to the lab manual for shipping details. 

 
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6.8 
TUMOR RESPONSE ASSESSMENT 
Subjects will be evaluated under Treating Investigator review for disease response according to 
the International Myeloma Working Group (IMWG) uniform response criteria Appendix E. 
Response categories include sCR, CR, nCR, VGPR, PR, SD, and progressive disease (PD).In 
addition, minimal response (MR) will be evaluated as an alternate response following EBMT 
modified criteria (Appendix E).  
For subjects in whom achievement of a sCR, CR, or nCR is suspected, a repeat bone marrow 
biopsy and aspirate (showing < 5% myeloma cells in the marrow, in addition to the other criteria 
in Appendix E) will be required to document the initial response. For confirmation of response, an 
aspirate but not a biopsy is required. All response categories (sCR, CR, nCR, and VGPR) require 
2 consecutive assessments made after baseline and before the start of new therapy. If a subject is 
being followed by serum M-protein only, a response must be confirmed by a negative UPEP even 
if negative at baseline. SFLC will be repeated to confirm an MR or better.  
PD requires 2 consecutive assessments made at any time before classification as relapse or 
progression and/or the institution of new therapy when clinically possible. 
6.9 
OPTIONAL CORRELATIVE STUDIES 
In addition to the required bone marrow aspirate samples for MRD analysis [1) Screening 2) Pre-
transplant, 3) Post-transplant), 4) End of Cycle 8, 5) End of Treatment, 6) 1, 2, 3, and 5 years after 
EOT], for patients who consent additional samples will be collected including bone marrow 
aspirate, peripheral blood, and buccal swabs. As a companion study to the proposed clinical trial, 
studies will be conducted aimed at identifying markers of response to the CRd regimen. The 
correlative studies will focus on the (1) evaluations of markers of response, and (2) pre-treatment 
myeloma cell characteristics. Briefly, we will collect samples prior to treatment and at indicated 
time points. The first objective is to determine tumor characteristics, which predict at least very 
good partial response (VGPR). VGPR has been associated with longer progression survival and 
overall survival.25,26 The results will complement ongoing efforts to identify markers of VGPR 
using samples already collected from VDD, RVD, RVDD, and CRd frontline clinical trials, with 
a broader goal to provide rationale for individualized therapy as a method of improving VGPR or 
CR/nCR. In addition to global assessment of pretreatment profiling and genetic variants, which 

 
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will be correlated with a response, we will prospectively evaluate selected characteristics and 
markers of response identified in our proteomics studies to date, and other emerging markers of 
response including Cereblon. 
If the subject provides additional consent, please obtain research samples (peripheral blood and 
bone marrow aspirates) at the time points below. In the event that adequate sample cannot be 
obtained, these studies may be run using any superfluous sample obtained from the required 
samples for MRD analysis for patients who have given consent 
• 
Screening* 
• 
Pre-transplant/Post-transplant 
• 
End of C8 
• 
Time of response (to confirm complete response), and/or 
End of Treatment visit 
*Please also obtain a buccal mucosa swab at screening. 
Assays may include: 
 
1.  Proteomics 
2. Tumor cell 
• 
Gene micro array 
• 
SNP analysis 
• 
Analysis of genetic variants 
2. Additional Biomarker Studies 
• 
Cereblon expression 
 
Specimen Collection Instructions: 
• 
BM aspirate) 
• 
Peripheral blood Serum  
• 
Buccal swab 
 
Please note that supplies for correlative sample collection will not be provided 
 
Please refer to the Laboratory Manual for detailed collection, processing and shipping 
instructions. 
 
Label all specimens with the following: 
1. Subject initials 
2. Subject study number (will include protocol number) 
3. Visit at which sample was drawn (i.e. C1D4) 
4. Date sample drawn (i.e. mm/dd/yyyy) 
5. Time sample drawn (24 hour clock) 

 
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6. Sample type (eg. plasma, serum, bone marrow cells, tumor cells) 
 
Shipping Instructions: 
 
1. An inventory sheet provided in the lab manual including a complete list of samples shipped 
(patient number, timepoint, study #) must accompany each shipment. 
2. An electronic copy (Word or Excel) of the sample list must also be sent via email.  The 
listing must also include a contact name, address and phone number of the person who is 
responsible for the shipment.  They should sign and date the form. 
3. Please email the Myeloma Lab at the University of Chicago (myeloma-
lab@bsd.uchicago.edu) as notification of an incoming shipment. 
4. Please ship Monday, Tuesday, Wednesday or Thursday, as shipments cannot be received 
on weekends and/or on holidays. 
 
Please note that collection and processing supplies will not be provided however a FedEx account 
number will be provided for shipments.  
 
Andrzej J Jakubowiak, MD, PhD 
900 E 57th St 
KCBD 7240 LB17 
Chicago, IL 60637 
Business Phone   (773) 702-1345 or 773-834-1592 
Business Fax 773-248-330-6027 
 
Note: Please follow your institution’s policy regarding destruction of patient samples upon 
withdrawal of informed consent. 
7 
STUDY DISCONTINUATION 
Subjects may withdraw from the study at any time.  Subjects who withdraw will be monitored for 
AEs, as described in Section 8.3. The Lead Principal Investigator may elect to discontinue the 
study at any time. 
The Treating Investigator may remove a subject from the study for the following reasons: 
• 
Disease progression 
• 
Noncompliance with study procedures 
• 
Requirement for alternative therapy 
• 
Subject no longer consents to participate in the study 

 
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• 
Intercurrent illness that interferes with study assessments 
• 
Incidence or severity of AEs that indicates a potential health hazard to the subject 
• 
Suspected pregnancy or positive pregnancy 
• 
Death 
• 
Reports of any death should include date of death and specific cause (disease under 
study of specific other cause) and information about autopsy if the cause of death was 
unknown 
The Lead Principal Investigator must be contacted to discuss any impending discontinuation of a 
study subject/patient prior to withdrawal from the study.  If withdrawal occurs prior to discussion 
with the Lead Principal Investigator, they must be notified within 24 hours via email with a copy 
to the University of Chicago CRA.  
If the reason for withdrawal is the occurrence of an AE, the subject will be followed until such 
events resolve, stabilize, and, according to the Treating Investigator’s judgment, there is no need 
of further follow-up.  The reason for withdrawal from the study will be documented in the case 
report form. 
8 
ADVERSE EVENTS 
8.1 
ADVERSE EVENTS DEFINITIONS 
An adverse event (AE) is any untoward medical occurrence in a study subject administered an 
investigational product and that does not necessarily have a causal relationship with this treatment.  
An AE therefore can be any unfavorable and unintended sign (including laboratory finding), 
symptom or disease temporally associated with participation in an investigational study, whether 
or not considered drug-related.  In addition to new events, any increase in the severity or frequency 
of a pre-existing condition that occurs after the subject signs a consent form for participation is 
considered an AE.  This includes any side effect, injury, toxicity, or sensitivity reaction.  
An unexpected AE is any adverse drug event, the specificity or severity of which is not consistent 
with the current IB or prescribing information for a marketed compound.  Also, reports which add 
significant information on specificity or severity of a known, already documented AE constitute 
unexpected AEs.  For example, an event more specific or more severe than described in the IB 
would be considered “unexpected”.    

 
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Whenever possible, the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
should be used to describe the event and for assessing the severity of AEs (see Appendix D).  Any 
events representing a change in the CTCAE Grade need to be reported on the AE case report form.  
This includes any change in laboratory values.  For AEs not adequately addressed in the CTCAE, 
the severity table below may be used: 
Table 5-7 
Severity 
Description 
GRADE 1 – Mild 
Transient or mild discomfort; no limitation in 
activity; 
no 
medical 
intervention/therapy 
required. 
GRADE 2 – Moderate 
Mild to moderate limitation in activity—some 
assistance may be needed; no or minimal 
medical intervention/therapy required. 
GRADE 3 – Severe 
Marked limitation in activity, some assistance 
usually required; medical intervention/therapy 
required, hospitalizations possible. 
GRADE 4 – Life-
threatening 
Extreme limitation in activity, significant 
assistance required; life-threatening (immediate 
risk 
of 
death); 
significant 
medical 
intervention/therapy required, hospitalization or 
hospice care probable. 
GRADE 5 – Fatal 
Death 
 
Any condition, laboratory abnormality, or physical finding with an onset date prior to the subject 
signing consent for study participation is considered to be pre-existing in nature and part of the 
subject’s medical history and are considered AEs only if they worsen. 
8.2 
CAUSALITY 
Using the following criteria, the relationship of the AE to the study drug should be assessed as 
follows:  Definite, Probable, Possible, Unlikely, Unrelated. 

 
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8.3 
ADVERSE EVENTS REPORTING PROCEDURES 
Information about all AEs, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory tests or other means, will be 
collected and recorded and followed as appropriate. 
All AEs (e.g., any new event or worsening in severity or frequency of a pre-existing condition or 
laboratory finding) with an onset date on or after Cycle 1 Day 1 of treatment must be documented 
on the appropriate CRF. Adverse Events which occur after consent but prior to the start of 
treatment must be reported if they are considered related to study procedures.  Details of the event 
must include severity, relationship to study drug, duration, action taken, and outcome.  Serious 
adverse events (SAEs) will be recorded on the appropriate SAE form.  All AEs that are considered 
related to study drug must be followed to resolution or stabilization if improvement is not expected.  
AEs should be reported from Day 1 of treatment through 30 days post-last dose of study drug 
(Carfilzomib) or initiation of a new anti-cancer therapy, whichever occurs first.  For subjects who 
continue to ASCT, AEs will be recorded for 30 days post last dose of Cycle 4 or until the start of 
stem cell collection if earlier. AEs will not be recorded during the transplant period (stem cell 
collection through start of consolidation) but  should be collected again starting at Cycle 5 Day 1 
or the first cycle of consolidation following ASCT. In addition, the Treating Investigator should 
report any AE that may occur after this time period that is believed to have a reasonable possibility 
of being associated with study drug.  If a subject is enrolled but discontinues study prior to 
receiving any study drug, only SAEs that are considered related to study procedures must be 
reported through the end-of-study visit.  AEs which completely resolve and then recur should be 
recorded as a new AE.  For subjects who complete the end of study visit less than 30 days following 
their last dose of study drug, a follow up of ongoing AEs should be attempted by telephone, and 
documented in the subject’s source.  AEs continuing at 30 days post-last dose should have a 
comment in the source by the Treating Investigator that the event has stabilized or is not expected 
to improve. 
The Treating Investigator is responsible for evaluating all AEs for relationship to study drug and 
for seriousness, obtaining supporting documents, and determining that documentation of the event 
is adequate. Adverse events will be assigned a severity grade using the NCI-CTCAE grading scale 

 
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v4.0. The treating investigator must assess all abnormal laboratory results for their clinical 
significance. If any abnormal laboratory result is considered clinically significant, the treating 
investigator must provide details about the action taken with respect to the test drug and about the 
patient’s outcome. All Grade 3 and 4 laboratory abnormalities must be recorded as AEs on the 
CRF.  Grade 1 and 2 abnormalities should only be recorded if they require treatment or are 
otherwise considered clinically significant by the Treating Investigator. 
The Site or Lead Principal Investigator may delegate these duties to Sub-investigators and must 
ensure that these Sub-investigators are qualified to perform these duties under the supervision of 
the Principal Investigator and that they are listed on the FDA Form 1572 and delegation log. 
8.4 
SERIOUS ADVERSE EVENTS  
Information about all serious adverse events (SAE) will be collected and recorded on the 
appropriate SAE form. To ensure patient safety, each serious adverse event must be reported to 
the Lead Investigator and the University of Chicago Comprehensive Cancer Center (via paper SAE 
form and electronic submission  in Velos) within 24 hours of learning of its occurrence.  
8.4.1 
SERIOUS ADVERSE EVENT DEFINITION 
An SAE is one that meets any the following criteria:  
• 
Death 
• 
Life threatening experience defined as any adverse experience that places the subject, in 
the view of the Treating Investigator, at immediate risk of death at the time of occurrence; 
i.e., it does not include a reaction that, had it occurred in a more severe form, might have 
caused death. 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization (except 
scheduled hospitalizations for non-acute, unrelated cause such as an elective surgery) 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect in the offspring of an exposed subject 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE, when, based upon appropriate medical 
judgment, it jeopardizes the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 

 
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Any death occurring within 30 days of the subject receiving study drug, regardless of the subject 
having discontinued from the study must be reported to the Lead Investigator/ University of 
Chicago Comprehensive Cancer Center as an SAE. 
8.4.2 
SERIOUS AND UNEXPECTED SUSPECTED ADVERSE REACTION (SUSAR) 
A serious adverse event is considered to be a suspected adverse reaction if there is evidence to 
suggest a causal relationship to the study agent. This may include a single occurrence of an event 
strongly associated with drug exposure (e.g. Stevens Johnson Syndrome), one or more occurrence 
of an event otherwise uncommon in the study population, or an aggregate analysis of specific 
events occurring at greater frequency than expected from historical controls. 
Unexpected events are those not listed at the observed specificity or severity in the protocol, 
consent, investigator brochure, FDA approved package insert, or elsewhere in the current IND 
application. This includes adverse events listed in the protocol, consent or IND as occurring within 
the class of drugs or otherwise expected from the drug’s pharmacological properties but which 
have not been previously observed with this investigational agent. ALL serious and unexpected 
suspected adverse reactions (SUSARs) occurring on this clinical trial must be reported to the 
FDA. Refer to section 8.5 for reporting guidelines. 
The lead institution (University of Chicago) is responsible for notifying the appropriate Regulatory 
Agencies, when required, and in accordance with applicable laws and regulations of any Expedited 
Safety Reports. Generally, these are all SAEs that are judged to be unexpected and related to study 
drug(s), as specified in ICH E2B guidelines: Clinical Safety Data Management Data Elements for 
Transmission of Individual Case Safety Reports. However, certain Regulatory Agencies may have 
additional requirements for expedited safety report submissions. 
ALL Serious Adverse Events, whether or not they are considered related to the study agent 
MUST be reported to the Lead Principal Investigator and to the University of Chicago 
Comprehensive Cancer Center (via entry on the SAE form in Velos).  Refer to Section 8.5 
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8.5 
SERIOUS ADVERSE EVENT REPORTING AND DOCUMENTATION 
REQUIREMENTS 
All SAEs (except those that occur during ASCT more than 30 days after the last dose of CRd at 
cycle 4 unless considered to be related to CRd treatment) from the time that the subject signs 
consent for study participation through 30 days after the last administered dose of study drug must 
be reported to the Lead Principal Investigator and to the University of Chicago Comprehensive 
Cancer Center via paper submission. The SAE should also be entered electronically as soon as 
possible. All SAEs regardless of relationship to study drug must be followed to resolution or to 
stabilization if improvement or resolution is not expected. 
If a subject is permanently withdrawn from the study because of a SAE, this information must be 
included in the initial or follow-up SAE report as well as the appropriate form for Study 
Discontinuation. 
A copy of the SAE form (found in Velos) should be sent via fax or via email to the University of 
Chicago 
Cancer 
Clinical 
Trials 
Office 
(fax 
number 
773-702-1561 
or 
email 
to 
qaccto@bsd.uchicago.edu) according to the timeframe in section 8.6.1. 
All MedWatch Form 3500A SAE forms must include the patient number, age, sex, weight, severity 
of reaction (e.g. mild, moderate, severe), relationship to study drug(s) (e.g. probably related, 
unknown relationship, definitely not related), date and time of administration of study drug(s) and 
all concomitant medications and medical treatment provided.  The Treating Investigator is 
responsible for evaluating all adverse events to determine whether criteria for “serious” as defined 
above are present. If a subject is permanently withdrawn from the study because of a SAE, this 
information must be included in the initial or follow-up SAE report form as well as the Study 
Discontinuation report form. 
The appropriate University of Chicago coordinator will be responsible for notifying the Regulatory 
Agencies as required.  
8.5.1 
EXPEDITED REPORTING BY LEAD PRINCIPAL INVESTIGATOR TO ONYX 
The University of Chicago CRA will inform Onyx in writing by email or facsimile of any SAE 
within 24 hours of being aware of the event.  The date of awareness should be noted on the report.  
This must be documented on a MedWatch Form 3500A.  This form will be supplied to Onyx 

 
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within 24 hours/1 business day or at the latest on the following working day.  The initial report 
must be as complete as possible, including details of the current illness and (serious) adverse event, 
and an assessment of the causal relationship between the event and the investigational product(s).  
Information not available at the time of the initial report (e.g., an end date for the adverse event or 
laboratory values received after the report) must be documented on a follow-up FDA MedWatch 
Form 3500A.  A final report to document resolution of the SAE is required.  
The Onyx protocol number (IST-CAR-578) and the institutional protocol number should be 
included on SAE reports to Onyx.  A copy of the fax transmission or email confirmation of the 
SAE report (or on the fax cover letter) sent to Onyx should be attached to the SAE and retained 
with the patient records 
 
Onyx Drug Safety and Pharmacovigilance Contact Information: 
Fax: 800-783-7954 or 650-266-0501 
SAE Hotline: 650-266-2501 
Email: adverse.events@onyx.com 
8.5.2 
 INVESTIGATOR REPORTING RESPONSIBILITES 
The conduct of the study will comply with all applicable safety reporting requirements. 
All adverse experience reports must include the patient number, age, sex, weight, event diagnosis 
(if known) or signs/symptoms, severity of reaction (mild, moderate, severe), relationship to study 
drug (probably related, unknown relationship, definitely not related), date and time of 
administration of test medications and all concomitant medications, and medical treatment 
provided.   The Treating Investigator is responsible for evaluating all adverse events to determine 
whether criteria for “serious” and as defined above are present.  
Participating sites are responsible for reporting all SAEs to the Lead Principal Investigator.  The 
Lead Principal Investigator will be responsible for reporting SAEs to Onyx (as outlined above) 
and the FDA. 
The Treating Investigator is responsible for notifying their respective Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC) in accordance with local regulations of all SAEs. 
Events occurring at a participating site should be reported to the local IRB of record according to 

 
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their policies and procedures and may be reported to the University of Chicago IRB if they meet 
current reporting criteria.  
It is the responsibility of the University of Chicago coordinator on behalf of the Lead Principal 
Investigator to notify all participating sites of all serious unexpected suspected adverse reactions 
that occur on this clinical trial and which are reported to the FDA as an IND Safety Report (21 
CFR 312.32). A copy of the completed Form 3500A (MedWatch) and/or IND Safety Report 
Narrative will be provided to the responsible Regulatory Manager by the IND coordinator for 
distribution to all participating sites.  
8.5.3 
FDA REPORTING BY THE LEAD PRINCIPAL INVESTIGATOR 
This study will be conducted under an IND held by Andrzej Jakubowiak at the University of 
Chicago. 
Current FDA regulations require that all SUSARs (see definition in section 8.4.1) occurring on 
this trial, other findings that suggest a significant risk to humans exposed to the investigational 
drug (e.g. information from pooled analysis of multiple studies), and any clinically significant 
increase in the rate of an expected serious adverse reaction be reported as an IND Safety Report.   
In order to meet these requirements, the lead principal investigator will review all reported serious 
adverse events as they occur to determine if FDA reporting is required and will conduct a literature 
search to seek new safety information and review and analyze all safety information from this 
clinical trial at least annually and more frequently as appropriate. 
Individual Event Reports: FDA Form 3500A (MedWatch) will be completed for all SAEs that 
require FDA reporting. This will be completed by the designated research staff at each site. The 
completed MedWatch form for fatal or life-threatening events must be returned to the Lead 
Investigator/ University of Chicago CRA within 4 calendar days. All other events must be received 
within 10 calendar days. 
Other findings that suggest significant risks to the subject: A narrative description summarizing 
all relevant findings will be provided by the lead principal investigator along with a copy of any 
relevant publications (if applicable).  

 
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Clinically Significant Increase in Frequency of Events: A narrative description summarizing all 
relevant findings will be provided by the lead principal investigator along with details of individual 
cases (if applicable).  
All MedWatch reports are due to the designated University of Chicago CRA (and will be 
forwarded to the University of Chicago Clinical Trials Office IND coordinator) according to the 
specified timeline regardless of whether or not all information regarding this event is available. If 
applicable, a follow-up report should be provided to the University of Chicago CRA/ IND 
coordinator once additional information on the event is available. 
The completed MedWatch form and/or safety narrative will be forwarded to the FDA by the 
University of Chicago Comprehensive Cancer Center – Cancer Clinical Trials Office (CCTO) on 
behalf of the IND Holder within the appropriate timeframes as designated in 21 CRF 312.32. 
8.5.4 
ADVERSE EVENT UPDATES/IND SAFETY REPORTS 
Onyx shall notify the Treating Investigator via an IND Safety Report of the following information: 
• Any AE associated with the use of the drug in this study or other studies that is both serious 
and unexpected 
• Any findings from tests in laboratory animals that suggest a significant risk for human 
subjects including reports of mutagenicity, teratogenicity or carcinogenicity. 
The Treating Investigator shall notify his/her IRB/IEC promptly of these new serious and 
unexpected AEs or significant risks to subjects in accordance with their policies. 
The Lead Principal Investigator must keep copies of all AE information, including correspondence 
with Onyx and the IRB/IEC on file (see Section 12.2.3 for records retention information). 
8.6 
PREGNANCY  
Pregnancy of a female subject or the female partner of a male subject occurring while the subject 
is on treatment or within 4 weeks after the subject’s last dose of study drug are considered 
expedited reportable events.  Study drugs—both lenalidomide and carfilzomib—are to be 
discontinued immediately and the subject instructed to return any unused lenalidomide to the 
Treating Investigator.  The pregnancy must be reported within 24 hours of the Treating 
Investigator’s knowledge of the pregnancy by phone and facsimile using the SAE form (Velos 

 
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SAE form as well as FDA MedWatch 3500A) to the University of Chicago CRA either by fax or 
by email.  The Treating Investigator must inform the University of Chicago in writing by email or 
facsimile of any pregnancy within 24 hours / 1 business day at the latest on the following workday 
of being aware of the event.  The University of Chicago must report pregnancy as an SAE directly 
to Onyx Drug Safety as well, using expedited reporting procedures listed in Section 8.5. 
The Treating Investigator will follow the pregnant female until completion of the pregnancy, and 
must notify the Lead Principal Investigator at the University of Chicago. It is the responsibility of 
the coordinator on behalf of the Lead Principal Investigator to notify Onyx Drug Safety of the 
outcome as specified below.  The Treating Investigator will provide this information as a follow-
up to the initial SAE. 
If the outcome of the pregnancy meets a criterion for immediate classification as an SAE—
spontaneous abortion (any congenital anomaly detected in an aborted fetus is to be documented), 
stillbirth, neonatal death, or congenital anomaly—the Treating Investigator should repeat the 
procedures for expedited reporting of SAEs as outlined above. 
Any suspected fetal exposure to lenalidomide must be reported to Celgene and Onyx within 
24 hours of the Lead Principal Investigator being made aware of the event.  The pregnant female 
should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling. 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Treating Investigator 
suspects may be related to the in utero exposure to lenalidomide should also be reported to the 
Lead Principal Investigator and subsequently to Celgene and Onyx by the University of Chicago 
coordinator. 
In the event of a live “normal” birth, Celgene and Onyx Drug Safety should be advised as soon as 
the information is available. 

 
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9 
STATISTICAL METHODS AND DATA ANALYSIS 
9.1 
OBJECTIVES 
9.1.1 
PRIMARY OBJECTIVES 
The primary objective of this Phase 2 trial is to determine the efficacy of the CRd combination 
regimen as measured by response, defined as the rate of  stringent CR (sCR) after 8 cycles of 
CRd (4 cycles of induction + ASCT + 4 cycles of CRd consolidation). 
9.1.2 
SECONDARY OBJECTIVES 
Secondary objectives include determining the best objective overall response rate (ORR) 
defined as partial response or better (>PR), the rate of VGPR or better, near complete response 
or better (sCR/CR/nCR), the time to progressive disease, duration of response, and 
progression-free and overall patient survival distributions. 
9.1.3 
EXPLORATORY OBJECTIVES 
Additional exploratory objective include evaluation of the status of minimal residual disease 
in patients who achieve a CR 1) after induction (first 4 cycles), 2) post-transplant, 3) after 8 
cycles, 4) end of CRd treatment (cycle 18) 5) or any point that bone marrow is performed for 
assessment of CR response on CRd therapy. Additional prospective evaluation of candidate 
markers of response to CRd established in ongoing frontline CRd trial in newly diagnosed 
myeloma will be completed (Jakubowiak et al, ASH 2011, ASCO 2012, Blood 2012). In 
addition, we will ask patients to consent to provide research samples for additional evaluations 
of prognostic markers with a goal to established marker-based individualized therapy with CRd 
with or without transplant. 
Bone marrow biopsies are optional with patient consent for research purposes at the end 
induction, post-transplant, end of 8 cycles of CRd (end of cycle 4 CRd consolidation), and end 
of treatment, per section 6.6.  In order to accrue an adequate sample size for MRD assessment 
in patients who are suspected of having a sCR, CR, or nCR at this time given other disease-
related tests, we will over-accrue above the original sample size, N = 53, to N=70.  Given this 
additional sample size, we hypothesize a 65-70% consent rate for the necessary optional 
marrow biopsies.  A 65-70% consent rate would afford a total sample size of approximately 
45-49 patients, which would afford interrogation of the hypothesis that this regimen will 

 
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improve the rate of MRD after 4 CRD induction cycles, ASCT, and 4 cycles of CRD 
consolidation from 25% estimated MRD rate in the CRD trial without transplant to 45% with 
transplant, with approximately 80% power with 5% type II error. 
9.2 
POPULATION FOR ANALYSIS 
The Intent-to-Treat (ITT) population of patients will be defined as all patients who receive at 
least one dose of carfilzomib and lenalidomide.  If a patient fails to receive these drugs, the 
patient will be replaced. The primary efficacy results in the study will be based on data from 
this population.  Patients in this population who have inadequate data to assess efficacy 
according to the criteria for response in section 8 will be considered treatment failures for this 
analysis.  Patients in this population will be analyzed according to the treatment they were 
actually scheduled to receive, regardless of any errors of dosing or dose modifications. 
Analysis of safety will be performed on the set of patients who receive any study drug, formally 
the same group as comprises the ITT population. 
9.3 
STUDY DESIGN AND SAMPLE SIZE 
This is single-arm, open label phase II study to determine the rate of sCR after a total of 8 cycles 
of CRd (i.e. 4 cycles of CRd induction  and 4 cycles post ASCT consolidation) in patients who 
were enrolled into initial treatment with CRd and received at least one dose of carfilzomib and/or 
lenalidomide.  The historical comparison population is the recently completed CRd phase I/II 
frontline therapy study which incorporated a deferred transplant design.  The response rate 
determined in the current trial will be compared to, and be expected to exceed, the rate of sCR 
after the same duration of CRd therapy, 8 cycles.  Mature data from the recently completed CRd 
phase I/II trial indicates that 13 of 44 (30%) patient attained a sCR when receiving 8 cycles of CRd 
frontline therapy. 
For primary objective of the study, at least 53 and up to 70 patients will be enrolled to the CRd 
induction phase of this trial, with the expectation that the patients will receive ASCT, CRd 
consolidation, CRd maintenance, and recommended lenalidomide maintenance off protocol if 
able.  To minimize the sample size, the study was originally designed as a Simon 2-stage study 
design with interim analysis after the enrollment of the first 27 patients, with the trial to continue 
enrollment if 12 of the first 27 patients achieved sCR at the end of 4 cycles of consolidation (or 

 
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after a total of 4 cycles before and 4 cycles post-transplant). This design did not take into account 
that it takes approximately 1 year for each subject to reach the primary end-point evaluation, which 
would require either extended study delay or the study would complete enrollment by the time 27 
patients were evaluable for this interim primary end-point. Therefore, the study is revised to a 
single-stage.  The sample size was increased to 53 patients, and further to 70 for MRD assessment, 
based upon the updated mature results of our prior CRd trial for patient at the completion of 8 
cycles of frontline therapy without transplant and the consent rate for optional bone marrow biopsy 
for MRD assessment in the early portion of conducting this trial, respectively.. The sample size of 
53 minimally necessary to test whether the rate of sCR would be 50% or greater in the current trial 
after 8 cycles of CRd ((i.e. 4 cycles of CRd induction and 4 cycles post ASCT consolidation) 
versus 30%, the sCR rate after 8 induction cycles in the historical comparison population.  This 
trial will  have 5% type I error (1-sided) and 10% type II error (90% power) to interrogate the 
stated hypothesis. With 70 patients, this trial will have 10% type II error (90% power) with 5% 
type I error (2-sided) to interrogate the stated hypothesis. 
ANALYSIS PLAN 
9.3.1 
PRIMARY OBJECTIVE 
 
The study’s primary endpoint, attainment of sCR will be assessed at the completion of the 8 cycle 
of CRd (at the conclusion of the 4th consolidation cycle).  All patients enrolled and receiving any 
CRd treatment will be evaluable for this endpoint, with the exception of patients that decline to 
receive transplant for reasons unrelated to toxicity and/or efficacy.  Patients in that category will 
be replaced. All other patients who discontinue treatment before receiving 4 cycles of CRd 
induction and transplantation will be considered treatment failures for assessment of the study’s 
primary endpoint. Patients who receive less than 4 cycles of consolidation will be evaluable for 
primary end point provided that they received at least lenalidomide and/or carfilzomib in post-
transplant period for at least 4 months at the completion of 4 months of post-transplant treatment.  
Patients not meeting the minimum consolidation therapy as just described will be considered 
treatment failures for the study’s primary endpoint.  
. 

 
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9.3.2 
SECONDARY OBJECTIVES 
 
Secondary objectives include the overall response rate, defined as at least a partial response to 
therapy (>PR), at least VGPR and at least nCR rate, time to progression, duration of response, and 
progression-free and overall survival.  The rate of overall response will be reported along with its 
exact 95% binomial confidence interval.  Time to event endpoints will be estimated using the 
product-limit method of Kaplan and Meier.  Follow-up time for these endpoints will be calculated 
from the date of first treatment (D1C1 of CRd induction).  For time to progression, patients that 
do not experience progression during follow-up will be censored on the date of their last clinical 
examination.  Duration of response will be assessed conditional upon achieving at least a partial 
response.  Follow-up time for this endpoint will be calculated from the date of the clinical 
examination which confirmed the response, until the date of disease progression, or censoring at 
the date of last clinical follow-up.  For progression-free survival, follow-up time will continue 
from the date of first therapy until the date of documented disease progression or death.  Patients 
not reach either milestone during follow-up will be censored on their date of last clinical 
assessment. 
9.3.3 
EXPLORATORY OBJECTIVES 
Patients first enrolled onto this trial who achieve suspected CR will be evaluated for minimal 
residual disease using multicolor flow cytometry and gene sequencing (Sequenta, Inc). Patients 
with marker characteristics determined to predict response to CRd will be evaluated for time to 
events.  The rate of MRD in those with at least a CR after 8 cycles of CRD (4 induction cycles, 
ASCT, and 4 consolidation cycles) will be estimated along with 95% confidence intervals.The 
proportion of patients alive and free of disease progression at 2 years post ASCT, will be estimated 
using the product limit method of Kaplan and Meier. 
9.3.4 
SAFETY ANALYSIS   
 
Safety analysis will be based on the incidence, intensity, and type of adverse events, and clinically 
significant changes in the patient’s physical examination, vital signs, and clinical laboratory 
results.  Safety variables will be tabulated and presented for all patients in the study.  Exposure to 
study drug and reasons for discontinuation of study treatment will be tabulated. 

 
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All adverse events occurring on study will be listed in by-patient data listings.  Treatment emergent 
events will be tabulated, where treatment emergent is defined as any adverse event that occurs 
after administration of the first dose of study drug and through the End of Study visit or up through 
30 days after the last dose of study drug, any event that is considered drug-related regardless of 
the start date of the event, or any event that is present at baseline but worsens in intensity or is 
subsequently considered drug-related by the Treating investigator and/or Lead Principal 
Investigator.  Events that are considered related to treatment (possibly, probably or definitely drug-
related) will also be tabulated.  Deaths, serious adverse events and events resulting in study 
discontinuation will be tabulated. Of note 30 days following the last dose of CRd, during ASCT 
period patients will be considered to be off-study so no toxicities will be recorded from that period. 
Change from baseline in clinical laboratory parameters will be summarized across time on study, 
and the frequency of clinically significant abnormal laboratory values will be tabulated.  Similarly, 
changes in vital sign parameters will be summarized over time, and any abnormal values will be 
tabulated. 
10 
INVESTIGATIONAL PRODUCT 
10.1 
CARFILZOMIB DESCRIPTION 
Please refer to the Carfilzomib manual provided by Onyx for detailed information. Carfilzomib is 
a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-1-((S)-4-methyl-1-
((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-
morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide.  The molecular formula 
isC40H57N5O7 and the molecular weight is 719.91.  It specifically functions as an inhibitor of the 
chymotrypsin-like activity of the 20S proteasome which leads to the accumulation of protein 
substrates within the cell and induction of apoptosis.   
10.1.1 
FORMULATION 
Carfilzomib for Injection will be provided as a lyophilized powder which, when reconstituted, 
contains 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM sodium citrate buffer 
(pH 3.5) containing 10% (w/v) sulfobutylether--cyclodextrin (SBE--CD, Captisol®).   

 
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10.1.2 
STORAGE 
Lyophilized Carfilzomib for Injection must be stored at 2–8ºC under the conditions outlined in the 
separate Pharmacy Manual, in a securely locked area to which access is limited to appropriate 
study personnel. 
10.1.3 
ACCOUNTABILITY 
Onyx, Inc. and the Lead and Site Principal Investigator will maintain records of each shipment of 
investigational product.  The records will document shipment dates, method of shipment, batch 
numbers, and quantity of vials contained in the shipment.  Upon receipt of the investigational 
product, the designated recipient at the study site will inspect the shipment, verify the number and 
condition of the vials, and prepare an inventory or drug accountability record.  
Drug accountability records must be readily available for inspection by representatives of Onyx 
and by regulatory authorities.  
Empty and partially used vials should be accounted for and destroyed at the study site in 
accordance with the internal standard operating procedures.  Drug destruction records must be 
readily available for inspection by representatives of Onyx and by regulatory authorities.  
Only sites that cannot destroy unused drug on-site will be required to return their unused supply 
of investigational product. 
10.1.4 
CARFILZOMIB ORDERING 
Carfilzomib will be provided at no cost by Onyx Pharmaceuticals. Drug orders will be made by 
the institution’s investigational drug services. After full IRB approval and study activation 
including site initiation, the following documents need to be submitted to Onyx Clinical 
Research: 
• 1572 (including investigational pharmacy shipping address as identification in section 7) 
• Principal Investigator’s current CV and license 
• IRB letter of approval for protocol and consent 

 
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• Onyx Site Contact Information Sheet 
After the site receives approval for drug shipment, drug orders can be placed directly using the 
Onyx Pharmaceuticals Carfilzomib Drug order form for IST-CAR-578. 
10.2 
LENALIDOMIDE 
10.2.1 
DESCRIPTION 
Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with anti-angiogenic and 
anti-neoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) 
piperidine-2,6-dione. The empirical formula for lenalidomide is C13H13N3O3, and the gram 
molecular weight is 259.3. 
Lenalidomide is off-white to pale-yellow solid powder.  It is soluble in organic solvent/ water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 
to 0.5 mg/mL.  Lenalidomide has an asymmetric carbon atom and can exist as the optically active 
forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero.  
Lenalidomide is available in 5 mg, 10 mg, 15 mg and 25 mg capsules for PO administration.  Each 
capsule contains lenalidomide as the active ingredient and the following inactive ingredients: 
lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.  
The 5 mg and 25 mg capsule shell contains gelatin, titanium dioxide and black ink.  The 10 mg 
capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink.  
The 15 mg capsule shell contains gelatin, FD&C blue #2, titanium dioxide and black ink. 
10.2.2 
SUPPLY 
Commercially available REVLIMID® (lenalidomide) capsules are supplied through the Revlimid 
REMS® program as the drug is approved for indications in this study. Lenalidomide is for PO 
(oral) administration only. 
10.2.3 
STORAGE CONDITIONS 
Store lenalidomide at 25°C (77 °F) away from direct sunlight; excursions permitted to 15-30°C 
(59-86 °F). 

 
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10.2.4 
ACCOUNTABILITY 
Bottles of lenalidomide will contain a sufficient number of capsules to last for one cycle of dosing.  
Sites will be required to record and document subject compliance regarding lenalidomide dosing. 
10.2.5 
PRESCRIBING INFORMATION 
Lenalidomide will be provided in accordance with the Revlimid REMS® program of Celgene 
Corporation.  Per standard Revlimid REMS® requirements, all physicians who prescribe 
lenalidomide for research subjects enrolled into this trial must be registered in must comply with 
all requirements of the Revlimid REMS® program.  Prescriptions must be filled within 7 days.  
Only enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle.  
Unused Revlimid will be counted and documented by each site.  Unused Revlimid will be returned 
to Celgene by the site using instructions provided by Celgene. 
10.2.6 
SPECIAL HANDLING INSTRUCTIONS 
Females of child-bearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 
10.3 
DEXAMETHASONE 
Dexamethasone may be given IV or PO 
10.3.1 
DESCRIPTION 
Dexamethasone, a synthetic adrenocortical steroid, is a white to practically white, odorless, 
crystalline powder.  It is stable in air.  It is practically insoluble in water. 
10.3.2 
FORMULATION 
Dexamethasone is a commercially available PO drug, supplied as 2 and 4 mg tablets. 
10.3.3 
STORAGE CONDITIONS 
Store dexamethasone at controlled room temperature 20 to 25ºC (68 to 77ºF) 
10.3.4 
ACCOUNTIBILITY 
Sites will be required to record and document subject compliance regarding dexamethasone 
dosing. 

 
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11 
REGULATORY OBLIGATIONS 
11.1 
INFORMED CONSENT 
No Investigator may involve a human being as a subject in research unless the Investigator has 
obtained the legally effective informed consent of the subject or the subject’s legally authorized 
representative.  An Investigator shall seek such consent only under circumstances that provide the 
prospective subject or the subject’s legally authorized representative sufficient opportunity to 
consider whether or not to participate, and that minimize the possibility of coercion or undue 
influence.  The information that is given to the subject or the representative shall be in a language 
understandable to the subject or representative. 
The University of Chicago will provide the Treating Investigator with a sample consent form 
developed by the University of Chicago.  Local and/or institutional requirements may require 
disclosure of additional information in the informed consent.  Any changes to the consent form 
must be submitted to the University of Chicago for approval, prior to submission to the 
participating site IRB/IEC.  The participating site IRB/IEC will review the consent form for 
approval.  A copy of the IRB/IEC approval form must be submitted to the University of Chicago 
prior to initiation of the study at the participating site. 
Before implementing any study procedure, informed consent shall be documented by the use of a 
written consent form approved by the IRB/IEC and signed and dated by the subject or the subject’s 
legally authorized representative at the time of consent.  A copy of the signed informed consent 
will be given to the subject or subject’s legally authorized representative.  The original signed 
consent must be maintained by the Lead and Site Principal Investigator and available for inspection 
by the designated University of Chicago coordinator at any time. 
11.2 
COMPLIANCE WITH LAWS AND REGULATIONS 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), 
the Declaration of Helsinki, Health Canada, any applicable local health authority, and Institutional 
Review Board (IRB) or Ethics Committee requirements. 

 
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This study must have the approval of a properly constituted IRB or Ethics Committee.  Before the 
investigational drug is shipped to the Lead or Site Principal Investigator, the Lead Investigator or 
designee will provide Onyx with a copy of the IRB or Ethics Committee approval letter stating 
that the study protocol and any subsequent amendments and informed consent form have been 
reviewed and approved. 
The Lead and Site Principal Investigator or designee will be responsible for obtaining annual IRB 
or Ethics Committee re-approval throughout the duration of the study.  Copies of the Investigator’s 
annual report to the IRB or Ethics Committee and copies of the IRB or Ethics Committee 
continuance of approval must be provided to Onyx as follows: 
Onyx Inc. 
Regulatory Department 
2100 Powell St. 
Emeryville, CA 94608 
The Lead and Site Principal Investigator is also responsible for notifying their IRB or Ethics 
Committee of any significant adverse events that are serious and/or unexpected. 
Onyx will provide study sites with any expedited safety reports generated from any ongoing 
studies with carfilzomib, changes to the Investigator’s Brochure, and any other safety information 
which changes the risk/benefit profile of carfilzomib during the conduct of the study, to allow 
him/her to fulfill his/her obligation for timely reporting to the IRB/ECs and other Investigators 
participating in the study. 
Upon completion of the trial, the Lead Principal Investigator must provide the IRB or Ethics 
Committee and Onyx with a summary of the trial’s outcome. 
11.3 
PRE-STUDY DOCUMENTATION REQUIREMENTS 
Before the start of the study, the following documents must be on file with the University of 
Chicago: 
• 
A U.S. Form FDA 1572 signed by the Principal Investigator 

 
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• 
Current Curriculum Vitae (CV) for the Principal Investigator and all Sub-Investigators 
• 
Current IRB/IEC membership list and/or Department of Health and Human Services number 
• 
Copies of all appropriate laboratory certifications and laboratory normal ranges 
• 
IRB/IEC approval of the protocol 
• 
IRB/IEC approved informed consent and approval letter 
o The informed consent must also be reviewed and approved by the University of 
Chicago Cancer Clinical Trials Office 
• 
IRB/IEC approval of any advertising materials to be used for study recruitment, if applicable 
(also to be approved by the University of Chicago) 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Investigational drug accountability standard operating procedures 
• 
Health Insurance Portability and Accountability Act forms, if required 
11.4 
SUBJECT CONFIDENTIALITY 
Subject medical information obtained as part of this study is confidential, and must not be disclosed 
to third parties, except as noted below.  The subject may request in writing that medical information 
be given to his/her personal physician. 
The Investigator/Institution will permit direct access to source data and documents by Onyx, its 
designee, the FDA and/or other applicable regulatory authority.  The access may consist of trial-
related monitoring, audits, IRB or Ethics Committee reviews, and FDA inspections. 
Release of research results should preserve the privacy of medical information and must be carried 
out in accordance with Department of Health and Human Services Standards for Privacy of 
Individually Identifiable Health Information, 45 CFR 164.508. 
12 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
All protocol amendments will be implemented by the University of Chicago and must receive 
IRB/IEC approval before implementation, except where necessary to eliminate an immediate 
hazard to subjects.  Amendments should only be submitted to the IRB/IEC after consideration of 
Onyx.  Only the Lead Investigator can authorize any modifications, amendments, or termination 

 
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of the protocol. Once a protocol amendment has been approved by the University of Chicago IRB, 
the Regulatory Manager will send the amended protocol and consent form to the affiliate 
institutions electronically for submission to the affiliate institution’s IRB. The Site Principal 
Investigator or designee must send a copy of the approval letter from the IRB for the amendment, 
along with the revised Informed Consent form (as applicable), to the University of Chicago.  The 
University of Chicago version date and/or amendment number must appear on the affiliate consent 
form and on the affiliate IRB approval letter (the version date can be found on the footer of every 
page of the protocol and consent form, and the amendment number can be found on the University 
of Chicago IRB amendment approval letter sent with the amendment). 
The University of Chicago jointly with the study supporters and the Lead Principal Investigator 
reserves the right to terminate the study according to the study contract.  The Site and Lead 
Principal Investigator or designee should notify jointly the IRB/IEC in writing of the study’s 
completion or early termination and send a copy of the notification to the regulatory affairs 
manager at the University of Chicago Cancer Clinical Trials Office. 
12.2 
STUDY DOCUMENTATION AND ARCHIVE 
12.2.1 
SOURCE DOCUMENTS 
Source records are original documents, data, and records (e.g., medical records, raw data collection 
forms, pharmacy dispensing records, recorded data from automated instruments, laboratory data) 
that are relevant to the clinical trial.  The Site and Lead Principal Investigators will prepare and 
maintain adequate and accurate source documents.  These documents are designed to record all 
observations and other pertinent data for each subject enrolled in this clinical trial.  Source records 
must be adequate to reconstruct all data transcribed onto the case report forms. 
12.2.2 
CASE RERPORT FORM COMPLETION 
All required data must be recorded in the Velos database in at the completion of each cycle.  All 
case report forms must be completed by designated study personnel. Each screened (consented) 
patient is to be entered into Velos within 48 hours of enrollment approval.   

 
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AEs are to be entered in real time. SAEs are to be entered in Velos on the SAE reporting form 
within 24 hours of the site’s knowledge of the event. All other data to be entered within 30 days 
of source acquisition. 
12.2.3 
ARCHIVAL OF RECORDS 
According to 21 CFR 312.62I, the Site and Lead Principal Investigators shall retain records 
required to be maintained under this part for a period of 2 years following the date a marketing 
application is approved for the drug for the indication for which it is being investigated.  If no 
application is to be filed or if the application is not approved for such indication, the Site and Lead 
Principal Investigator shall retain these records until 2 years after the investigation is discontinued 
and the FDA or applicable regulatory authorities are notified. 
The Site and Lead Principal Investigator must retain protocols, amendments, IRB/IEC approvals, 
copies of the Form FDA, signed and dated consent forms, medical records, case report forms, drug 
accountability records, all correspondence, and any other documents pertaining to the conduct of 
the study. 
12.2.4 
CLINICAL MONITORING PROCEDURES 
 
Clinical studies coordinated by The University of Chicago must be conducted in accordance with 
the ethical principles that are consistent with Good Clinical Practices (GCP) and in compliance 
with other applicable regulatory requirements. 
This study will be remotely monitored by the designated University of Chicago Medicine 
Clinical Research Associate (CRA).  
Prior to subject recruitment, a participating site will undergo site initiation teleconference to be 
conducted by the designated University of Chicago Medicine CRA and Lead Principal 
Investigator.  The site’s principal investigator and his or her study staff should make every effort 
in attending the site initiation meeting. Study-related questions or issues identified during the 
site initiation meeting will be followed-up by the appropriate UCM personnel until they have 
been answered and resolved. 
Monitoring will be conducted to verify the following:  
 Adherence to the protocol 

 
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 Completeness and accuracy of study data and samples collected 
 Compliance with regulations 
Participating sites will also undergo a site close-out teleconference upon completion, termination 
or cancellation of a study to ensure fulfillment of study obligations during the conduct of the 
study, and that the Site Principal Investigator is aware of his/her ongoing responsibilities.  
12.2.5 
DATA SAFETY AND MONITORING  
 
The University of Chicago Medical Center is responsible for data and safety monitoring for this 
study, including reviewing and monitoring the study’s scientific progress, accrual rate and any 
serious adverse events. This protocol will undergo weekly review at the University of Chicago 
multi-institutional data and safety monitoring teleconference as per procedures specified by the 
UCCCC NCI-approved Data and Safety Monitoring Plan. 
Each participating site is responsible for participating in Data Safety Monitoring (DSM), 
including participating in the teleconference. Prior to study start up, sites will be asked to submit 
their Data Safety Monitoring procedures for review by the University of Chicago. Drug 
accountability should be included in the monitoring plan.  
The study will conduct teleconferences at a rate determined by the Lead Principal Investigator 
to review the following: 
 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 
Protocol deviations are to be documented within 7 calendar days of awareness of the event using 
the Protocol Deviation Form in Velos or using a Notice of Protocol Deviation form on paper that 
is sent to the UCM CRA or appropriate representative at the University of Chicago Medicine. 
12.2.6 
PROTOCOL DEVIATIONS 
Protocol deviations are to be documented using the Notice of Protocol Deviation Form in the 
Velos clinical trial management system. Deviations that are considered major because they 

 
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impact subject safety or alter the risk/benefit ratio, compromise the integrity of the study data, 
and/or affect subjects’ willingness to participate in the study must be reported into the Velos 
system within 7 days. 
12.2.7 
QUALITY ASSURANCE AND AUDITING 
 
In addition to the clinical monitoring procedures, the University of Chicago Comprehensive 
Cancer Center will perform routine Quality Assurance Audits of investigator-initiated clinical 
trials as described in the NCI-approved UC CCC DSM Plan. Audits provide assurance that trials 
are conducted and study data are collected, documented and reported in compliance with the 
protocol. Further, quality assurance audits ensure that study data are collected, documented and 
reported in compliance with Good Clinical Practices (GCP) Guidelines and regulatory 
requirements. The audit will review subjects enrolled at the University of Chicago in accordance 
with audit procedures specified in the UC CCC Data and Safety Monitoring plan. For institutions 
who are forma members of the Personalized Cancer Care Consortium (PCCC), the UC CCC will 
conduct on site quality assurance audits on average every two years during the enrollment and 
treatment phase of the study. 
Auditing procedures for participating sites that are not full members of the PCCC must be specified 
and approved by the UC CCC Clinical Research Advisory Committee.  In general, for sites that 
are not full members of the PCCC, auditing responsibility will be delegated to the participating 
center, with the annual audit report forwarded to the University of Chicago for review. 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory authority, 
the site investigator must immediately inform the University of Chicago Cancer Clinical Trials 
Office and Regulatory Manager that such a request has been made. 
 

 
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13 
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8. Rajkumar SV, Jacobus S, Callander N, et al. Phase III trial of lenalidomide plus 
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12. Arastu-Kapur S, Shenk K, Parlati F and Bennett M. Non-Proteasomal Targets of 
Proteasome Inhibitors Bortezomib and Carfilzomib. Blood (ASH Annual Meeting 
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13. Kirk CJ, Jiang J, Muchamuel T, Dajee M, Swinarski D, Aujay M, Bennett MK, 
Yang J, Lewis E, Laidig G and Molineaux CJ. The Selective Proteasome Inhibitor 
Carfilzomib Is Well Tolerated in Experimental Animals with Dose Intensive 
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Summary 
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Approval 
(www.fda.gov/cder/foi/nda/2003/21602_Velcade.htm)  
15. Bross PF, Kane R, Farrell AT, Abraham S, Benson K, Brower ME, Bradley S, 
Gobburu JV, Goheer A, Lee SL, Leighton J, Liang CY, Lostritto RT, McGuinn 
WD, Morse DE, Rahman A, Rosario LA, Verbois SL, Williams G, Wang YC, . 
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16. Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk, KD, Sun CM, Demo SD, 
Bennett, SD, van Leeuwen, F, Chanan-Khan, A and Orlowski, RZ. Potent activity 
of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, 
against preclinical models of multiple myeloma. Blood. 2007 Nov 1;110(9):3281-
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17. Alsina M, Trudel S, Vallone M, Molineaux C, Kunkel L and Goy A. Phase 1 Single 
Agent Antitumor Activity of Twice Weekly Consecutive Day Dosing of the 
Proteasome Inhibitor Carfilzomib (PR-171) in Hematologic Malignancies. Blood 
(ASH Annual Meeting Abstracts), 2007; 110: 411. 
18. Jagannath S, Vij R, Stewart K, Somlo G, Jakubowiak A, Trudel S, Schwartz R, 
Siegel D, Kunkel L, The Multiple Myeloma Research Consortium (MMRC). Final 
results of PX-171-003-A0, part 1 of an open-label, single-arm, phase II study of 
carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma 
(MM). J ClinOncol. 2009 27:15s (suppl; abstr 8504). 
19. Wang L, Siegel D, Kaufman JL, Stewart AK, Jakubowiak AJ, Alsina M, Kukreti 
V, Bahlis NJ, McDonagh KT, Belch A, Sebag M, Gabrail N, Le MH, Bennett MK, 
Kunkel L, Kauffman M, Orlowski RZ, Vij R, and The Multiple Myeloma Research 
Consortium (MMRC).  Updated Results of Bortezomib-Naïve Patients in PX-171-
004, An Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) 
in Patients with Relapsed or Refractory Myeloma (MM). Blood (ASH Annual 
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20. Siegel D, Wang L, Orlowski RZ, Kaufman JL, Stewart AK, Kukreti V, Alsina M, 
Jakubowiak AJ, Jagannath D, McDonagh KT, Belch A, Bahlis NJ, Shustik C, Le 
MH, Kunkel L, Bennett MK, Kauffman M, Vij R, and The Multiple Myeloma 
Research Consortium (MMRC)PX-171-004, An Ongoing Open-Label, Phase II 
Study of Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory 
Myeloma (MM); Updated Results From the Bortezomib-Treated Cohort.Blood 
(ASH Annual Meeting Abstracts), Nov 2009; 114: 303 
21. Badros AZ, Vij R, Martin T, Zonder JA, Woo T, Wang, Lee S, Wong A, and 
Niesvizky R. Phase I Study of Carfilzomib in Patients (Pts) with Relapsed and 
Refractory Multiple Myeloma (MM) and Varying Degrees of Renal 
Insufficiency.Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 3877. 
22. Dredge K, Horsfall R, Robinson S, Zhang L-H, Lu L, et al. Orally administered 
lenalidomide (revlimid) is anti-angiogenic in vivo and inhibits endothelial cell 
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23. Corral LF, Haslett PAJ, Muller FW, Chen R, Wong LM, Ocampo CJ, Patterson RT, 
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24. Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man H-W, et al. Enhancement 
of cytokine production and Ap-1 transcriptional activity in T cells by thalidomide-
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305:1222-1232, 2003. 
25. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, 
Gupta D, Chauhan D, Treon SP, Richarson PG, Schlossman RL, Morgan GJ, Muller 
GW, Stirling DI, Anderson KC. Thalidomide and immunomodulatory derivatives 
augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98:210-
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26. Niesvizky R, Wang L, Orlowski RZ, Bensinger W, Alsina M, Gabrail N, Gutierrez 
A, Lori Kunkel, Michael Kauffman, and The Multiple Myeloma Research 
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Plus Lenalidomide and Low Dose Dexamethasone (CRd) in Relapsed and 
Refractory Multiple Myeloma (MM). Blood (ASH Annual Meeting Abstracts), Nov 
2009; 114: 304. 
27. Jakubowiak, AJ et al. Carfilzomib, Lenalidomide, and Dexamethasone In Newly 
Diagnosed Multiple Myeloma: Initial Results of Phase I/II MMRC Trial. Blood 
(ASH Annual Meeting Abstracts) 2010 116: Abstract 862 
28. Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D et at. A phase 1, 2 study of 
carfilzomib in combination with lenalidomide and low-dose dexamethasone as a 
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29. Jakubowiak AJ et al. Final results of a frontline phase 1, 2 study of carfilzomib, 
lenalidomide, and low-dose dexamethasone (CRd) in Multiple Myeloma. ASH 
Annual Meeting Abstracts) 2011 Abstract 631 
30. Jakubowiak AJ et al. ASCO 2012 and Blood 2012, June 4, EPub ahead of print 
31. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo 
F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, 
Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; 
GIMEMA Italian Myeloma Network. Bortrezomib with thalidomide plus 
dexamethasone compared with thalidomide plus dexamethasone as induction 
therapy before, and consolidation therapy after, double autologous stem-cell 
transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. 
Lancet. 2011 Nov 26;378(9806):1846 
 
 
 
 
 

 
 
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APPENDIX A.  SCHEDULE OF TESTS AND OBSERVATIONS 
PROCEDURES 
Screen 
CRd Induction Cycles 1-4 
DAY 
 
-21 to -
1 
1 
2 
8 
9 
15 
16 
22 
 
End of 
Cycle 
4 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical/Treatment History 
X 
 
 
 
 
 
 
 
 
Skeletal Survey2 
X 
 
 
 
 
 
 
 
 
ECG3 
X 
 
 
 
 
 
 
 
 
Physical Exam5 
X 
X4 
 
 
 
 
 
 
 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height, Weight, BSA 
X 
X 
 
 
 
 
 
 
 
24-hour urine7 
X 
X4,7 
 
 
 
X7 
 
 
X7 
Urinalysis 
X 
 
 
 
 
 
 
 
 
Coagulation Tests8 
X 
 
 
 
 
 
 
 
 
CRP 
X 
 
 
 
 
 
 
 
 
Hematology9 
X 
X 
 
(X)10 
 
(X)10 
 
 
 
Serum Chemistry 
 
X11 
X11 
X12 
X11 
X12 
X11 
X12 
 
 
Pregnancy Test13 
X 
X 
 
X14 
 
X14 
 
X14 
 
Disease Assessment 
 
 
 
 
 
 
 
 
X15 
β2-microglobulin 
X 
 
 
 
 
 
 
 
 
SPEP, UPEP16 
X 
X4 
 
 
 
X17 
 
 
X 
Immunofixation – Serum and Urine 
X 
X4 
 
 
 
X17 
 
 
X 
BM Aspirate/biopsy, cytogenetics, FISH18 
X 
 
 
 
 
 
 
 
X18 
Plasmacytoma Evaluation31 
X 
 
 
 
 
 
 
 
 
Quantitative Igs 
X 
X4 
 
 
 
X17 
 
 
X 

 
 
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PROCEDURES 
Screen 
CRd Induction Cycles 1-4 
DAY 
 
-21 to -
1 
1 
2 
8 
9 
15 
16 
22 
 
End of 
Cycle 
4 
 
SFLC19 
X 
 
 
 
 
 
 
 
X19 
Neurological Assessment20 
X 
X20 
 
 
 
 
 
 
 
Correlative Samples21 
X 
 
 
 
 
 
 
 
X21 
Bone marrow aspirate sample for MRD 
analysis32 
X 
 
 
 
 
 
 
 
X 
CT-PET33 
X 
 
 
 
 
 
 
 
X 
Adverse Events22 
 
Ongoing 
Concomitant Medications 
 
Ongoing 
Register Patient into Revlimid REMS® 
program and prescribe lenalidomide24 
X 
 
 
 
 
 
 
 
 
Carfilzomib25 
 
X 
X 
X 
X 
X 
X 
 
 
Revlimid® (Lenalidomide)26 
 
X 
X 
X 
X 
X 
X 
 
 
Dexamethasone27 
 
X 
X27 
X 
X27 
X 
X27 
X 
 
*Following cycle 4, subjects will proceed to Stem Cell Collection and Autologous Stem Cell Transplant (section 6.4) 
PROCEDURES 
CRd Consolidation Cycles 5-8 
(Following ASCT Days 70-90 but not 
more than 120) 
CRd Maintenance Cycles 9-
18 
End 
of 
Tx 
LTF
U 
DAY 
 
1 
2 
8 
9 
15 
16 
22 
End 
of 
Cycle 
830 
1 
2 
8 
15 
16 
22 
 
 
 
Skeletal Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

 
 
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PROCEDURES 
CRd Consolidation Cycles 5-8 
(Following ASCT Days 70-90 but not 
more than 120) 
CRd Maintenance Cycles 9-
18 
End 
of 
Tx 
LTF
U 
DAY 
 
1 
2 
8 
9 
15 
16 
22 
End 
of 
Cycle 
830 
1 
2 
8 
15 
16 
22 
 
 
 
ECG3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical Exam5 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
X 
 
Height, Weight, BSA 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
24-hour urine7 
X7 
 
 
 
 
 
 
 
X7 
 
 
 
 
 
X7 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology9 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Serum Chemistry 
X11 
 
X11 
 
X11 
 
 
X11 
X11 
 
 
 
 
 
X 
 
Pregnancy Test13 
X 
 
 
 
X14 
 
 
 
X14 
 
 
X14 
 
 
X14 
 
Disease Assessment 
 
 
 
 
 
 
 
X15 
 
 
 
 
 
X1
5 
 
X23 
β2-microglobulin 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
SPEP, UPEP16 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
Immunofixation – Serum and Urine 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
BM Aspirate/biopsy, cytogenetics, 
FISH18 
 
 
 
 
 
 
 
X18 
 
 
 
 
 
 
X18 
X 
Plasmacytoma Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Quantitative Igs 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
SFLC19 
 
 
 
 
 
 
 
X19 
 
 
 
 
 
 
X19 
 
Neurological Assessment20 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Correlative Samples21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X21 
 

 
 
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PROCEDURES 
CRd Consolidation Cycles 5-8 
(Following ASCT Days 70-90 but not 
more than 120) 
CRd Maintenance Cycles 9-
18 
End 
of 
Tx 
LTF
U 
DAY 
 
1 
2 
8 
9 
15 
16 
22 
End 
of 
Cycle 
830 
1 
2 
8 
15 
16 
22 
 
 
 
Bone marrow aspirate sample for 
MRD analysis32 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X32 
CT-PET33 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X33 
Adverse Events22 
Ongoing 
 
Concomitant Medications 
Ongoing 
 
Carfilzomib25 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
 
Revlimid® (Lenalidomide)26,28 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X28 
Dexamethasone27 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
Survival and New Cancer Evaluation 29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
* Variations of ± 3 days of the scheduled visit are permitted however doses of carfilzomib may only be rescheduled by up to 2 days 
(Section 5.2.3). 
**The CRd consolidation cycles are cycle 5 – 8.  Maintenance cycles are 5-18 for patients that do not proceed to ASCT. 
 
Footnotes for Appendix A 
+    Documented informed consent must be obtained within ≤ 30 days prior to initiation of therapy. 
1. Includes neuropathy history.  
2. May be within 30 days planned treatment start.  Includes: lateral radiograph of the skull, anteroposterior and lateral views of the spine, and anteroposterior 
views of the pelvis, ribs, femora, and humeri.   Skeletal surveys performed outside of the 30 day window may be considered for inclusion.  Please contact 
the Lead Principal Investigator and/or/CRA on a case-by-case basis. End of treatment skeletal survey only if clinically indicated. 
3. 12-lead ECG, including QTc interval. End of treatment ECG only if clinically indicated. 
4. For Day 1 of cycle 1, screening results may be used if within 7 days of treatment start.   
5. Complete physical exam (including vital signs [systolic and diastolic blood pressure, respiration, pulse, oral temperature], height, weight, calculation of 
body surface area [BSA]) and ECOG score) required at screening and Day 1 of each cycle.  .  
6. Systolic and diastolic blood pressure, pulse, respiration, temperature approximately 1 hour before dosing.   

 
 
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7. 24 hour urine total protein, urine protein electrophoresis (UPEP), and urine protein immunofixation. For subjects whose disease is being monitored 
through UPEP, additional post baseline 24-hour urine collections are required as indicated. 
8. Prothrombintime, activated partial thromboplastin time, and international normalized ratio.  
9. Hemoglobin, hematocrit, WBC with complete differential, RBCs, platelet count.  Results must be reviewed before dosing. 
10. Cycles 1 and 2 only and subsequent cycles as clinically indicated or per institutional standard of care.      
11. Full serum chemistry panel at Screening, Days 1, 8, and 15 of Cycles 1-8, and Day 1 of Cycles 9+: sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, uric acid, total protein, albumin, calcium, phosphorus, magnesium, total bilirubin, alkaline phosphatase, ALT, AST, LDH.  Results 
must be reviewed before dosing in Cycles 1 and 2. 
12. Abbreviated serum chemistry panel on Days 2, 9, and 16 of Cycles 1 and 2 only or as clinically indicated (e.g., risk factors for tumor lysis syndrome):   
sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, uric acid.    
13. Pregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not had a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally post-menopausal for at least 24 consecutive months (i.e., menses within the 
preceding 24 months)  See Appendix F of protocol for details.    
14. Pregnancy tests must occur within 10-14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled within 7 days.  
FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on therapy (including breaks 
in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide.  Females with irregular menstruation must have a 
pregnancy test weekly for the first 28 days and then every 14 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide and 
at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods. 
15. After 4 cycles, subjects are evaluated before receiving ASCT. It is anticipated that all patient will proceed to ASCT but if patient becomes not eligible, 
continuation of CRd treatment as per maintenance schedule can be granted by the Lead Principal Investigator.. 
16. Serum protein electrophoresis and urine protein electrophoresis (the latter only for those whose disease is being followed by UPEP).  Subjects with 
baseline urine protein greater than 200 mg/24 hours must have a UPEP to confirm VGPR or better.  Obtain blood for M-protein levels measured by 
SPEP or quantitative immunoglobulins for those subjects in whom SPEP/UPEP are felt to be unreliable (IgA type multiple myeloma), depending upon 
which studies were positive at baseline. 
17. Disease assessments on Day 15 of Cycle 1 (only) are only for assessing onset of early response, not for definitive achievement of response.  
18. Bone marrow aspirate and biopsy - quantify % myeloma cell involvement; bone marrow sample for cytogenetics and fluorescent in situ hybridization 
(FISH). Bone marrow aspirate and biopsy should be performed at screening, end of cycle 4 (pre-transplant), 3-months post-transplant, and the end of 
CRd consolidation (end of cycle 8). See sections 6.3-6.5. Repeat bone marrow biopsy/aspirate if CR is suspected (e.g., end of cycle 4) and as appropriate 
to confirm achievement of sCR, CR, or nCR (aspirate only—biopsy not required).If institution has established flow-based multi-color study for minimal 
residual disease (MRD), this evaluation should include MRD evaluation. Bone marrow biopsy/aspirate performed outside of the 30 day window may be 
considered for inclusion.  Please contact the Lead Principal Investigator and/or the CRA on a case-by-case basis. (Cytogenetics is required at screening 
only. If cytogenetics is completed at a time point other than screening, the results should be captured in eCRF) 
19. SFLC repeated only to confirm CR. 
20. Screening and Day 1 of every cycle. Includes neurologic exam (to detect peripheral neuropathy and/or changes in pre-existing neuropathy) and 
examination of clinical AEs indicative of neuropathy.  Collect FACT/GOG neurotoxicity questionnaire at each time point above. 
21. Peripheral blood and bone marrow aspirate samples collected at screening, time of response (to confirm complete response), and/or end-of-treatment 
visit. Buccal mucosa swab will be collected at screening only. 

 
 
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22. AEs will be collected from the time of signing informed consent. 30 days following the last dose of CRd, during ASCT period, patients will be considered 
to be off-study so no toxicities will be recorded for this period. AE tracking will re-commence at the initiation of Cycle 5. All concomitant medications 
must be recorded on the concomitant medications case report form from 21 days before Day 1 through 30 days following the last dose of study drugs. 
23. Assessment for disease progression in subjects who did not progress during treatment.  At least every 3 months (+/- 30 days) for 5 years from safety 
follow-up visit (which must be 28days (+/- 3 days) post-last study treatment). 
24. Lenalidomide must be prescribed through and in compliance with the Revlimid REMS® program of Celgene Corporation.  Prescriptions must be filled 
within 7 days.  Consideration should be given to prescribing lenalidomide 5 to 7 days in advance of Day 1 of each cycle to allow time for required patient 
and prescriber surveys, and drug shipment to patient.  Any unused Revlimid® (lenalidomide) should be returned to the patient for disposition in accordance 
with the Revlimid REMSt® program. 
25. Cycles 1-8: Days 1, 2, 8, 9, 15 & 16.  Cycles 9-18 Days 1, 2, 15 & 16 
26. Daily on Days 1-21 followed by a 7-day rest period every 28 days.  On day coinciding with carfilzomib administration, lenalidomide should be taken at 
least 4 hours after the carfilzomib dose and may be self-administered at home by the subject.  On days that carfilzomib is not administered, lenalidomide 
should be taken at approximately the same time each day. 
27. Days 1, 8, 15 and 22.  Dexamethasone is given between 30 minutes and 4 hours before carfilzomib on days they coincide. Cycles 5-8 dexamethasone will 
be   reduced down to 20 mg on days 1, 8, 15 and 22. Cycles 9-18 represent the CRd Maintenance Phase of therapy and the dose of dexamethasone will 
remain 20 mg on days 1, 8, 15 and 22. Subjects may be given 4 mg dexamethasone p.o. or IV on Days 2, 9 and 16 in Cycles 1 and 2 prior to carfilzomib 
infusion if signs of tumor flare are present.  This will be prescribed at the Treating Investigator’s discretion.  
28. Single-agent Lenalidomide maintenance therapy, is recommended using last tolerated dose of lenalidomide for 21 days in 28 day cycles after CRd protocol 
treatment (cycles 1-18) is completed. 
29. Patients will be followed for survival and development of any new cancers, at least every 3 months.  Reports of any death should include date of death 
and specific cause (disease under study or specify other cause).     
30. Evaluations at the end Cycle 8 may be done on Day 1 of the next Cycle 9 
31. Plasmacytoma evaluation is required at screening only and may be completed as physical exam or imaging if indicated and at the treating investigator’s 
discretion. After screening, plasmacyotoma evaluation is required only for patients who have no other measurable disease and/or at investigator’s 
discretion. 
32. Two bone marrow samples for central Minimal Residual Disease (MRD) analysis by flow at the University of Chicago and by NGS at Adaptive 
Biotechnologies will be collected from all subjects: 1) screening (sample is required for calibration of MRD by gene sequencing In the event that a 
superfluous bone marrow aspirate –BMA- sample from screening was not available, slides of BMA smear or clot from a time prior to enrollment can be 
used), 2) end of cycle 4, 3) post-transplant, 4) end of cycle 8, 5) end of cycle 18 (EOT), 6) 1, 2, 3, and 5 years after EOT for all subjects; 7) any time that 
a bone marrow is performed as SOC to assess CR response. For any bone marrow collected after Cycle 4, Cycle 8 or Cycle 18, the visit may be done on 
Day 22-28 of that cycle.  
33. A CT-PET will be performed to confirm MRD-negative disease per Standard of Care, at every time-point when MRD is checked. A bone marrow done 
as SOC a year after the EOT BM will be tested for MRD and a CT-PET done to confirm MRD-negative disease. 
 
 
 
 

 
 
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APPENDIX B. MULTIPLE MYELOMA STAGING                                                             
A. Durie-Salmon Staging 
Stage I  
All of the following must be present: 
• Hemoglobin > 10.5 g/dL or hematocrit >32% 
• Serum calcium level normal (≤ 12mg/dL) 
• Low serum myeloma protein production rates as evidenced by all of the 
following:  
o IgG peak < 5g/dL  
o IgA peak < 3g/dL  
o Bence Jones protein < 4g/24 h  
• No bone lesions  
 
Stage II 
All patients who do not meet criteria for Stage I or III are considered Stage II. 
Stage III 
One of the following abnormalities must be present: 
• Hemoglobin < 8.5 g/dL, hematocrit < 25%  
• Serum calcium >12 mg/dL  
• Very high serum or urine myeloma protein production rates as evidenced by one 
or more of the following:  
• IgG peak > 7g/dL  
• IgA peak > 5g/dL  
• Bence Jones protein > 12g/24 h  
• > 3 lytic bone lesion on bone survey (bone scan not acceptable)  
 
Sub-classification 
a:         Serum creatinine < 2.0 mg/dL 
b:         Serum creatinine >2.0 mg/dL 
 
 
B. International Myeloma Working Group International Staging System (ISS) 
1. 
Stage I: B2M < 3.5 plus serum albumin >3.5 (med S 62m) 
2. 
Stage II: B2M < 3.5 but serum alb. < 3.5 OR B2M 3.5 - < 5.5 (med S 44m) 
3. 
Stage III: B2M > 5.5 (med S 29m) 
4. 
Subclassify stages 1+2 according to cr< or > 2 and stage 3 according to low 
platelets (< 130k) or high LDH 
 
 
IMWG criteria for symptomatic myeloma: 
 

 
 
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All three criteria must be met: 
1. Clonal bone marrow plasma cells and/or documented clonal plasmacytoma 
2. Presence of serum and/or urinary monoclonal protein 
3. Evidence of end-organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically: 
     -Hypercalcemia: serumcalcium ≥ 11.5 mg/dl or 
     -Renal insufficiency: serum creatinine >2 mg/dl or 
-Anemia:  hemoglobin  at least 2 g/dl below the lower limit of normal or a hemoglobin 
<10 g/dl or 
 -Bone lesions: lytic lesions, osteopenia or pathologic fractures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX C.  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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5 OCT 2015 
 
APPENDIX D.  NCI CTCAE VERSION 4.0 
 
 
Common 
Terminology 
Criteria 
for 
Adverse 
Events 
(CTCAE) 
of 
the  
National Cancer Institute (NCI) v4.0 
 
Publish Date:  September 15, 2009 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_5x7.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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5 OCT 2015 
 
APPENDIX E.  RESPONSE CRITERIA FOR MULTIPLE MYELOMA 
Table E1: IMWG Criteria 
Response 
IMWG criteria1,2 
sCR 
Stringent 
Complete 
Response 
CR as defined below plus:  
• normal FLC ratio and  
• absence of clonal cells in bone marrow by immunohistochemistry 
or 2 – 4 color flow cytometry 
CR 
Complete 
Response 
• Negative immunofixation on the serum and urine and  
• disappearance of any soft tissue plasmacytomas and  
• < 5% plasma cells in bone marrow.   
• In patients with only FLC disease, a normal FLC ratio of 0.26–1.65 
is required. 
VGPR 
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/24 h.   
• In patients with only FLC disease, >90% decrease in the difference 
between involved and uninvolved FLC levels is required. 
PR 
Partial 
Response 
• 50% reduction of serum M-protein and reduction in 24 hours urinary 
M-protein by >90% or to < 200 mg/24 h 
• If the serum and urine M-protein are unmeasurable,3 a > 50% 
decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria 
• If serum and urine M-protein are not measurable, and serum free 
light assay is also not measureable, > 50% reduction in plasma cells 
is required in place of M-protein, provided baseline bone marrow 
plasma cell percentage was > 30% 
• In addition to the above listed criteria, if present at baseline, a > 50% 
reduction in the size of soft tissue plasmacytomas is also required 
Stable 
Disease 
• Not meeting criteria for CR, VGPR, PR or progressive disease 

 
 
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All relapse categories (CR, sCR, VGPR, and PD) require two consecutive assessments made 
at anytime before the institution of any new therapy; complete response and PR and SD 
categories also require no known evidence of progressive or new bone lesions if radiographic 
studies were performed.  VGPR and CR categories require serum and urine studies regardless 
of whether disease at baseline was measurable in serum, urine both or either.  Radiographic 
studies are not required to satisfy these response requirements. Bone marrow assessments need 
not be confirmed.  For progressive disease, serum M-component increases of ≥ I gm/dl are 
sufficient to define response if starting M-component is ≥ 5 g/dl.    
 
IMWG clarification for coding PD:   
• clarified that bone marrow criteria for PD are to be used only in patients without 
measurable disease by M protein and by FLC levels.   
• clarified that 25% increase refers to M protein, FLC, and bone marrow results and does not 
refer to bone lesions, soft tissue plasmacytomas or hypercalcemia.  Note the lowest 
response value does not need to be a confirmed value. 
 
Table E2:Additional response criteria for specific disease states1,2,3,4 
Minor response in patients with relapsed and 
refractory myeloma adapted from the EMBT 
criteria3 
≥ 25% but < 49% reduction of serum M protein 
and reduction in 24 hour urine M protein by 50 – 
89%, which still exceeds 200 mg/24hrs. 
 
In addition to above; if present at baseline, 25-
49% reduction in the size of soft tissue 
plasmacytomas is also required 
 
Progressive 
disease 
Increase of > 25% from lowest response value in any one of the following: 
• 
Serum M-component (the absolute increase must be > 0.5 g/dL)4and/or  
• 
Urine M-component (the absolute increase must be > 200 mg/24 
h)and/or  
• 
Only in patients without measurable serum and urine M-protein, the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be > 10 mg/dL 
• 
Only in patients without measurable serum and urine M-protein and 
without measurable disease by FLC levels, bone marrow plasma cell 
percentage (absolute % must be ≥ 10%)  
• 
Definite development of new bone lesions or soft tissue plasmacytomas 
or definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas 
• 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) 
that can be attributed solely to the plasma cell proliferative disorder 

 
 
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No increase in size or number of lytic bone 
lesions (development of compression fractures 
does not exclude response) 
Near Complete Response nCR 
The 
absence 
of 
myeloma 
protein 
on 
electrophoresis, with positive immunofixation, 
stable bone disease, and a normal serum calcium 
concentration 
Immunophenotypic CR 
Stringent CR plus 
Absence of phenotypic abarrent PC (clonal) in 
bone marrow with a minimum of one million of 
total BM cells analyzed by multiparametric flow 
cytometry (with ≥4 colors) 
Molecular CR 
Stringent CR plus negative ASO-PCR (sensitivity 
10-5) 
1. Durie et al. International uniform response criteria for multiple myeloma. Leukemia 
2006;20:1467-73 
2. S. Vincent Rajkumar, Jean-Luc Harousseau, Brian Durie, Kenneth C. Anderson, 
Meletios Dimopoulos, Robert Kyle, Joan Blade, Paul Richardson, Robert Orlowski, 
David Siegel, Sundar Jagannath, Thierry Facon, Hervé Avet-Loiseau, Sagar Lonial, 
Antonio Palumbo, Jeffrey Zonder, Heinz Ludwig, David Vesole, Orhan Sezer, Nikhil 
C. Munshi, and Jesus San Miguel. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus 
Panel 1 . Blood First Edition Paper, prepublished online February 3, 2011;DOI 
10.1182/blood-2010-10-299487 
3. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar 
SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani 
SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, 
Anderson KC. A Phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl 
J Med 348:2609, June 2, 2003. 
4. Richardson et al. Bortezomib or High-Dose Dexamethasone for Relapsed Multiple 
Myeloma. N Eng J Med. 352:2487-98, 2005 
 
 
 
 

 
 
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APPENDIX F. RISKS OF FETAL EXPOSURE, PREGNANCY TESTING      
GUIDELINES AND ACCEPTABLE BIRTH CONTROL METHODS  
Risks Associated with Pregnancy 
 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has 
the effect of the lenalidomide on human eggs and sperm.  Lenalidomide is structurally related 
to thalidomide.  Thalidomide is a known human teratogenic active substance that causes severe 
life-threatening birth defects.  An embryofetal development study in animals indicates that 
lenalidomide produced malformations in the offspring of female monkeys who received the 
drug during pregnancy.  The teratogenic effect of lenalidomide in humans cannot be ruled out.  
Therefore, a risk minimization plan to prevent pregnancy must be observed. 
 
All study participants must be registered into the mandatory Revlimid REMS® program and 
be willing and able to comply with the requirements of Revlimid REMS®. 
 
Females of childbearing potential (FCBP) must agree to use 2 reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual intercourse during the 
following time periods related to this study: 
 
• 
for at least 28 days before starting lenalidomide; 
• 
while participating in the study 
• 
for at least 28 days after discontinuation from the study. 
 
The 2 reliable methods of contraception must include 1 highly effective method—intrauterine 
device, hormonal (birth control pills, injections, or implants), tubal ligation, or partner's 
vasectomy—and 1 additional effective barrier method—latex condom, diaphragm, or cervical 
cap.  FCBP must be referred to a qualified provider of contraceptive methods if needed. 
 
Because of the increased risk of venous thromboembolism in patients with multiple myeloma 
taking lenalidomide and dexamethasone, combined oral contraceptive pills are not 
recommended. If a patient is currently using combined oral contraception the patient should 
switch to one of the effective method listed above. The risk of venous thromboembolism 
continues for 4−6 weeks after discontinuing combined oral contraception. The efficacy of 
contraceptive steroids may be reduced during co-treatment with dexamethasone. 
 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased 
risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in patients with neutropenia. 
 
Before starting lenalidomide: 
 
Female subjects 
 

 
 
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• 
FCBP must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
initiating lenalidomide.  The first pregnancy test must be performed within 10-14 days 
before, and the second pregnancy test must be performed within 24 hours beforeprescribing 
lenalidomide (prescriptions must be filled within 7 days). 
• 
The subject may not receive lenalidomide until the investigator has verified that the results 
of these pregnancy tests are negative. 
 
Male subjects 
 
• 
Must agree to use a latex condom during sexual contact with FCBP while participating in 
the study and for at least 28 days following discontinuation from the study even if he has 
undergone a successful vasectomy. 
 
During study participation and for 28 days following discontinuation from the study 
 
All subjects 
 
• 
If pregnancy or a positive pregnancy test occurs in a study subject or in the partner of a 
male study subject during study participation, lenalidomide must be immediately 
discontinued. 
Female subjects 
 
• 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, at study 
discontinuation, and at day 28 following discontinuation from the study.  If menstrual 
cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then 
every 14 days while on study, at study discontinuation, and 14 and 28 days after 
discontinuation from the study. 
• 
In addition to the required pregnancy testing, the investigator must confirm with FCBP that 
she is continuing to use 2 reliable methods of birth control at each visit. 
• 
Pregnancy testing and counseling must be performed if a subject misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment must 
be discontinued during this evaluation. 
 
Male subjects 
 
• 
Must agree to use a latex condom during sexual contact with FCBP while participating in 
the study and for at least 28 days following discontinuation from the study even if he has 
undergone a successful vasectomy. 
 

 
 
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APPENDIX G: COCKROFT-GAULT ESTIMATION OF CRCL 
 
Cockroft-Gault estimation of creatinine clearance (CrCl): 
(Cockroft 1976; Luke 1990) 
 
CrCl (mL/min) for males: 
(140-age) x (weight, kg) 
 
 
 
 
72 x (serum creatinine, mg/dL) 
 
 
CrCl (mL/min) for males: 
(140-age) x (weight, kg) x 0.85 
 
 
 
 
72 x (serum creatinine, mg/dL) 
 
*Measured creatinine clearance on 24 hour urine collection can be used and is acceptable. If 
measured CrCl is different than calculated, measured CrCl should be used for eligibility 
assessment and/or dose modifications. 
 
 
 

 
 
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APPENDIX H:    
FACT/GOG-NEUROTOXICITY QUESTIONNAIRE, VERSION 
4.0 
By circling one (1) number per line, please indicate how true each statement has been for you 
during the past 7 days. 
ADDITIONAL CONCERNS 
Not 
at all 
A 
little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
I have numbness or tingling in my hands……… 
0 
1 
2 
3 
4 
I have numbness or tingling in my feet………… 
0 
1 
2 
3 
4 
I feel discomfort in my hands…………………. 
0 
1 
2 
3 
4 
I feel discomfort in my feet…………………… 
0 
1 
2 
3 
4 
I have joint pain or muscle cramps…………… 
0 
1 
2 
3 
4 
I feel weak all over…………………………… 
0 
1 
2 
3 
4 
I have trouble hearing………………………… 
0 
1 
2 
3 
4 
I get a ringing or buzzing in my ears………… 
0 
1 
2 
3 
4 
I have trouble buttoning buttons……………… 
0 
1 
2 
3 
4 
I have trouble feeling the shape of small objects 
when they are in my hand……………………… 
0 
1 
2 
3 
4 
I have trouble walking………………………… 
0 
1 
2 
3 
4 
 
 
________________________________ 
Sources:  Cella DF, Tulsky DS, Gray G, Sarafian B, Lloyd S, Linn E, et al.  The functional 
assessment of cancer therapy (FACT) scale:  development and validation of the general 
measure.  J ClinOncol 1993;11(3):570-79. 
 
 

 
 
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APPENDIX I:    
IMWG CRITERIA FOR THE DIAGNOSIS OF MYELOMA 
Diagnosis   
Diagnostic Criteria: All Three 
Required 
Symptomatic multiple myelomaa 
• 
Monoclonal plasma cells in 
the bone marrow >/=10% 
and/or presence of a biopsy-
proven plasmacytoma  
• 
Monoclonal protein present 
in the serum and/or urineb  
• 
Myeloma-related organ 
dysfunction (>/=1)c  
 [C] Calcium 
elevation in 
the blood 
(serum 
calcium 
>10.5 mg/l 
or upper 
limit of 
normal 
[R] Renal 
insufficiency 
(serum 
creatinine 
>2mg per 
100 ml) 
[A] Anemia 
(hemoglobin 
<10 g per 
100 ml or 2 
g <normal) 
[B] Lytic 
bone lesions 
or 
osteoporosisd  
Monoclonal gammopathy of 
undetermined significance 
(MGUS) 
• 
Serum monoclonal protein 
lowe  
• 
Monoclonal bone marrow 
plasma cells <10% 
• 
No evidence of end-organ 
damage attributable to the 
clonal plasma cell disorder: 

 
 
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5 OCT 2015 
 
o Normal serum 
calcium, 
hemoglobin level 
and serum creatinine 
o No bone lesions on 
full skeletal X-ray 
survey and/or other 
imaging if 
performed 
o No clinical or 
laboratory features 
of amyloidosis or 
light chain 
deposition disease  
Smoldering or indolent myelomaf 
• 
Monoclonal protein present 
in the serum 3 g per 100 ml 
or higher or  
• 
Monoclonal plasma cells 
10% or greater present in 
the bone marrow and/or a 
tissue biopsy 
• 
No evidence of end-organ 
damage attributable to the 
clonal plasma cell disorder: 
o Normal serum 
calcium, 
haemoglobin level 
and serum creatinine 
o No bone lesions on 
full skeletal X-ray 
survey and/or other 
imaging if 
performed 
o No clinical or 
laboratory features 
of amyloidosis or 
light chain 
deposition disease  
Solitary plasmacytoma of bone  
• 
Biopsy-proven 
plasmacytoma of bone in a 
single site only. X-rays and 

 
 
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magnetic resonance 
imaging and/or 
• 
FDG PET imaging (if 
performed) must be 
negative outside the 
primary site.  
• 
The primary lesion may be 
associated with a low serum 
and/or urine M-component 
• 
The bone marrow contains 
no monoclonal plasma cells 
• 
No other myeloma-related 
organ dysfunction  
Adapted with permission from Kyle and Rajkumar, Criteria for diagnosis, staging, risk stratification 
and response assessment of multiple myeloma..Leukemia 2009; 23: 3–9. 
aThese criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA 
becomes smoldering or indolent myeloma. 
bIf no monoclonal protein is detected (non-secretory disease), then >/= 30% monoclonal bone marrow 
plasma cells and/or a biopsy-proven plasmacytoma required. 
cA variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for 
therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma 
related. 
dIf a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) is the sole 
defining criteria, then >/= 30% plasma cells are required in the bone marrow. 
eLow is defined as serum M protein <3.0 g per 100 ml. 
fThese criteria identify Stage IA myeloma by Durie/Salmon stage.