Phase I/II Study of Carfilzomib in Combination With Bendamustine and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: Suzanne Lentzsch, MD

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Study Title 
Phase I/II study of carfilzomib in combination with bendamustine 
and dexamethasone in patients with newly diagnosed multiple 
myeloma 
Protocol Number 
 
AAAJ2359 
Institution Name 
Columbia University Medical Center 
Principal Investigator 
Siyang Leng, MD 
Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Herbert Irving Pavilion, 9th floor 
161 Fort Washington Avenue 
New York, NY 10032 
NCT02002598

 
 
 
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PROTOCOL SYNOPSIS 
 
TITLE:  Phase I/II study of carfilzomib in combination with bendamustine and dexamethasone 
in patients with newly diagnosed multiple myeloma (MM) 
 
OBJECTIVES 
 
 
Primary Objective 
 
Determine the MTD of carfilzomib (CFZ) in combination with 
bendamustine and dexamethasone 
 
Secondary Objectives 
 
Determine the overall response rate (ORR)  
 
Determine duration of response (DOR) 
 
Determine progression free survival (PFS) 
 
Determine time to best response 
 
Determine overall survival (OS) 
 
Evaluate the safety and toxicity 
 
Stem cell collection parameters using the regimen as induction 
 
STUDY DESIGN 
 
This is a phase I/II study to define dose-limiting toxicity and determine 
preliminary evidence for efficacy of CFZ in combination with bendamustine 
and dexamethasone for patients with newly diagnosed MM. This trial is an 
open-label, single-center, dose escalation safety study. Doses will be 
allocated to patients using a two-stage Up-and-Down dose escalation 
scheme without intra-patient dose escalation. Patients will receive CFZ on 
days 1, 2, 8, 9, 15, and 16 every 28 days with dose escalation from 27 to 36, 
then 45, then 56 mg/m2.  No matter what target dose the subject will receive, 
doses on days 1 and 2 in the first cycle will always be 20 mg/m2, followed 
by the target dose for all subsequent dates and cycles. Bendamustine will be 
given IV on days 1 and 2 with dose escalation up to 90 mg/m2. 
Dexamethasone 20 mg PO or IV will be given on days 1, 2, 8, 9, 15, 16, 22 
and 23 of each 28-day cycle. Study treatment will be given until 8 cycles are 
completed or until disease progression, whichever comes first. This protocol 
can also be used as induction therapy for transplant. 
 
STUDY 
POPULATION 
 
Approximately 26 evaluable subjects (men and women at least 18 years of 
age) will participate in this study. 
INCLUSION 
CRITERIA  
 
Patients must have histologically or cytologically confirmed symptomatic 
MM, Salmon-Durie Stage II or III, or International Staging System II or III. 
Patients must be untreated. 
 
EXCLUSION 
CRITERIA 
 
Patients who have had systemic therapy for MM. Local radiation therapy for 
symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic 
fracture) are permitted. Patients are also allowed up to 2 cycles of high dose 
steroids (maximum total dose of 320 mg dexamethasone or equivalent) if 
needed for symptomatic disease before study enrollment 

 
 
 
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PROCEDURES 
 
Eligible patients will be entered on study centrally at the Columbia University 
Medical Center. Each patient enrolled in the study will be registered in the 
CUMC’s Clinical Trials Management Application (CTMA) at study entry. 
Each patient enrolled will be assigned a sequential study identifier by CTMA. 
Following registration, patients should begin the research treatment within 
one week. 
 
STUDY 
TREATMENT 
Patients will receive CFZ infusion on days 1, 2, 8, 9, 15, and 16 every 28 
days, with initial dose 20 mg/m2 and dose escalation up to 56 mg/m2.  
Bendamustine will be given IV on days 1 and 2 with dose escalation up to 
90 mg/m2, and dexamethasone 20 mg PO or IV on days 1, 2, 8, 9, 15, 16 and 
22 of each 28-day cycle. 
 
STATISTICAL 
METHODS 
 
1. 
Two-stage Up-and-Down dose escalation scheme (Storer’s schema D, 
with a one-patient-per-level run-in) without intra-patient dose 
escalation 
2. 
Logistic regression model 
3. 
Fisher’s exact test 
4. 
Kaplan-Meier estimator 
5. 
Monte Carlo simulation  
 
 
 
 
 

 
 
 
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1 
INTRODUCTION........................................................................................................9 
1.1 
Disease Specific Background ............................................................................9 
1.2 
Proteasome Background ....................................................................................9 
1.3 
Carfilzomib Background ....................................................................................9 
1.4 
Bendamustine Background ..............................................................................11 
1.5 
Study Rationale ................................................................................................11 
1.6    Dose Rationale .................................................................................................12 
2 
OBJECTIVES ............................................................................................................14 
2.1 
PRIMARY Objective .......................................................................................14 
2.2 
Secondary Objectives .......................................................................................14 
3 
EXPERIMENTAL PLAN .........................................................................................15 
3.1 
Study Design ....................................................................................................15 
3.2 
Number of Centers ...........................................................................................16 
3.3 
Number of subjects ..........................................................................................16 
3.4 
Estimated StuDy duration ................................................................................16 
4 
SUBJECT  SELECTION ..........................................................................................17 
4.1 
Inclusion Criteria .............................................................................................17 
4.2 
Exclusion Criteria ............................................................................................18 
5 
SUBJECT ENROLLMENT ......................................................................................19 
6 
TREATMENT PROCEDURES ...............................................................................22 
6.1 
Drug Preparation and Administration ..............................................................22 
6.1.1 
Carfilzomib .......................................................................................22 
6.1.2 
BENDAMUSTINE ...........................................................................22 
6.1.3 
DEXAMETHASONE .......................................................................23 
6.2 
Definition of Dose-limiting Toxicity ...............................................................23 
6.3 
Dose Reductions/Adjustments .........................................................................23 
6.3.1 
Dose Reductions for Hematologic Toxicities: ..................................24 
6.3.2 
Dose Reductions for Non-Hematologic Toxicities ...........................25 
6.3.3 
Missed Doses ....................................................................................29 
6.3.4 
Changes in Body Surface Area .........................................................29 
6.3.5 
Dosing Modifications........................................................................29 

 
 
 
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6.4 
Safety Considerations ......................................................................................29 
6.4.1 
Guidelines for Monitoring, Prophylaxis, and Treatment of Tumor 
Lysis Syndrome (TLS) ......................................................................30 
6.5 
Concomitant Medications ................................................................................31 
6.5.1 
Required Concomitant Medications .................................................31 
6.5.2 
Optional and Allowed Concomitant Medications.............................32 
6.5.3 
Excluded Concomitant Medications .................................................32 
7 
STUDY EVALUATION ............................................................................................33 
7.1 
Screening (within ≤ 28 days of registration unless otherwise 
noted) ................................................................................................33 
7.2 
During Study Treatment ...................................................................33 
7.3 
Discontinuation of stUdy treatment ..................................................34 
7.4 
Follow-up ..........................................................................................35 
7.5 
Duration of study treatment ..............................................................35 
7.6 
Duration of follow – up.....................................................................35 
8 
STUDY CALENDAR ................................................................................................36 
9 
STUDY DISCOTINUATION ...................................................................................40 
9.1 
DISCONTINUATION OF STUDY TREATMENT .......................................40 
9.2 
Followup after discontinuation of study treatment ..........................................40 
10 
MEASUREMENT OF EFFECT ..............................................................................41 
10.1 
Definitions.........................................................................................41 
10.2 
Guidelines for Evaluation of Measurable Disease ............................42 
10.3 
Response Criteria ..............................................................................42 
10.4 
Confirmatory Measurement/Duration of Response ..........................45 
10.5 
Response Review ..............................................................................45 
11 
ADVERSE EVENTS .................................................................................................46 
11.1 
Adverse Event Definitions ...............................................................................46 
11.2 
Adverse Events Reporting Procedures.............................................................47 
11.3 
Serious Adverse Events Definitions ................................................................48 
11.4 
Serious Adverse Event Reporting and Documentation Requirements ............49 
11.5 
Pregnancy .........................................................................................................51 
12 
STATISTICAL CONSIDERATIONS .....................................................................53 

 
 
 
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12.1 
Study Design/Endpoints...................................................................................53 
12.2 
Stratification Factors ........................................................................................53 
12.3 
Sample Size/Accrual Rate ................................................................................53 
12.4 
Analysis of Primary Endpoint ..........................................................................53 
12.5 
Analysis of Secondary Endpoints ....................................................................54 
12.6 
Dose Assignment Algorithm............................................................................54 
12.7 
Justification of Design .....................................................................................55 
13 
INVESTIGATIONAL PRODUCT...........................................................................57 
13.1 
Carfilzomib Description ...................................................................................57 
13.2 
Formulation ......................................................................................................57 
13.3 
Storage .............................................................................................................57 
13.4 
Accountability ..................................................................................................57 
14 
CORRELATIVE STUDIES ......................................................................................58 
15 
REGULATORY OBLIGATIONS ...........................................................................60 
15.1 
Informed Consent.............................................................................................60 
15.2 
Compliance with Laws and Regulations..........................................................60 
15.3 
Subject Confidentiality ....................................................................................61 
16 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ...........................................62 
16.1 
Protocol Amendments and Study Termination ................................................62 
16.2 
Ethical and Scientific Conduct of the Clinical Study ......................................62 
16.3 
study documentation and archive .....................................................................62 
16.4 
Data Safety and monitoring Committee ..........................................................63 
16.5 
QUALITY CONTROL AND QUALITY ASSURANCE ...............................64 
17 
REFERENCES ...........................................................................................................65 
APPENDIX A.  STAGING OF MYELOMA: DURIE-SALMON SYSTEM AND 
INTERNATIONAL STAGING SYSTEM ..............................................................68 
APPENDIX B. INTERNATIONAL MYELOMA WORKING GROUP 
DIAGNOSTIC CRITERIA .......................................................................................69 
APPENDIX C:  NCI-CTCAE VERSION 4.0 ......................................................................70 
APPENDIX D:  PERFORMANCE STATUS CRITERIA.................................................71 
 
LIST OF TABLES 
Table 1. Dose Escalation Schema 

 
 
 
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Table 2.  Dose Reduction Guidelines for Thrombocytopenia 
Table 3.  Dose Reduction Guidelines for Neutropenia 
Table 4.  Carfilzomib dose adjustment guidelines summary for non-hematologic toxicities 
Table 5.   Carfilzomib Dose Adjustment Guideline for Renal Dysfunction 
Table 6.  Bendamustine Dose Management based on non-hematologic toxicities 
Table 7.  Dexamethasone Treatment Adjustments 
Table 8.  Severity table of Adverse Events additional to CTCAE 
Table 9.  Dose-specific probabilities of dose-limiting toxicity assumed for Monte Carlo simulation to 
assess the operating characteristics  
 
LIST OF FIGURES 
Figure 1. Operating characteristics of design estimated from Monte Carlo simulations of trial design.   
 
LIST OF APPENDICES 
1. Appendix A. Staging of myeloma: Durie-Salmon system and international staging system 
2. Appendix B. International myeloma working group diagnostic criteria 
3. Appendix C. NCI-CTCAE version 4.0 
4. Appendix D. Performance status criteria 
 
LIST OF ABBREVIATIONS 
 
Abbreviation  
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BSA 
body surface area 
BTZ  
bortezomib  
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CFZ  
Carfilzomib  
CHF 
congestive heart failure 
CR 
complete response 
CrCl 
Creatinine Clearance 
CRF 
case report form(s) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMA 
Clinical Trials Management Application 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
FCBP 
Females of childbearing potential 
FDA 
Food and Drug Administration 
FLC 
free light chain 
GCP 
Good Clinical Practice  
h 
hour(s) 
ICH 
International Conference on Harmonization 
Ig 
Immunoglobulin 

 
 
 
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IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
kg 
kilogram(s) 
LDH 
lactate dehydrogenase 
mg 
milligram(s) 
mL 
milliliter(s) 
MM 
multiple myeloma 
mm2 
millimeter(s) squared 
mm3 
millimeter cubed 
NHL 
non-Hodgkin’s lymphoma 
ORR 
overall response rate 
PD 
progressive disease 
PFS 
progression free survival 
PO 
per os (orally) 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBC 
red blood cell 
SAE 
serious adverse event 
sCR 
stringent complete response 
SD 
stable disease 
SPEP 
serum protein electrophoresis  
TLS 
Tumor lysis syndrome 
TTP 
time to progression 
UPEP 
urine protein electrophoresis 
VGPR 
very good partial response 

 
 
 
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1 
INTRODUCTION   
 
1.1 
DISEASE SPECIFIC BACKGROUND 
 
Multiple myeloma (MM) is a malignant plasma cell disorder resulting in approximately 11,000 
deaths in the United States each year. It is estimated that between 60,000-80,000 people are 
currently under treatment for refractory or relapsed MM. (1) Prognosis and survival have 
improved over the last 20 years, but the disease is still universally fatal despite efforts to develop 
new and more effective chemotherapeutic regimens. Therefore, new  regimens need to be 
developed for patients prior to  peripheral blood stem cell transplant and for those unable to 
tolerate the toxicity of transplant. 
 
1.2 
PROTEASOME BACKGROUND 
The proteasome is a multicatalytic proteinase complex that is responsible for degradation of a 
wide variety of protein substrates within normal and transformed cells.  Intracellular proteins 
targeted for degradation by the proteasome are first ubiquitinated via the ubiquitin conjugation 
system.  Ubiquitinated proteins are cleaved within the proteasome by one or more of three 
separate threonine protease activities: a chymotrypsin-like activity, a trypsin-like activity, and a 
caspase-like activity.   
 
1.3 
CARFILZOMIB BACKGROUND 
Carfilzomib (CFZ) is a novel, highly selective epoxyketone proteasome inhibitor that produces 
potent and sustained proteasome inhibition both in vitro and in vivo. CFZ appears to lack many of 
the off-target activities frequently associated with bortezomib (BTZ). This lack of off-target 
activity may account for observed differences in tolerability seen with CFZ including lack of 
significant neuropathy and minimal neutropenia and diarrhea. To date, single agent CFZ has been 
evaluated in Ph 1 and 2 studies in >600 patients, and the vast majority of patients treated had 
relapsed and/or refractory MM. In these settings, CFZ has demonstrated durable single-agent 
activity and was well-tolerated in patients with advanced stage disease with co-morbidities 
including baseline neuropathy or renal insufficiency.  
 
In the phase II clinical trial PX-171-003-A1 with carfilzomib as a monotherapy, 266 patients had 
received a median of five prior treatments with a median of 13 different anti-myeloma drugs; 
nearly all of the patients had been previously treated with Velcade.  Patients received CFZ single 
agent (20 mg/m2 intravenously (IV) on days 1, 2, 8, 9, 15, and 16) every 28 days for the first 
cycle, with the dose then being escalated to 27 mg/m2 on the same schedule for up to 12 cycles. 
(2) At the time of reporting, 30% had completed at least 6 cycles of study treatment, 
approximately 11% had completed 12 cycles, among 257 patients evaluable for response, 0.4% 
(one patient) had a complete response (CR), 4.7% had a very good partial response (VGPR), and 
19% had a partial response (PR), for an overall response rate of 24%; an additional 12% of 
patients had a minimal response, yielding an overall clinical benefit rate of 36%. Stable disease 
(SD) for at least 6 weeks was achieved in 32%. Among patients with a PR or better, the median 
DOR was 7.4 months. Among patients with a minimal response, the median DOR was 6.3 
months, indicating durable minor responses. CFZ was well-tolerated. Based on these data, 
Carfilzomib was approved by the US Food and Drug Administration (FDA) in July2012. 
 

 
 
 
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Singhal et al presented the results of parallel safety analyses of patients from four Ph 1 and 2 
studies with CFZ.(3) Toxicity consisted mainly of myelosuppression. Grade 3/4 hematologic 
toxicities consisted of thrombocytopenia in 18% of patients, lymphopenia in 11%, neutropenia in 
8%, and anemia in 7%.  Grade 3/4 nonhematologic toxicities included fatigue in 6% of patients; 
pneumonia and congestive cardiac failure in 3% each; nausea, dyspnea, increased blood 
creatinine levels, and increased blood uric acid levels in 1% each; and diarrhea in 0.4%. Grade 
1/2 peripheral neuropathy was present in 77% of patients at baseline; new-onset neuropathy was 
infrequent, with grade 3 or lower neuropathy occurring in less than 1% of patients.  The excellent 
safety/tolerability profile of CFZ has permitted prolonged administration (in some cases over 24 
mos of continuous therapy including extension study) with minimal dose modifications. The low 
level of neuropathy seen with CFZ provides a new and promising option for patients with pre-
existing neuropathy from either underlying disease or prior neuropathic anti-myeloma therapy. 
 
Combination of CFZ with lenalidomide and dexamethasone with escalated dose of CFZ 27 mg/m2, 
lenalidomide 25 mg, and dexamethasone 40 mg/day, showed acceptable tolerability in patients 
heavily pre-treated with bortezomib (BTZ) and immunomodulatory agents.  The combination 
yielded a 59% overall response rate (ORR) without reaching the maximum tolerated dose 
(MTD).(4)  
 
A phase I/II clinical trial investigating CFZ in combination with lenalidomide and dexamethasone 
for newly diagnosed MM patients also showed high response rate. CFZ dose was escalated to 36 
mg/m2, and no dose-limiting toxicities were observed (MTD was not reached). After completion 
of eight cycles, all patients (n=19) achieved at least a partial remission with 63% ≥VGPR, 37% 
CR/near CR. Side effects were mostly mild,  and no significant peripheral neuropathy was 
observed.(5)  
 
Dr. Sonneveld and colleagues recently reported their experience with Carfilzomib combined with 
thalidomide and dexamethasone (CARTHADEX) as induction therapy prior to transplantation. In 
their study of 34 patients, the median time to maximum response was 1 cycle and responses 
occurred across all cytogenetic risk groups. Furthermore, stem cell harvest was accomplished in 
all studied subjects showing that a Carfilzomib based regimen is feasible in preparation for ASCT. 
(6) 
 
There is additional data to support the use of a CFZ based regimen in the upfront setting. Dr. Kolb 
and colleagues presented their study on the use of Carfilzomib, Melphalan, and Prednisone (CMP) 
in Elderly patients with de-novo Myeloma (ASCO Abstract 8009, 2012). The maximum tolerated 
dose of CFZ in the phase 1 portion of the study was 36 mg/m2. Of the 26 patients evaluable for 
response, the overall response rate was 92% including 42% with a VGPR or better. These results 
compared favorably to those achieved with other melphalan/novel compound based regimens 
including MPV, MPT and MPR.(7) 
 
Finally, there is evidence that combining a proteasome inhibitor with Bendamustine is safe and 
well tolerated. Dr. Berdeja and colleagues at the Sarah Cannon Research Institute presented their 
study on the use of Bendamustine, Bortezomib, and Dexamethasone (BBD) as first line therapy 
for patients with MM who are not eligible for transplantation. Bendamustine was given at a dose 
of 80 mg/m2 at two different dosing schedules for up to 8 cycles of therapy. There were no grade 

 
 
 
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4 hematologic adverse events and only 33-40% Grade 3 hematologic events. The response rate was 
similar in both groups with an overall response rate varying between 78-90%.(8) 
 
1.4 
BENDAMUSTINE BACKGROUND 
Bendamustine, a bifunctional alkylating agent, which has little cross-resistance with other 
alkylating agents, was approved by the US Food and Drug Administration (FDA) for the treatment 
of CLL and rituximab-refractory, indolent B-cell non-Hodgkin’ lymphoma (NHL). Bendamustine 
has also been approved in Europe for the treatment of MM.(9) A dose escalation study of 
bendamustine in patients with relapsed MM determined the MTD to be 100 mg/m2 on days 1 and 
2, with a response rate of 55%.  A prospective, randomized clinical trial showed superiority of 
combined bendamustine and prednisone when compared with the standard melphalan/prednisone 
in terms of response rate, time to treatment failure, and quality of life.(10) Our group performed a 
phase I/II trial using bendamustine combined with lenalidomide for patients with relapsed or 
refractory MM, and data was recently published.(11) The MTD was identified at 75 mg/m2 
bendamustine and 10 mg lenalidomide. Among the 29 patients, 24% achieved a VGPR and 52% 
PR, with an ORR of 76%. The estimated 1 and 2 year OS was 93% and 62% respectively. We did 
not observe any severe non-hematologic side effects or severe peripheral neuropathy in this trial. 
Despite the fact that combination therapy with bendamustine and lenalidomide is very promising, 
this therapy harbors an increased risk of neutropenia. In addition many patients have received 
lenalidomide before and develop drug resistance.  
 
The pharmacokinetics of Bendamustine excretion has been studied with results recently 
published.(12) After a single 60minute intravenous dose of radioactive Bendamustine was 
administered, patients had blood, urine and feces samples collected for analysis. Approximately 
half the administered dose was recovered in the urine and a quarter in the feces with less than 5% 
of the administered dose recovered in the urine as unchanged Bendamustine. Clearance of 
Bendamustine from the plasma was rapid with a t1/2 of ~40 minutes. The conclusion of the study 
was that Bendamustine is extensively metabolized with subsequent excretion in both the feces and 
urine. Accumulation of Bendamustine was not anticipated in cancer patients with renal or hepatic 
impairment because of the short half-life.  
1.5 
STUDY RATIONALE 
Results of phase I/II trials using CFZ or bendamustine indicate that both drugs are very potent for 
the treatment of MM. The drugs have different intracellular targets and the combination may result 
in additive/synergistic anti-myeloma effects without showing cross-resistance.  Lack of significant 
toxicities of CFZ suggests that this drug is favorable for use in combination therapies especially in 
patients who are suffering from pre-existing neuropathy. In the proposed phase I/II clinical trial, 
we will investigate the safety and efficacy of CFZ in combination with bendamustine and 
dexamethasone for newly diagnosed MM. The combination is very promising in order to overcome 
drug resistance combined with a favorable toxicity profile and might be very effective.  
 
One study that has particular relevance to our proposed work was published in Leukemia and 
Lymphoma by Dr. Fenk and Colleagues (13). In this study, the investigators enrolled 50 patients 
with relapsed/refractory multiple myeloma and offered treatment with escalating doses of 
Bendamustine with Bortezomib and dexamethasone. The overall response rate was 84% with 
manageable toxicity.    Median time to progression was 8 months and median overall survival was 
20 months. 

 
 
 
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At the annual ASCO meeting in June 2013, a phase 1/2 study was presented by Dr. Bereneson and 
colleagues (ASCO Abstract 8599) showing that CFZ is a suitable replacement for bortezomib in 
many different regimens. Their study included patients receiving bendamustine. The authors 
concluded that replacement of bortezomib with CFZ in a bortezomib-containing combination 
regimen often leads to responses and is well tolerated. 
 
1.6    
DOSE RATIONALE 
A phase 1b/2 dose escalation study (PX-171-007) of single agent CFZ administered is ongoing 
and as of  23 April 2010, over 65 patients with solid tumors had started treatment in the initial 
Phase 2 portion of the study at 36 mg/m2 (bolus administration). A review of the tolerability of 
36 mg/m2 CFZ in these patients  indicates that this regimen was very well tolerated with only one 
DLT (Grade 3 fatigue) and an overall adverse event (AE) profile similar to that seen with the 
27mg/m2 CFZ experience with bolus dosing (see investigator brochure for details).  There were 
no significant DLTs observed; the majority of discontinuations on the study were due to 
progressive disease (PD). Because of the long-term tolerability CFZ, the Phase 1b portion of this 
study was reopened, and a separate arm for MM was added. In the same trial, more recently 
patients have been treated with CFZ given as a 30-minute infusion in order to potentially 
minimize Cmax-related infusion events. The protocol was amended and doses 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.  Papadopoulos, et al presented the result 
of PX-171-007 trial at the 2010 ASH showing that in patients with R/R MM, single-agent CFZ as 
30-minute IV infusion was well-tolerated at doses 20/36, 20/45 and 20/56 mg/m2 with near 
complete proteasome inhibition. A dose  level of 56 mg/m2 is being expanded as the 
recommended phase 2 dose on 30-minute IV infusion schedule (14). All protocols using ≥36 
mg/m2 CFZ are now administering the drug as a 30-minute infusion.  
In addition to the above observations, a phase I study of CFZ in patients with relapsed and 
refractory MM was reported at the 2009 American Society of Hematology meeting.  which 
demonstrated that CFZ can be safely administered to patients with substantial renal impairment 
(creatinine clearance [CrCl] < 30, including patients on dialysis) without dose adjustment. A 
phase I study of CFZ in patients with relapsed and refractory multiple myeloma and varying 
degrees of renal insufficiency has been initiated and preliminary results were reported at the 2009 
American Society of Hematology meeting. (15) At the time of this preliminary analysis, 22 
patients had been treated on the trial.  Ten patients had CrCl  > 80 mL/min; 9 had CrCl 50-79 
mL/min; 9 patients had creatinine clearance 30-49 mL/min; 9 patients had CrCl < 30 mL/min and 
2 patients were on chronic dialysis.  Adverse events in these patient groups were similar 
regardless of degree of renal dysfunction and included anemia, fatigue, and diarrhea as the most 
common adverse events observed.   
These data indicate that CFZ does not exacerbate underlying renal dysfunction, and confirm the 
“pre-renal” etiology of the BUN/creatinine elevations observed with IV bolus CFZ. 
Bendamustine is a drug which is approved and has been widely used in therapy for MM, NHL, 
breast cancer and other malignancies for 46 years. Based on several phase III trials, 
bendamustine received FDA approval for CLL (100 mg/m2) and NHL (120 mg/m2 d1 and d2) in 
the US. Due to the extensive experience and large amount of safety and toxicity data on 
bendamustine in hematologic malignancies, we think it is safe to use bendamustine dose 

 
 
 
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escalation up to 90 mg/m2 in combination with CFZ for patients with newly diagnosed  MM (16). 

 
 
 
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2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
 
Determine the MTD of CFZ in combination with bendamustine and dexamethasone 
 
2.2 
SECONDARY OBJECTIVES 
 
 
Determine the anti-tumor efficacy (ORR) of the combination of CFZ plus bendamustine and 
dexamethasone 
 
Determine DOR 
 
Determine progression free survival (PFS) 
 
Determine overall survival (OS).  
 
Determine time to Best Response 
 
Evaluate the safety and toxicity. 
 
Stem cell collection parameters after using the protocol as induction regimen  
 

 
 
 
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3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a phase I/II, open label, single-center, non-randomized dose escalation study. The primary 
endpoint of this study is dose-limiting toxicity (DLT), to define the recommended phase II dose 
of CFZ in combination with bendamustine and dexamethasone in patients with newly diagnosed 
MM. This study defines the phase II dose as the combination at which 20% of treated patients 
would be predicted to experience DLT (as defined in Section 6.2). 
 
Doses will be allocated to patients using a two-stage Up-and-Down dose escalation scheme, (17) 
(Storer's schema D, with a one-patient-per-level run-in) without intra-patient dose escalation. The 
details of this escalation are described in Section 12.6. A maximum of 28 patients will be 
enrolled. Using this schema, enough patients will be enrolled at a dose level near the MTD that 
the study will have the power of a typical stand-alone Phase 2 study. 
 
The secondary endpoint is to determine preliminary evidence of efficacy of CFZ in combination 
with bendamustine and dexamethasone, including overall response rate, DOR, PFS, time to best 
response, , overall survival (OS) and evaluate the dose and toxicity. Patients will receive CFZ on 
days 1, 2, 8, 9, 15, and 16 every 28 days. Bendamustine will be given IV on days 1 and 2 with 
dose escalation up to 90 mg/m2 and dexamethasone 20 mg PO or IV on 1, 2, 8, 9, 15, 16 and 22, 
23 of each 28-day cycle.  This regimen can also be used as induction treatment for autologous 
stem cell transplant. 
 
 
 
 
 
 
 
 
 
 
 
For patients deemed to be ineligible for transplant by their treating physician, up to 8 cycles of 
CFZ, bendamustine and dexamethasone (CBd) will be administered. Upon completion, patients 
will be recommended to receive maintenance therapy off trial, with carfilzomib preferentially, or 
another regimen at the discretion of the treating physician. Patients who have started maintenance 
carfilzomib (36 mg/m2 on days 1, 2, 15, 16) per the previous version of this protocol will be 
allowed to continue for up to 2 years.  
For patients deemed to be eligible for transplantation by their treating physician, 4 cycles of CBd 
will be given followed by the collection of peripheral blood stem cells. A 4-week window is 
Table 1.  Dose Escalation Schema (all dose levels of Carfilzomib will 
start at 20mg/m2 day 1 and 2 of cycle 1 as a lead in dose) 
 
Carfilzomib 
Bendamustine 
Dexamethasone 
-1 
27 mg/m2 
60 mg/m2
20mg 
1 
27 mg/m2 
70 mg/m2 
20mg 
2 
36mg/m2 
70 mg/m2 
20mg 
3 
36 mg/m2 
90 mg/m2 
20mg 
4 
45 mg/m2 
90 mg/m2 
20mg 
5 
56mg/m2 
90 mg/m2 
20mg  

 
 
 
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allowed to accommodate scheduling of the stem cell collection. Peripheral blood stem cells 
should be mobilized with granulocyte-colony stimulating factor +/- plerixafor. Chemotherapy 
based mobilization techniques, (with Cytoxan for example) are not permitted in order to allow 
the comparison of the transplant and non-transplant arm. After stem cell collection, all patients 
will then receive additional 4 cycles of CBd followed by autologous stem cell transplant. In order 
to compare both arms, patients in the stem cell transplant arm should receive altogether 8 cycles 
CBd prior to transplant. After stem cell transplant, patients will be recommended to receive 
maintenance therapy off trial, with carfilzomib preferentially, or another regimen at the discretion 
of the treating physician. Patients who have started maintenance carfilzomib (36 mg/m2 on days 
1, 2, 15, 16) per the previous version of this protocol will be allowed to continue for up to 2 
years. 
 
3.2 
NUMBER OF CENTERS 
Columbia University Medical Center in New York, NY. 
 
3.3 
NUMBER OF SUBJECTS 
26 evaluable subjects (men and women who are at least 18 years of age) will participate in this 
study.  
 
3.4 
ESTIMATED STUDY DURATION 
The anticipated accrual duration is 2 years. The study duration is approximately 4 years. 

 
 
 
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4 
SUBJECT  SELECTION 
4.1 
INCLUSION CRITERIA   
Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study.   
 
Disease-related: 
 Patients must have histologically or cytologically confirmed symptomatic MM, Salmon-
Durie Stage II or III, or International Staging System II or III or fulfill the CRAB criteria 
(see Appendix A, B). Patients should not have previously been treated. Finally, patients 
must meet at least one of the following parameters of measurable disease: 
 
Bone marrow plasmacytosis with> 10% plasma cells, or sheets of plasma cells, or 
biopsy proven plasmacytoma which must be obtained within 6 weeks prior to 
registration. 
 
Measurable levels of monoclonal protein (M-protein): ≥1 g/dL on serum protein 
electrophoresis (SPEP) or 200 mg of monoclonal light chain on a 24 hour urine 
protein electrophoresis (UPEP) or involved free light chain (FLC)  10 mg/dL ( 100 
mg/L) which must be obtained within 4 weeks prior to registration. 
Serum and urine M-protein levels should be determined by electrophoresis rather 
than by quantitative immunoglobulin (Ig) measurement. Exceptions are made in cases 
in which the M-spike value may be deemed to be unreliable (e.g. co-migrating M-
spike). In these cases, quantitative Ig should be used. To assess response and 
progression, however, SPEP values should only be compared to SPEP values and 
quantitative Ig values only to quantitative Ig values.  
 Prior kyphoplasty, vertebroplasty, local radiation therapy for symptomatic bone lesions 
(e.g., uncontrolled pain or high risk of pathologic fracture) are permitted  
 Patients are allowed up to two cycles of high dose steroids (maximum total dose of 
320mg Dexamethasone or equivalent) if needed for symptomatic disease before study 
enrollment 
 
Demographic:   
1. Age ≥ 18 years 
2. Life expectancy ≥ 3 months 
3. Eastern Cooperative Oncology Group (ECOG) performance status 0–2  
4. Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and 
serum direct bilirubin ≤ 2 mg/dL (34 µmol/L)  
5. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L  
6. Hemoglobin ≥ 8 g/dL (80 g/L) (subjects may be receiving red blood cell [RBC] 
transfusions in accordance with institutional guidelines)   
7. Platelet count ≥ 75 × 109/L  (≥ 30 × 109/L if myeloma involvement in the bone marrow is 
> 50%)  
8. CrCl ≥ 30 mL/minute, either measured or calculated using a standard formula (e.g., 
Cockcroft and Gault) 
9. LVEF ≥ 40%. 2-D transthoracic ECHO is the preferred method of evaluation. MUGA is 
acceptable if ECHO is not available. 
 

 
 
 
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Ethical/Other 
1.  Written informed consent in accordance with federal, local, and institutional guidelines.  
2. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to 
practice contraception.  
3. Male subjects must agree to practice contraception. 
  
4.2 EXCLUSION CRITERIA 
Disease-related 
1. Patients who have had chemotherapy for MM. Exception: local radiation therapy for 
symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic fracture).  
2. Patients currently receiving high dose systemic steroids for treatment of MM in excess of 
320mg total dose of dexamethasone or equivalent, patients who received an 
investigational agent within 5 half-lives of the agent. 
3. Patients with non-measurable MM or primary plasma cell leukemia (> 2.0 × 109/L 
circulating plasma cells by standard differential) 
 
Concurrent Conditions 
1. Pregnant or lactating females 
2. Major surgery within 21 days prior to enrollment 
3. Acute active infection requiring treatment should be under control 
4. Known human immunodeficiency virus (HIV) infection 
5. Known active hepatitis B or C infection 
6. Unstable angina or myocardial infarction within   4  months prior to enrollment, NYHA 
Class III or IV heart failure, uncontrolled angina, history of severe coronary artery 
disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or 
electrocardiographic evidence of acute ischemia or Grade 3 conduction system 
abnormalities unless subject has a pacemaker 
7. Uncontrolled hypertension or uncontrolled diabetes  
8. Uncontrolled, non-hematologic malignancy requiring active treatment.  
9. Patients with known brain metastases (treated or not) will be excluded from this clinical 
trial because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other AEs. 
10. Significant neuropathy (Grades 3–4, or Grade 2 with pain)  
11. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize CFZ), 
or similar chemical or biologic composition to Bendamustine or other agents used in the 
study. 
12. Contraindication to any of the required concomitant drugs or supportive treatments, 
including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, 
or intolerance to hydration due to preexisting pulmonary or cardiac impairment 
13. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis 
within 14 days prior to enrollment 
14. Any other clinically significant medical disease or condition that, in the Investigator’s 
opinion, may interfere with protocol adherence or a subject’s ability to give informed 
consent. 

 
 
 
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5 
SUBJECT ENROLLMENT 
Following registration, patients should begin the research treatment within one week. Issues that 
would cause research treatment delays should be discussed with the Investigator. If a patient does 
not receive study treatment following registration, the Study Coordinator should be contacted for 
required data submissions. Patients that do not receive any study treatment will not be evaluable 
for toxicity or response. 
 
Each patient enrolled in the study will be registered in the CUMC’s Clinical Trials Management 
Application (CTMA) at study entry.  Each patient enrolled will be assigned a sequential study 
identifier by CTMA. 
 
CUMC Research Participant Registration  
 
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures, along with applicable institutional policies and federal regulations. 
 
Only Investigators/Research personnel properly trained and delegated to consent subjects for this 
protocol will participate in the consenting process.  Furthermore, properly delegated/trained 
Physician Investigators (i.e., MD, MD PhD) are required to sign/verify a protocol specific 
Eligibility Checklist for each subject enrolled on the study, in addition to providing the relevant 
source documentation confirmation subject eligibility. 
 
All participants must be centrally registered through the Central Registration Office within 
Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of study 
treatment. 
 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST (excluding 
holidays and weekends). Same day patient registrations (and after hour registrations) will be 
accommodated on a case by case basis provided that the study team has expressed all time 
sensitive registration concerns/cases in a timely manner to the Central Registration Office.  
 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed 
IRB approved informed consent HIPAA form, and demographics forms must be submitted to the 
CPDM Central Registration Office via an email to CPDMRegistration@columbia.edu or fax to 
212.305.5292, with the subject line “AAAJ2359 Pending Subject Registration Request (PHI)”.  
Upon receipt, applicable subject information as well as a “pending eligibility” status will be 
entered into HICCC’s institutional database.  This status will remain until further source 
documentation is made available to confirm overall patient eligibility. Required materials for all 
pending registration submissions are as follows: 
 
 Completed/signed IRB approved/stamped Informed Consent Forms, including 
additional study ICFs (i.e. tissue, DNA, etc.) as applicable 

 
 
 
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 The completed/signed IRB approved HIPAA Authorization form 
 Completed/signed CPDM ICF checklist 
 Completed/signed HICCC personal census form 
 Completed/signed CPDM Demographics Note to File 
In order to confirm eligibility status, Investigators/designees (i.e., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to the 
Central Registration Office via email or fax: 
 
 The completed/signed study specific Eligibility Checklist  (signed by an Physician 
level Investigator) 
 Copies of source documentation necessary for each item to be verified on the CUMC 
specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (i.e., hematology, 
serum chemistry, pregnancy test when applicable, MRI reports, CT/bone 
scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) or other appropriate medical records capturing the 
consent process information, along with providing source documentation of 
any other items needed for screening/eligibility that are not captured in other 
source document forms (e.g., positive investigator statements of unique 
eligibility items not captured via other direct source documentation, 
concomitant medication lists, etc) 
o Protocol deviation/waiver approvals (if applicable) 
 Please note: subject line of email or fax should include the following: “AAAJ2359 
Complete Subject Registration Request (PHI)”. 
Upon Receipt of the above mentioned documentation, participant eligibility information will be 
verified by a qualified Central Registration Registrar. If any questions arise during the review 
process, queries in the form of emails will be addressed to the applicable study team personnel 
for clarification prior to enrollment. .All applicable finalized registration/eligibility information 
will then be entered into HICCC’s institutional database by the Central Registration Registrar.  
Upon completion, an official subject registration notification email will be sent to the PI/research 
team which will include eligibility/enrollment status, as well as subject ID information.  Protocol 
therapy may not be initiated prior to receipt of this notification from the Central Registration 
Office. 

 
 
 
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All screenfail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 
 
 
 
 

 
 
 
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6 
TREATMENT PROCEDURES 
6.1 DRUG PREPARATION AND ADMINISTRATION 
6.1.1 
CARFILZOMIB 
 
CFZ for Injection is supplied as a lyophilized parenteral product in single-use vials. 
The lyophilized product is reconstituted with D5W for Injection to a final CFZ 
concentration of 2.0 mg/mL prior to administration.  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.   
 
IV hydration will be given immediately prior to CFZ during Cycle 1.  This will 
consist of 250 to 500 mL normal saline or other appropriate IV fluid.  If lactate 
dehydrogenase (LDH) or uric acid is elevated (and/or in subjects considered still at 
risk for TLS) 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 (e.g., ≥ 2 L/day).  Subjects should be monitored 
periodically during this period for evidence of fluid overload (e.g. clinical 
examination).  
 
The infusion will be performed as per institutional guidelines. 
 
CFZ will be given as an IV infusion over 30 minutes.  The dose will be administered 
at a facility capable of managing hypersensitivity reactions.  Subjects will remain at 
the clinic under observation for at least 1 hour following each dose of CFZ in Cycle 1 
and following the dose on Cycle 2 Day 1.  During these observation times, post dose 
IV hydration (up to 500 mL normal saline or other appropriate IV fluid formulation) 
may be given at the discretion of the treating physician.  Subjects should be 
monitored periodically during this period for evidence of fluid overload.  
 
In subjects considered at risk for TLS, additional oral hydration may be considered at 
the Investigator’s discretion. Subject should be monitored for evidence of fluid 
overload. 
 
No matter what target dose the subject will receive, days 1 and 2 doses in the first 
cycle will always be 20 mg/m2.  For example, if subject is scheduled to receive 27 
mg/m2, 20 mg/m2 will be given on days 1 and 2 of cycle 1 only; followed by 27 
mg/m2 for all subsequent doses, same as 20/36 and 20/45 mg/m2 and 20/56 mg/m2 for 
the entire protocol. 
 
6.1.2 
BENDAMUSTINE 
 
Bendamustine is an FDA approved drug which will be provided by Teva 
Pharmaceuticals Industries Ltd (Petach Tikva, Israel) 
Patients will receive Bendamustine 70 or 90 mg/m2 IV on day 1 and 2 of each cycle. 
Bendamustine will be administered as an infusion over 60 minutes.  The infusion will be 
performed as per institutional guidelines 
Please note: the flush is not included in the total recommended infusion times. 
 

 
 
 
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6.1.3 
DEXAMETHASONE 
 
Dexamethasone will be administered 20 mg PO or IV on days 1, 2, 8, 9, 15,16, 22, 
23. Dexamethasone will be administered prior to CFZ doses on days 1, 2, 8, 9, 15, 16. 
 
Decadron, Hexadrol, Dexameth, Dexone, DXM, others. Commercially available in 
0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 6 mg tablets. 
 
 (Comments on Sections 6.2 and 6.3: in considering DLT definitions and dose modification 
guidelines for combination studies, we suggest using a rationally based approach when possible 
that takes into consideration the unique toxicities of each agent)  
 
6.2        DEFINITION OF DOSE-LIMITING TOXICITY  
Subjects will be evaluated for toxicity according to the Common Terminology Criteria for 
Adverse Events (CTCAE) of the National Cancer Institute version 4.0 (Appendix C).  
A DLT is defined as any of the below treatment emergent toxicities with attribution to one or 
more of the study drugs that occur during Cycle 1.  If a DLT occurs during Cycle 1 the patient 
does not need to be removed from study.  Toxicities that occur in subsequent cycles will be 
handled through dose modifications (Section 6.3) but will not affect the definition of MTD.   
Non-hematologic: 
 
New onset of ≥ Grade 2 neuropathy with pain 
 
≥ Any Grade 3 toxicity (excluding nausea, vomiting, diarrhea). Grade 3 Non-Hematologic 
AEs will be critically assessed by the Principal Investigator to determine attribution to study 
drugs. Attribution to study drug will define the DLT. 
 
≥ Grade 3 nausea, vomiting, or diarrhea despite maximal antiemetic/antidiarrheal therapy and 
related to study drug 
 
≥ Grade 4 fatigue lasting for ≥ 7 days 
 
Any non-hematologic toxicity requiring a dose reduction within Cycle 1  
 
Inability to receive Day 1 dose of Cycle 2 due to drug related toxicity persisting from Cycle 1 
or drug related toxicity newly encountered on Day 1 of Cycle 2.  
 
Hematologic: 
 
Grade 4 neutropenia  (ANC < 0.5 x 109/L) lasting for ≥ 7 days   
 
Febrile neutropenia (ANC < 0.50 x 109/L with a fever ≥ 38.3ºC)  
 
Grade 4 thrombocytopenia (platelets < 25.0 x 109/L) lasting ≥ 7 days despite dose delay 
 
Grade 3-4 thrombocytopenia associated with bleeding 
 
Any hematologic toxicity requiring a dose reduction within Cycle 1 
 
Inability to receive Day 1 dose of Cycle 2 due to drug related toxicity persisting from Cycle 1 
or drug related toxicity newly encountered on Day 1 of Cycle 2.  
 
6.3 
DOSE REDUCTIONS/ADJUSTMENTS  
The dose of CFZ and bendamustine should be held and/or reduced according to the following 
guidelines: 

 
 
 
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6.3.1 
DOSE REDUCTIONS FOR HEMATOLOGIC TOXICITIES: 
Study drug will be withheld from subjects with: Grade 4 thrombocytopenia  
Grade 4 anemia does not require the CFZ dose to be withheld.  However, subjects should receive 
supportive measures in accordance with institutional guidelines.  
The following table outlines the dose reduction guidelines for CFZ and bendamustine for 
thrombocytopenia and neutropenia: 
 
Table 2. Dose Reduction Guidelines for Thrombocytopenia 
 
Recommended Action 
When Platelets: 
Carfilzomib and bendamustine 
Fall to < 50 × 109/L 
Interrupt both drugs, follow CBC 
weekly 
Return to ≥ 75 × 109/L 
Resume at full dose 
Subsequently drop to < 50 × 109/L 
Interrupt both drugs, follow CBC 
weekly 
Return to ≥ 75 × 109/L 
Resume at 1 dose decrement on 
both drugs 
 
 
Table 3. Dose Reduction Guidelines for Neutropenia 
 
Recommended Action 
When ANC 
Carfilzomib and bendamustine 
Falls to < 0.5 × 109/L 
Interrupt both drugs 
add filgrastim if Grade 3 with 
fever or Grade 4, follow CBC 
weekly 
Returns to > 1.0 × 109/L 
(if neutropenia was the only toxicity 
noted) 
Resume at full dose on both drugs 
Returns to > 1.0 × 109/L 
(if other toxicity noted) 
Resume at 1 dose decrement on 
both drugs 
Subsequently drops to < 0.5 × 109/L  
 
Interrupt both drugs 
Returns to > 1.0 × 109/L 
Resume at 1 dose decrement on 
both drugs 

 
 
 
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6.3.2 
DOSE REDUCTIONS FOR NON-HEMATOLOGIC TOXICITIES 
Both study drugs should be held for ≥ Grade 3 events until resolved to ≤ Grade 1 or return to 
baseline.  
6.3.2.1 
CARFILZOMIB TREATMENT ADJUSTMENTS (NON-HEMATOLOGY 
TOXICITIES) 
After resolution of the event to ≤ Grade 1 or return to baseline, if the AE was not treatment-
related, subsequent treatment with CFZ may resume at full dose.  If the event was treatment-
related, subsequent treatment with CFZ will resume at one level dose reduction, i.e., to 27 mg/m2 
for subjects previously receiving 36 mg/m2 and to 36 mg/m2 for subjects previously receiving 45 
mg/m2.  If toxicity continues or recurs, a second CFZ dose reduction may be permitted the 
discretion of the investigator.  No more than two dose reductions will be permitted in an 
individual subject on study.  If toxicity continues or recurs after two dose reductions, the subject 
should be removed from study. 
 
If the subject tolerates the reduced dose for two cycles, subject may be dose escalated to the dose 
prior to reduction 
 
If there is no resolution of toxicity after 4 weeks of withholding treatment (up to 3 weeks for 
infection treatment), the subject will be withdrawn from the study. 
 
Table 4: Carfilzomib dose adjustment guidelines summary for non-hematologic toxicities 
CTCAE Category 
Adverse Event 
Carfilzomib Treatment 
Adjustment 
Allergic 
reaction/hypersensitivity 
Grade 2 – 3 
Hold until ≤ Grade 1, 
reinstitute at full dose. 
 
Grade 4 
Discontinue 
Metabolic 
Tumor lysis syndrome  
(≥ 3 of following: ≥ 50% increase in 
creatinine, uric acid, or phosphate; ≥ 
30% increase in potassium; ≥ 20% 
decrease in calcium; or ≥ 2-fold 
increase in LDH 
Hold CFZ until all 
abnormalities in serum 
chemistries have resolved.  
Reinstitute at full doses. 
Infection  
Infection Grade 3 or 4 
Hold CFZ until systemic 
treatment for infection 
complete.  If no neutropenia, 
restart at full dose.  If 
neutropenic, follow 
neutropenic instructions. If 
there is no resolution of 
toxicity after 3 weeks, the 

 
 
 
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subject will be withdrawn 
from the study. 
 
Herpes zoster or simplex of any 
grade 
Hold CFZ until lesions are 
dry. Reinstitute at full dose 
Neurology 
Grade 2 treatment emergent 
neuropathy with pain or Grade 3 
neuropathy 
Continue to dose.  If 
neuropathy persists for more 
than two weeks hold CFZ 
until resolved to ≤ Grade 2 
without pain. Then restart at 1 
dose decrement 
Neurology 
Grade 4 neuropathy 
Discontinue 
Renal  
 
CrCl ≤ 15 mL/min 
 
Hold until CrCl > 30 
mL/minute; restart at 1 dose 
decrement 
Cardiovascular 
Congestive heart failure (CHF) 
Any subject with symptoms of 
CHF, whether or not drug 
related, must have the dose 
held until resolution or return 
to baseline, after which 
treatment may continue at a 
reduced dose, with the 
approval of the Onyx Medical 
Monitor, or the subject may 
be withdrawn from the study.  
or the subject may be 
withdrawn from the study.  If 
no resolution after 2 weeks, 
the subject will be withdrawn 
from the study. 
Venous 
Thrombosis/embolism 
Grade 3 (uncomplicated) or Grade 4 
(life-threatening) 
Hold dose and start 
therapeutic anticoagulation; 
restart CFZ at Investigator’s 
discretion (maintain dose 
level) 
Others 
Other non-hematologic toxicity 
assessed as CFZ-related > Grade 3 
Hold dose until toxicity 
resolves to ≤ Grade 1 or 
baseline.  Restart at 1 dose 
decrement. 
 

 
 
 
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CFZ should be held for CrCl < 15 mL/min.  
  
Table 5:  
Carfilzomib Dose Adjustment Guideline for Renal Dysfunction 
Renal Dysfunction 
Recommended Action 
Normal to mild  
(CrCl >50 mL/min) 
Full dose 
Moderate  
(CrCl 15–50 mL/min) 
Full dose 
Severe 
(CrCl ≤ 15 mL/min) 
Hold CFZ until CrCl > 30 mL/min; restart  
at one level dose reduction 
 
6.3.2.2 
BENDAMUSTINE TREATMENT ADJUSTMENTS (NON-HEMATOLOGY 
TOXICITIES) 
There are no reductions in the bendamustine dose if bendamustine is given at 70 mg/m2. If AEs 
occur at 70 mg/m2 that require holding bendamustine, the dose will remain the same once 
treatment resumes. If Bendamustine is held for more than 4 weeks, sites should contact the 
Principal Investigator to discuss the appropriateness of continuing the patient on study. If an AE 
occurs at 90 mg/m2, the bendamustine dose will be reduced to 70 mg/m2 according to the table. 
 
Table 6. 
Bendamustine Dose Management based on non-hematologic toxicities 
Renal toxicity: CrCl ≤ 30 
ml/minute  
Hold bendamustine, if toxicity resolves to CrCl >30 ml/minute, 
restart the next cycle at the same dose level.  
Hepatic toxicity assessed as 
bendamustine related: 
moderated hepatic impairment 
(AST or ALT ≥ 2.5 times 
ULN and total bilirubin ≥ 1.5 
times ULN) 
Hold bendamustine and follow. If the toxicity resolves to AST or 
ALT < 2.5 times ULN and total bilirubin < 1.5 times ULN, restart 
the next cycle at the next lower dose level. IF AE occurred under 
70 mg/m2 of bendamustine and the dose is held for more than 4 
weeks the patients will be off study. 
 
 
6.3.2.3 
Dexamethasone Treatment Adjustments 
 
Table 7. 
Dexamethasone Treatment Adjustments 
CTCAE Category 
Adverse Event 
Dexamethasone Treatment 
Adjustment 
Gastrointestinal 
(All patients will be 
treated with H2 
Blockers, ranitidine, or 
omeprazole as per 
Section6.5.1) 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1-2 
If symptoms persist despite 
prophylaxis, decrease 
dexamethasone dose by 50% 
permanently. 
Dyspepsia, gastric or 
duodenal ulcer, gastritis ≥ 
Grade 3 (requiring 
hospitalization or surgery) 
Hold dexamethasone until 
symptoms are adequately controlled. 
Restart at 50% of current dose. If 

 
 
 
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symptoms persist, discontinue 
dexamethasone and do not resume 
Acute pancreatitis 
Discontinue dexamethasone and do 
not resume. 
Cardiovascular 
Edema 
≥ Grade 3 
Diuretics as needed, and decrease 
dexamethasone dose by 25%, if 
edema persists despite above 
measures, decrease dose to 50% of 
initial dose; discontinue 
dexamethasone and do not resume if 
symptoms persist despite 50% 
reduction. 
Neurology 
Confusion or Mood 
Alteration ≥ Grade 2 
(interfering with function 
and/or ADLs) 
Hold dexamethasone until 
symptoms resolve, restart at 50% of 
current dose. If symptoms persist 
despite above measures, discontinue 
dexamethasone and do not resume. 
Venous 
Thrombosis/embolism 
Grade 3 (uncomplicated) or 
Grade 4 (life-threatening) 
Hold dose and start therapeutic 
anticoagulation; restart CFZ at 
Investigator’s discretion (maintain 
dose level) 
Musculoskeletal 
Muscle Weakness ≥ grade 2 
(symptomatic and 
interfering with +/- function 
of ADLs) 
Decrease dexamethasone dose by 
25%, if weakness persists despite 
above measures, decrease dose to 
50% of initial dose; discontinue 
dexamethasone and do not resume if 
symptoms persist despite 50% 
reduction. 
Metabolic 
Hyperglycemia ≥ Grade 3 or 
higher 
Treatment with insulin or oral 
hypoglycemics as needed. If 
uncontrolled despite above 
measures, decrease dose by 25% 
decrements until levels are 
satisfactory. 
 
6.3.2.4 
Conditions Not Requiring Dose Reduction 
The following conditions are exceptions to the above guidelines.  Study drugs  do not need to be 
held in the following cases: 
 
Grade 3 nausea, vomiting or diarrhea (unless persisting > 3 days with adequate treatment of 
anti-emetics or anti-diarrheals)  
 
Grade 3 fatigue (unless persisting for >14 days) 
 
Alopecia 
 
Lymphopenia 
 

 
 
 
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6.3.3 
MISSED DOSES 
Missed doses will not be replaced during a cycle.  If a subject misses more than 1/3 doses of a 
treatment cycle for reasons other than toxicity, the subject will be discontinued.  
 
6.3.4 
CHANGES IN BODY SURFACE AREA  
Dose adjustments do not need to be made for weight gains/losses of ≤ 10%.  Subjects with a BSA 
of greater than 2.2 m2 will receive a capped dose based upon a 2.2 m2  BSA .  
6.3.5 
DOSING MODIFICATIONS 
Dose modifications and delays different from those stated in the protocol, for management of 
toxicities, will be permitted at the discretion of the Investigator. 
If the AE is not described in 6.3 and cannot be attributed to a specific drug e.g. (hyperglycemia 
and dexamethasone,) a dose reduction of both CFZ and bendamustine should be performed. 
 
6.4 
SAFETY CONSIDERATIONS 
Based upon the experience in the Phase 1 and 2 clinical studies with CFZ, the following 
observations are noted:  
 
A “first dose effect” has been seen, which is notable for fever, chills, rigors, and/or dyspnea 
occurring during the evening following the first day of infusion and an increase in creatinine 
on Day 2, which may be the clinical sequelae of rapid tumor lysis and/or cytokine release.    
 
Should a “first dose” effect occur at any point during Cycle 1 or 2, treatment with high dose 
glucocorticoids (e.g. methylprednisolone 50–100 mg) is recommended.  In addition, 
intravenous fluids, vasopressors, oxygen, bronchodilators, and acetaminophen should be 
available for immediate use and instituted, as medically indicated.  
 
Dexamethasone 20 mg PO or IV (part of treatment regimen) will be administered prior to all 
CFZ doses on days 1, 2, 7, 8, 15, 16.  
 
Acyclovir or similar should be given to all subjects with a history of herpes simplex or zoster, 
per institutional prophylaxis guidelines, unless contraindicated. 
 
CrCl changes are mostly transient, reversible, and non-cumulative. All subjects should be 
well hydrated.  Clinically significant electrolyte abnormalities should be corrected prior to 
dosing with CFZ. Renal function must be monitored closely during treatment with CFZ.  
Serum chemistry values (basic metabolic panel including creatinine) must be obtained and 
reviewed prior to each dose of CFZ during Cycles 1 and 2. CFZ must be held for subjects 
with a CrCl < 15 mL/min at any time during study participation as outlined in Section 6.3.2.1 
Table 5. 
 
Subjects with active or suspected infection of any kind that required systemic treatment 
should be treated with anti-infectives and the infection should be under control before the 
treatment starts.  
 
Thrombocytopenia has been transient and typically resolves during the week between 
treatments.  For platelet counts ≤ 50,000/mm3, treatment must be held.  If platelet counts 
drop again to ≤ 50,000/mm3 on the subsequent cycle, the dose of CFZ and bendamustine 
must be reduced or held according to the Dose Reductions / Adjustments rules outlined in 
Section 6.3.1. 

 
 
 
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 
Subjects should have anemia corrected in accordance with the Institutional guidelines. 
 
CFZ treatment can cause nausea, vomiting, diarrhea, or constipation sometimes requiring the 
use of antiemetics or antidiarrheals.  Fluid and electrolyte replacement should be 
administered to prevent dehydration. 
 
 Venous thromboembolic events (including deep venous thrombosis and pulmonary 
embolism) have been observed with CFZ.  Prophylactic anticoagulation or antiplatelet 
therapy should be prescribed in conjunction with CFZ and dexamethasone . The 
thromboprophylaxis regimen should be based on an assessment of the patient's underlying 
risks. Patients using oral contraceptives or a hormonal method of contraception associated 
with a risk of thrombosis should consider an alternative method of effective contraception 
during treatment with CFZ in combination with dexamethasone  
 
Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic 
purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred in 
patients receiving CFZ. Monitor for signs and symptoms of TTP/HUS. Discontinue CFZ if 
diagnosis is suspected. If the diagnosis of TTP/HUS is confirmed, then discontinue CFZ 
permanently. 
 
Cases of posterior reversible encephalopathy (PRES) have occurred in patients receiving 
CFZ. Consider a neuroradiological imaging (MRI) for onset of visual or neurological 
symptoms. Discontinue CFZ if PRES is confirmed. 
 
6.4.1 
GUIDELINES FOR MONITORING, PROPHYLAXIS, AND 
TREATMENT OF TUMOR LYSIS SYNDROME (TLS) 
TLS, which may be associated with multi-organ failure, has been observed in treatment Cycles 1 
and 2 in some patients with MM who have been treated with CFZ and bendamustine 
respectively.  
The following safety measures are mandatory for all subjects.  In addition, MM 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 (CrCl < 50 mL/min) should be considered to be at 
particularly high risk. 
     
6.4.1.1 
HYDRATION AND FLUID MONITORING FOR CFZ  
Oral and IV fluid hydration see section 6.1.1 
 
In subjects considered to be still at risk for TLS at completion of Cycle 1, hydration should 
be continued into Cycle 2, if clinically indicated.  Patients in whom this program of oral and 
IV fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal  
impairment will not be eligible to participate in the clinical trial. 
 
6.4.1.2 
BENDAMUSTINE ADMINISTRATION 
Bendamustine should be administered intravenously over 60 minutes on day 1 and day 2 after 
CFZ infusion of each cycle, additional hydration will be decided per physician discretion.  
 

 
 
 
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6.4.1.3 
LABORATORY MONITORING FOR TLS 
Appropriate chemistries, including creatinine, and complete blood counts (CBC) with platelet 
count should be obtained and reviewed at day 1 on each cycle prior to study drug dosing.  Results 
of laboratory studies must be reviewed and deemed acceptable prior to administering the CFZ 
and bendamustine dose.  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 both CFZ and bendamustine doses.  Subjects with such abnormalities should 
be re-evaluated again within the next 24 hours (or sooner, if clinically indicated) and then 
periodically as clinically indicated.    
 
6.4.1.4 
CLINICAL MONITORING FOR TLS 
Inform subjects of signs and symptoms that may be indicative of TLS, such as fevers, 
chills/rigors, dyspnea, nausea, vomiting, muscle tetany, weakness, or cramping, seizures, and 
decreased urine output.  Advise subjects to report such symptoms immediately and seek medical 
attention.  
 
6.4.1.5 
MANAGEMENT OF TUMOR LYSIS SYNDROME 
If TLS occurs, 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 TLS must be reported to Onyx as a Serious Adverse Event (SAE) through the normal 
process within 24 hours of the clinical site becoming aware of the event. 
 
6.5 
CONCOMITANT MEDICATIONS 
Concomitant medication is defined as any prescription or over-the-counter preparation including 
vitamins and supplements.  Concomitant medications should be recorded from 14 days before 
Day 1 through the end of the subject’s study participation.  Any change in concomitant 
medications must be recorded. 
If clinically indicated subjects should receive antibiotic prophylaxis with ciprofloxacin or other 
fluoroquinolone (or trimethroprim/sulfamethoxazole if fluoroquinoles are contraindicated).  In 
addition, subjects should receive acyclovir or similar (famiciclovir, valacyclovir) anti-varicella 
(anti-herpes) agent prophylaxis. 
 
6.5.1 
REQUIRED CONCOMITANT MEDICATIONS 
Female subjects of child-bearing potential must agree to use dual methods of contraception for 
the duration of the study.  Male subjects must agree to use a barrier method of contraception for 
the duration of the study if sexually active with a female of child-bearing potential. 
Patients should be treated with H2 blockers, ranitidine, or omeprazole. 

 
 
 
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All patients need anti-emetics either IV or PO prior to the infusion of Bendamustine. It is 
recommended that patients have anti-emetics as PRN medication available. 
 
6.5.2 
OPTIONAL AND ALLOWED CONCOMITANT MEDICATIONS 
Allopurinol (in subjects at risk for TLS due to high tumor burden) is optional and will be 
prescribed at the Investigator’s discretion.  These subjects may receive allopurinol 300 mg PO 
twice daily (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 
should be discussed with the Lead Principal Investigator. However, there may be an increased 
risk of severe skin toxicity when bendamustine and allopurinol are administered concomitantly.  
Subjects may receive RBC or platelet transfusions if clinically indicated in accordance with 
institutional guidelines.  Subjects who require repeated platelet transfusion support should be 
discussed with the Lead Principal Investigator 
Approved bisphosphonates and erythropoietic agents are allowed.  Subjects may receive 
antiemetics and antidiarrheals as necessary, but these should not be administered unless 
indicated.  Colony-stimulating factors may be used if neutropenia occurs but should not be given 
prophylactically during cycle 1.  
Subjects may receive RBC or platelet transfusions, if clinically indicated, per institutional 
guidelines.  Subjects who require repeated platelet transfusion support should be discussed.  
Subjects may receive supportive care with erythropoietin or darbepoetin, in accordance with 
institutional guidelines. 
Vitamins and supplements should be recorded on the concomitant medication page.  All 
transfusions and/or blood product related procedures must be recorded on the appropriate form. 
 
6.5.3 
EXCLUDED CONCOMITANT MEDICATIONS 
Concurrent therapy with an approved or investigative anticancer therapeutic with activity against 
MM is not allowed.  Other investigative agents (e.g., antibiotics or antiemetics) should not be 
used during the study. 

 
 
 
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7 
STUDY EVALUATION 
If a cycle is missed or a subject's study treatment and/or testing days need to be rescheduled due 
to the subject’s inability to comply with the study calendar (i.e., hospitalizations, business and 
vacation travel plans, illness, transportation issues, holidays, family emergencies, etc.), a window 
of  two (2) weeks is available for rescheduling the start of a cycle and procedures per the 
discretion of the investigator.   A window of +/- 1 day is allowed for rescheduling study visits 
other than day 1 visits, at the discretion of the principal investigator. For cycle 1 day 1, labs 
(except for CBC with differential, BMP, HFP) do not need to be repeated if they were drawn 
within 8 days of day of treatment. 
 
7.1 
SCREENING (WITHIN ≤ 28 DAYS OF REGISTRATION UNLESS OTHERWISE 
NOTED) 
 History & physical examination 
 Vital signs, AE assessment 
 Physical exam 
 ECOG Performance status 
 Baseline EKG and transthoracic Echocardiogram  
 CBC (with differential and platelets): should be performed < 48 hours prior to day 1. 
These labs should be resulted prior to the start of the subsequent cycle. 
 Optional correlative studies: 1 tube of blood 
 Calcium, phosphorus, sodium, potassium, serum creatinine, BUN, uric acid, LDH 
 Fasting glucose 
 TSH 
 Direct bilirubin 
 AST/ALT 
 Alkaline phosphatase 
 Protein, Albumin 
 Partial thromboplastin time (PTT)/PT/International Normalized Ratio (INR) 
 SPEP including M-spike, FLC 
 UPEP 
 24 hour urine collection for total protein 
 Immunofixation of serum and urine 
 Bone marrow aspirate/biopsy, cytogenetics (may be done within 6 weeks) 
 Beta 2 microglobulin  
 Quantitative Immunoglobulins (IgG, IgA, IgM) 
 Skeletal Survey (can be done within 8 weeks) 
 CXR 
 DEXA Scan hip and spine 
 Pregnancy test: Women of childbearing potential must have a negative serum or urine 
pregnancy test within 10-14 days and 24 hours of starting study drug. 
 Urinary collagen type 1 cross-linked N-telopeptide (NTX) 
 Serum Collagen type 1 cross-linked C-telopeptide (CTX)  
 
7.2 
DURING STUDY TREATMENT 
Day 1 of each cycle (q4 weeks) 
 History & physical examination 
 Vital signs, AE assessment 

 
 
 
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 Physical exam 
 ECOG Performance status 
 CBC (with differential and platelets): Results of day 1, 8, 15 of each cycle should be 
evaluated prior to start of drug treatment.  
 Optional correlative studies: 1 tube of blood  
 Calcium, phosphorus, sodium, potassium, serum creatinine, BUN, uric acid, LDH: 
Results of day 1, 8, 15 of each cycle should be evaluated prior to start of drug treatment  
 Total bilirubin 
 AST/ALT 
 Alkaline phosphatase 
 Protein, albumin 
 PTT/PT/INR 
 SPEP including M-spike, FLC 
 UPEP 
 24 hour urine collection for total protein 
 Quantitative Immunoglobulins (IgG, IgA, IgM) 
 Pregnancy test: Tests must be repeated every 4 weeks while on study treatment (every 14 
days for women with irregular menstrual cycles) and 4 weeks after the last dose of anti-
myeloma therapy.  
 Urinary collagen type 1 cross-linked N-telopeptide (NTX) 
 Serum Collagen type 1 cross-linked C-telopeptide (CTX)  
 
7.3 
DISCONTINUATION OF STUDY TREATMENT 
The following studies are required at the time of discontinuation of study treatment.  
 History & physical examination 
 Vital signs, AE assessment 
 Physical exam 
 Performance status 
 CBC (with differential and platelets)  
 Optional correlative studies: 1 tube of blood  
 Calcium, phosphorus, sodium, potassium, serum creatinine, BUN, uric acid, LDH  
 Total bilirubin 
 AST/ALT 
 Alkaline phosphatase 
 Protein, albumin 
 PTT/PT/INR 
 SPEP including M-spike, FLC 
 UPEP 
 24 hour urine collection for total protein 
 Quantitative Immunoglobulins (IgG, IgA, IgM) 
 Pregnancy test: Tests must be repeated every 4 weeks while on study treatment (every 14 
days for women with irregular menstrual cycles) and 4 weeks after the last dose of anti-
myeloma therapy.  
 Urinary collagen type 1 cross-linked N-telopeptide (NTX) 
 Serum Collagen type 1 cross-linked C-telopeptide (CTX)  
 Bone Marrow Aspiration and Biopsy with cytogenetic assessment 
 Assessment of minimal residual disease by Multiparameter Flow Cytometry  

 
 
 
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7.4 
FOLLOW-UP 
 History & physical examination 
 Physical exam  
 ECOG Performance status 
 CBC (with differential and platelets) 
 Calcium, phosphorus, sodium, potassium, serum creatinine, BUN 
 SPEP including M-spike, FLC 
 UPEP 
 24 hour urine collection for total protein 
 Immunofixation of serum and urine 
 Quantitative Immunoglobulins (IgG, IgA, IgM) 
 
7.5 
DURATION OF STUDY TREATMENT 
Study treatment will be given until progression of disease. This will consist of 8 cycles of 
induction therapy with CBd followed by stem cell transplant in those eligible.  After stem cell 
transplant or completion of CBd in those not eligible for transplant, carfilzomib maintenance is 
recommended but will be given outside the trial at the discretion of the treating physician. 
Patients who progress at any time will end protocol treatment. Patients will come off study 
treatment for unacceptable toxicity, patient refusal, pregnancy, non-compliance or any Grade 3/4 
toxicity that is severe and in the opinion of the sub-investigator dangerous to the patient. 
 
Only patients that completed at least 2 cycles of treatment will be considered evaluable and 
included in the analysis. 
 
7.6 
DURATION OF FOLLOW–UP 
Patient will be followed until death. Patients removed from study for unacceptable AEs will be 
monitored until resolution or stabilization of the AE. 
 
 

 
 
 
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8 
STUDY CALENDAR 
All pre-study scans, x-rays, biopsy, CBC (with differential and platelet count) and all required pre-study chemistries to be done up to 4 weeks 
before registration. If a cycle needs to be delayed due to the subject’s inability to comply with the study calendar (i.e., hospitalizations, business 
and vacation travel plans, illness, transportation issues, holidays, family emergencies, etc.), a two week delay is available for rescheduling of 
day 1 treatment and procedures per the discretion of the treating physician investigator.  A 4-week window is allowed between cycles 4 and 5 
for transplant eligible subjects in order to accommodate for scheduling of stem cell harvest. After discontinuation of therapy, subjects should be 
followed every 3 months (± 1 month) for the first two years, every 6 months (± 1 month) for years 2-5, and annually thereafter until death. See 
footnote 17 for study visit windows. Laboratory results (day 1, 8, 15 of each cycle) should be evaluated prior to start of drug treatment. 
 
Study parameters 
Baseline 
Cycle 1-82,17 
Discontinuation 
of therapy12 
Follow-up13
D-28 to D-1 D118 
D8 
D15 
History & Physical Examination, 
Height & Weight1 
X 
X 
 
 
X 
X 
VS, AE assessment 
 
X 
 
 
X 
 
Performance Status (ECOG) 
X 
X 
 
 
X 
X 
CBC (with differential and platelets)16  
X 
X 
X 
X
X 
X 
Basic Metabolic Panel (with 
creatinine)16  
X 
X 
X 
X 
X 
X 
Phosphorus 
X 
X 
X 
X
X 
X 
Baseline EKG and TTE 
X 
 
 
 
 
 
Glucose 
X19 
 
 
 
 
 
Total Bilirubin16  
X18
X 
X 
X 
X 
 
AST/ALT16 
X 
X 
X 
X 
 
 
Alkaline Phosphatase16 
X 
X 
X 
X 
 
 
Albumin16 
X 
X 
 
 
 
 

 
 
 
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Study parameters 
Baseline 
Cycle 1-82,17 
Discontinuation 
of therapy12 
Follow-up13
D-28 to D-1 D118 
D8 
D15 
TSH 
X 
 
 
 
 
 
PT, PTT, INR 
X 
X 
 
 
 
 
Uric Acid 
X 
X 
X 
X
X 
 
LDH 
X 
X 
X 
X
X 
 
SPEP3,7 
X 
X 
 
 
X
X 
Serum FLCs3,7 
X 
X 
 
 
X
X 
UPEP3,7 
X 
X 
 
 
X
X 
24 hour urine collection for total 
protein7 
X 
X 
 
 
X
X 
Immunofixation of serum and urine7 
X 
X 
 
 
X 
X
Bone Marrow Aspirate/Biopsy4 
May also be used for research purposes 
X7
 
 
 
X4 
 
Cytogenetics (bone marrow) 
X 
 
 
 
X 
 
Beta 2 Microglobulin 
X 
X 
 
 
X 
 
Quantitative Immunoglobulins5 
X 
X 
 
 
X 
 
Pregnancy test6 
X 
X 
 
 
 
 
DEXA Scan Hip and Spine14 
X 
 
 
 
X 
 
C-telopeptide, beta cross-linked, serum 
(CTX) 
X 
X 
 
 
X 
 

 
 
 
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Study parameters 
Baseline 
Cycle 1-82,17 
Discontinuation 
of therapy12 
Follow-up13
D-28 to D-1 D118 
D8 
D15 
Collagen cross-linked, urine (NTX)  
X 
X 
 
 
X 
 
Correlative serum sample20  
(optional;1 gold top tube with at least 5ml) 
X 
X 
 
 
X 
 
Minimal Residual Disease Assessment 
by Flow Cytometry15 
 
 
 
 
X 
 
For Stem Cell Transplantation 
Candidates ONLY: Mobilization will 
occur after cycle 4 
 
 
 
 
 
 
X-ray: skeletal survey with CXR8 
X 
 
 
 
X 
 
Carfilzomib  
 
X9 
X9 
X9 
Bendamustine  
 
X10 
 
 
 
 
Dexamethasone  
 
X11 
X11 
X11 
 
1. 
Physical exam including graded neuropathy, Height is obtained at baseline only; weight is measured at baseline, day 1 of each treatment cycle, at discontinuation of therapy, and 
at follow-up assessment visits. 
2. 
Results for VS, performance status, CBC with differential, chemistry with phosphorus should be evaluated prior to start of drug treatment. 
3. 
After baseline testing, the appropriate marker should be followed to assess response. This might be either SPEP, FLCs and/or UPEP.  Serum immunofixation should be performed 
in patients in which the M-protein spike became undetectable. 
4. 
Bone marrow aspirate/biopsy is obtained at the beginning and at the end of treatment, and at the following events: achievement of CR, relapse, PD.  One additional green top tube 
(5mL) of aspirate and/or leftover biopsy material will be used by Dr. Lentzsch’s lab and will require opt-in consent as part of the ICF process 
5. 
Includes lgG, IgA, IgM. 
6. 
All FCBP should complete a serum pregnancy test within 7 days prior to day 1 of cycle 1. The pregnancy test should be repeated in week 1 of every cycle (except for cycle 1). 
Postmenopausal women must have been amenorrheic for ≥ 12 months in order to be considered “of non-childbearing potential.” 
7. 
Required to document CR or PD  
8. 
Skeletal surveys in general are poor tools for following disease on a short term basis. Therefore, a skeletal survey should be performed at discontinuation of study treatment,  for 
symptoms that would suggest new bony lesions, and if deemed necessary by the sub-investigator, to be used as a tool for response assessment. 

 
 
 
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9. 
CFZ is administered IV on day1, 2, 8 ,9,15, and 16 of cycles 1-8. 
10. Bendamustine is administered IV on days 1 and 2 of cycles 1-8.  
11. Dexamethasone is administered IV or PO on days 1, 2, 8, 9, 15, 16,  22, 23 of cycles 1-8. 
12. To be performed within 4 weeks after completion of the last cycle. 
13. After discontinuation of therapy, subjects should be followed every 3 months (± 1 month) for the first two years, every  6 months (± 1 month) for years 2-5, and annually 
thereafter.  
14. To be performed at baseline or within one year before C1D1; and at the end of treatment or after 1 year, whichever comes first. 
15. Please note that MRD will be tested at best response.  
16. CBC and serum chemistry (BMP & HFP) need to be drawn on days 1, 8, and 15 of cycles 1-8 and days 1 and 15 of maintenance cycles; all other study labs do not need to be 
drawn if they were drawn within 8 days of C1 D1. 
17. A window of +/- 1 day is allowed for rescheduling study visits other than day 1 visits (labs should be drawn on day of chemo as indicated), at the discretion of the principal 
investigator. 
18. At baseline, order direct bilirubin for eligibility.  
19. At baseline, this is a fasting glucose 
20. Correlative sample should be taken with subject fasting and in the morning at screening, on day 1 of each cycle, and at discontinuation. 
21. Maintenance phase begins at Cycle 9 and subjects may receive maintenance treatments for a maximum of 2 years. 
22. CFZ is administered IV on days 1, 2, 15, and 16 of maintenance cycles 
23. Dexamethasone is administered IV or PO on days 1, 2, 15, and 16 of maintenance cycles. 

 
 
 
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9 
STUDY DISCOTINUATION 
9.1 
DISCONTINUATION OF STUDY TREATMENT  
The studies are required at the time of discontinuation of study treatment are listed on the study 
calendar. 
 
9.2 
FOLLOWUP AFTER DISCONTINUATION OF STUDY TREATMENT 
After discontinuation of study treatment, patients should be followed for disease progression and 
death  every three months (± 1 month) for the first 2 years. Follow-up can be performed by a 
local physician/oncologist.  Data will be collected by the research team from the treating 
physician. 

 
 
 
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10 
MEASUREMENT OF EFFECT 
Definitions of response are based on the latest International Myeloma Working Group (IMWG ) 
uniform response criteria as published in Blood in May 2011. (18)  
 
10.1 DEFINITIONS 
10.1.1 M-protein 
Synonyms include M-spike, monoclonal protein, myeloma protein, monoclonal paraprotein, and 
M-component. 
 
10.1.2 Response Terms 
The following response terms will be used: CR, sCR, VGPR, PR, SD or NR, plateau, and 
progression or relapse. See section 10.3 for Response Criteria. 
 
10.1.3 Measurable Disease 
Patients who have a measurable serum or urine M-protein. A “measurable” serum M-protein is 
>1 g/dL and a ‘measurable” urine M-spike is >200 mg/24 hours or involved FLC  10 mg/dL ( 
100 mg/L). 
 
10.1.4 Evaluable Disease 
Patients who do not have a “measurable” serum or urine M-spike. 
 
10.1.5 Oligosecretory Myeloma 
Patients with MM who have NEVER had “measurable” disease, but have had a detectable 
monoclonal protein in their serum and/or urine. 
 
 

 
 
 
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10.2 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
10.2.1 Bone Radiographs 
Not required to document response. If bone radiographs are obtained, their findings must be 
consistent with the bone response criteria. 
 
10.2.2 Bone Progression 
Caution must be exercised to avoid rating progression or relapse on the basis of variation of 
radiologic technique alone. Compression fracture does not exclude continued response and may 
not indicate progression. When progression is based on skeletal disease alone, it should be 
discussed with the Investigator before removing the patient from the study. 
 
10.2.3 Clarification of Test Indications 
The percentage reductions and/or increments of the M-protein in the serum and urine required for 
sCR, VGPR, PR, plateau, and progression (see section 10.3) apply to only those patients with 
“measurable” values of the serum and the urine. Immunofixation studies of both serum and urine 
are to document CR regardless of registration values. 
 
10.2.4 Monoclonal Protein Considerations 
Serum and urine M-protein levels should be determined by electrophoresis rather than by 
quantitative Ig measurement. Exceptions are made in cases in which the M-spike value may be 
deemed to be unreliable. In these cases, quantitative Ig should be used. To assess response and 
progression, however, SPEP values should only be compared to SPEP values and quantitative Ig 
values only to quantitative Ig values. Small migrating M-proteins (usually IgA M-proteins) are 
contaminated by normal γ-globulins that are often greater in quantity than the M-spike itself. In 
cases in which the M-spike is large and narrow on agarose (some specimens >4 g/dL) the actual 
Ig level (by greater than 1500 mg/dL) can be underestimated due to technical staining properties 
of the agarose gel. 
 
10.3 RESPONSE CRITERIA 
10.3.1 Complete Response (CR) 
Patients who have complete disappearance of an M-protein and no evidence of MM in the bone 
marrow are considered to have CR. To be considered CR, patients must meet all of the following 
criteria: 
 Complete disappearance of M-protein from serum: There must be no detectable serum 
M-protein on immunofixation. 
 Complete disappearance of M-protein from urine: There must be no detectable M-protein 
on immunofixation. 
 Bone marrow biopsy demonstrating <5% plasma cells. No increase in size or number of 
lytic bone lesions. 
 Disappearance of soft tissue plasmacytomas. 
 There must be no evidence of PD, including no increase in the number/size of lytic bone 
lesions, or by other parameters. 
 
10.3.2 Stringent Complete Response (sCR) 
In addition to CR criteria (defined above), these patients have a normal FLC ratio and have no 

 
 
 
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clonal cells by bone marrow immunohistochemistry or immunofluorescence. Clonal cells 
detected in the bone marrow by immunohistochemistry or immunofluorescence are considered 
abnormal if there is a kappa/lambda ratio of  >4:1 or <1:2 after examination of a minimum of 100 
cells. 
 
10.3.3 VGPR 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or at least a 
90% reduction in serum M-protein with a urine M-protein <100 mg/24 hours. 
 
10.3.4 Partial Response (PR) 
PR requires all of the following: 
 ≥50% reduction in the level of the serum monoclonal paraprotein. 
 Reduction in 24-hour M-protein either by 90% or to <200 mg. 
 If the serum and urine M-protein are not measurable (i.e., <1.0 g/dL at registration), a 
50% decrease in the difference between involved and uninvolved FLC levels is required 
in place of M-protein criteria.  
 If serum and urine M-protein are not measurable and serum FLC are also not measurable, 
a ≥50% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy must 
be documented provided that baseline bone marrow percentage was  to 30%. 
 ≥50% reduction in size of soft tissue plasmacytoma (by radiography or clinical 
examination). 
 No increase in the number or size of lytic bone lesions (development of a compression 
fracture does not exclude response). 
 As above, there must be no evidence of PD by other parameters. Patients who meet some, 
but not all, of the criteria for PR are classified as MR, providing the remaining criteria 
satisfy the requirements for MR. 
 
10.3.5 Minor Response (MR) 
Adopted from the EBMT criteria(19) requires all of the following: 
 25% but <49% reduction of serum M protein and reduction in 24-hour urine M-protein 
by 50 to 89% which still exceeds 200 mg per 24-hour. 
 In addition to the above criteria, if present at baseline, 25-49% reduction in the size of 
soft tissue plasmacytomas is also required. 
 No increase in size or number of lytic bone lesions (development of compression fracture 
does not exclude response). 
 
10.3.6 Stable Disease (SD) 
Failure to meet response criteria outlined above. This is considered SD or no response. 
 
10.3.7 Disease Plateau 
(Note: plateau is not a distinct response category) 
This category will not be applied to patients with non-secretory or oligosecretory myeloma. A 
patient in CR, PR, or MR (see Sections above) will be further classified as being in plateau if the 
following criteria are met: 

 
 
 
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 Serum and/or urine M-protein values must be stable for a period of at least 12 weeks. 
Stable values are defined as a continued CR or in the case of patients with residual M-
protein, absence of progression. 
 Any patient with measurable disease who is continuing to have “improvement” in serum 
or urine response criteria would not be considered in plateau. “Improvement” is defined 
as a decrease in the serum or urine M spike by >25% in a 4 week interval, with absolute 
decrements of at least 0.5 g/dL for serum and 200 mg/24 hours for urine. He or she might 
be approaching a better level of response, and therefore, should not yet be deemed in 
plateau until the improvement has leveled off. 
 DATE of plateau will be the first date of suspected plateau. Date cannot be assigned until 
CONFIRMATION that the patient is in plateau (that is at least 12 weeks later). 
 
10.3.8 Relapse or Progression  
Patients will be considered to have relapse or progression if one of the following criteria is met. 
The investigation that qualified as progression should be repeated and verified on a subsequent 
occasion only if treating physician deems it clinically necessary. It is strongly recommended that 
the immunofixation be repeated on patients who are being considered as “relapsed” from CR 
status. PD should be used for calculation of time to progression and PFS end points for all 
patients including those in CR (including primary PD and disease progression on or off study 
treatment). 
 
Requires any or more of the following: 
Increase of >25% from lowest response value in any of the following: 
 Serum M-component and/or (the absolute increase must be >0.5 g/dL) 
 Urine M-component and/or (the absolute increased must be >200mg/24hr) 
 Only in patients without measurable serum and urine M-protein levels: the difference 
between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. 
 Only in patients without measurable serum and urine M protein levels and without 
measurable disease by FLC levels, bone marrow plasma cell percentage: the absolute % 
must be at least 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 or 2.65 mmol/l) 
that can be attributed solely to the plasma cell proliferative disorder. 
 
Patients with a global deterioration of health status requiring discontinuation of study treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression, 
even after discontinuation of study treatment. 
 
10.3.9 Clinical Relapse 
Requires one or more of the following: 
 Direct indicators of increasing disease and/or end organ dysfunction. It is not used in 
calculation of TTP or PFS, but is listed here as something that can be reported optionally 
for use in clinical practice. 
 Development of new soft tissue plasmacytomas or bone lesions. 

 
 
 
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 Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum 
of the products of the cross-diameters of the measurable lesion. 
 Hypercalcemia (11.5 mg/dL) [2.65 mmol/L]. 
 Decrease in hemoglobin >2g/dL [1.25 mmol/L]. 
 Rise in serum creatinine by 2 mg/dL or more [177 μmol/L or more]. 
 
10.4 CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
10.4.1 Confirmed Response 
In order to be classified as a response, confirmation of serum M-protein results must be made by 
verification on two consecutive determinations 4-6 weeks apart. 
 In patients whose M-protein is not measurable, serum FLCs will be followed to access 
response as noted above. If serum FLCs are not measurable, bone marrow biopsy will be 
performed to document response after every two cycle per study calendar. 
 Bone marrow aspirate and biopsy are not required to document or confirm PR or, MR. 
Bone Marrow biopsy and aspiration will be required to confirm CR, PD, or relapse. 
Exception: for patients with non-secretory and oligosecretory myeloma only, a bone 
marrow is required to document all response categories including progression. 
 
10.4.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded since the study 
treatment started). 
 
10.4.3 Duration of Disease Free Survival  
The duration from the start of CR to the time of relapse from CR. DFS applies only to patients in 
complete CR. 
 
10.4.4 Duration of Stable Disease (SD) 
SD is measured from the start of study treatment until the criteria for progression are met, taking 
as reference the smallest measurements recorded since the study treatment started. 
 
10.4.5 Progression Free Survival (PFS) 
PFS is defined as the duration of time from start of study treatment to time of progression or 
death, whichever occurs first. 
 
10.4.6 Time to Progression (TTP) 
Duration from start of treatment to disease progression, with deaths from causes other than 
progression censored. 
 
10.5 RESPONSE REVIEW 
The CUMC Data Safety and Monitoring Plan includes provisions for independent review and 
confirmation of responding patients on clinical trials. All reported responders on this trial will be 
subject to independent review and confirmation. 

 
 
 
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11 
ADVERSE EVENTS 
11.1 
ADVERSE EVENT DEFINITIONS  
An 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”.    
 
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 C).  
Any events representing a change in the CTCAE Grade need to be reported on the AE case report 
form (CRF).  This includes any change in laboratory values.   
 
For AEs not adequately addressed in the CTCAE, the severity table below may be used: 
 
Table 8: Severity table of Adverse Events additional to CTCAE 
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 
 

 
 
 
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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. 
 
Using the following criteria, the relationship of the AE to the study drug should be assessed as 
follows:   
 
Yes:  The event is suspected to be related if:  
 
there is a clinically plausible time sequence between onset of the AE and administration 
of study treatment; and/or 
 
there is a biologically plausible mechanism for the study treatment to cause or contribute 
to the AE; and/or  
 
the event responds to withdrawal of the study medication (dechallenge) and/or recurs 
with rechallenge (when clinically feasible); and/or 
 
the AE cannot be reasonably attributed to concurrent/underlying illness, other drugs, or 
procedures 
 
No:  
 
the AE is more likely to be explained by the subject’s clinical state, underlying disease, 
concomitant medication, study or non-study procedure; and/or 
 
the time of occurrence of the AE is not reasonably related to administration of study 
treatment; and/or 
 
the event is unlikely to be related to the investigational product(s) 
 
11.2 
ADVERSE EVENTS REPORTING PROCEDURES 
All AEs (e.g., any new event or worsening in severity or frequency of a pre-existing condition or 
laboratory finding) with an onset date after the subject signs consent for study participation must 
be promptly documented on the appropriate summary.  Details of the event must include severity, 
relationship to study drug, duration, action taken, and outcome.  SAEs will be recorded on the 
appropriate 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 the time the subject signs consent through 30 days post-last dose of 
study drug or initiation of a new anti-cancer therapy, whichever occurs first.  In addition, the 
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 registered but 
discontinues study prior to receiving any study drug, AEs 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 Investigator that the event has stabilized or is not expected to improve. 
 

 
 
 
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The Principal Investigator is responsible for evaluating all AEs, obtaining supporting documents, 
and determining that documentation of the event is adequate.  AEs will be assigned a severity 
grade using the NCI-CTCAE grading scale v4.0.   
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 Investigator. 
The Principal Investigator may delegate these duties to Subinvestigators and must ensure that 
these Subinvestigators are qualified to perform these duties under the supervision of the Principal 
Investigator and that they are listed on the FDA Form 1572.   
 
11.3 
SERIOUS ADVERSE EVENTS DEFINITIONS 
An SAE is one that meets the following criteria:  
 
Death 
 
Life threatening experience defined as any adverse experience that places the subject, in the 
view of the 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. 
 
An Unanticipated Problem (UP) is any incident, experience or outcome involving risk to 
subjects or others in any human subjects research that meets all of the following criteria:  
 
Unexpected (in terms of nature, severity or frequency) given (a) the research procedures 
that are described in the IRB-approval protocol and informed consent document, and (b) 
the characteristics of the subject population being studied;  
 
Related or possibly related to participation in such research (i.e., there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the 
procedures involved in such research); and  
 
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic or social harm) than was previously known or 
recognized  
 
A Suspected Adverse Reaction (SAR) is any AE for which there is a reasonable possibility 
that it was caused by the drug. 
 
Reasonable possibility means that there is evidence to suggest a causal relationship between 
the drug and the AE.  Examples of reasonable possibility are: 

 
 
 
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 A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure. 
 One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug. 
 An aggregate analysis of specific events observed in a clinical trial that indicates that 
those events occur more frequently in the drug treatment group than in a concurrent 
or historical control group. 
 
The S-I must report the following SARs: 
 
To the FDA, as soon as possible, but no later than 7 calendar days after the S-I's initial 
receipt of the information, any unexpected fatal or life-threatening SAR. 
 
To the FDA and all participating investigators, as soon as possible but no later than 15 
calendar days after the S-I determines that information qualifies for reporting, in an IND 
safety report, any SAR that is both serious and unexpected. 
 
To the FDA and all participating investigators, as soon as possible but no later than 15 
calendar days after the S-I determines that the information qualifies for reporting, any 
findings from epidemiological studies, pooled analysis of multiple studies or clinical 
studies, whether or not conducted under an IND or by the S-I, that suggest a significant 
risk in humans exposed to the drug.  
 
To the FDA and all participating investigators, as soon as possible, but no later than 15 
calendar days after the S-I determines that the information qualifies for reporting, any 
findings from animal or in vitro testing, whether or not conducted by the S-I, that suggest 
a significant risk in humans exposed to the drug.  
 
To the FDA and all participating investigators, as soon as possible, but no later than 15 
calendar days after the S-I determines that the information qualifies for reporting, any 
clinically important increase in the rate of a Serious SAR over that listed in the protocol or 
Investigator Brochure. 
 
Expected SAEs and AEs should be included in the IND Annual Reports. 
 
Follow-up information to a safety report should be submitted as soon as the relevant 
information is available.  However, if the results of a sponsor’s investigation show that an 
adverse drug experience not initially determined to be reportable are so reportable, the 
sponsor must report such experience as soon as possible, but no later than 15 calendar days 
after the determination is made. 
 
To the CUMC IRB: 
1. Unanticipated Problems (UPs) must be reported promptly, but not later than 7 calendar 
days following the occurrence of the UP or the Principal’s Investigator’s acquiring 
knowledge of the UP. 
2. Expected AEs must be reported at the time of continuing review of a protocol. 
11.4 
SERIOUS ADVERSE EVENT REPORTING AND DOCUMENTATION 
REQUIREMENTS 
 

 
 
 
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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 sponsor as an SAE. All SAEs 
occurring from the time that the subject signs consent for study participation through 30 days 
after the last administered dose of study drug will be reported.  SAEs for screen failures should 
not be reported.  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. 
The sponsor 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. 
This submission of Investigational New Drug (IND) Safety Reports (North America) or 
Suspected Unexpected Serious Adverse Reactions (SUSARS [Europe]) will be cross referenced 
according to local regulations to Onyx Investigational Compound Number (IND, CSA, etc.) at 
the time of submission.  
The Investigator is also responsible for notifying the Institutional Review Board (IRB) or 
Independent Ethics Committee in accordance with local regulations, of all SAEs.   
 
Expedited Reporting by Investigator to Teva 
The Investigator must inform Teva in writing by Fax at the contact information listed below of 
all Expedited Safety Reports submitted to the relevant Regulatory Agencies. These notifications 
should be performed in parallel to the Regulatory Agency submissions [e.g., within 7 calendar 
days for any Fatal or Life-threatening SUSARs and within 15 calendar days for all other 
SUSARs}, but in no case any later than 1 business day from the submission date. This must be 
documented on a FDA 3500A MEDWATCH or CIOMS I (for EU studies) form.  This form must 
be completed and supplied to Teva in English.  
The initial report must be as complete as possible, at a minimum including the SAE term(s), 
patient identifier, date of awareness of the event,  an assessment of the causal relationship 
between the event and the investigational product(s), and name of the reporter (investigator).  
Information not available at the time of the initial report (e.g., an end date for the AE or 
laboratory values received after the report) must be documented on a follow-up MEDWATCH or 
CIOMS I form, and submitted to Teva in the same timelines as outlined above.   
All other SAE’s will be sent to Teva. on a biannual basis in the form of a line listing in English.  
The line listing must include the following information; patient initials, date of birth, sex, SAE 
onset date, SAE stop date, event name (term), outcome, date of first dose of study drug(s), date of 
last dose of study drug(s) prior to the event,  action taken with study drug(s)the Investigator’s 
assessment of causality (relationship to Bendamustine), and the Investigator’s assessment of 
expectedness to Bendamustine.  The sponsor reserves the right to review the CRFs or source 
documents in response to any inquires by regulatory agencies that the sponsor may receive. 

 
 
 
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Teva Drug Safety and Pharmacovigilance Contact Information: 
Teva Fax:  
(215) 619-3825 
e-mail:  us.clinops.sae@tevapharm.com 
 
Expedited Reporting by Investigator to Onyx 
The Investigator must inform Onyx in writing by Fax at the contact information listed below of 
all SAEs and Expedited Safety Reports submitted to the relevant Regulatory Agencies.  These 
notifications should be performed in parallel to the Regulatory Agency submissions [e.g., within 
7 calendar days for any Fatal or Life-threatening SUSARs and within 15 calendar days for all 
other SUSARs}, but in no case any later than 1 business day from the submission date. This must 
be documented on a FDA 3500A MEDWATCH or CIOMS I (for EU studies) form.  This form 
must be completed and supplied to Onyx in English.  
The initial report must be as complete as possible, at a minimum including the SAE term(s), 
patient identifier, date of awareness of the event,  an assessment of the causal relationship 
between the event and the investigational product(s), and name of the reporter (investigator).  
Information not available at the time of the initial report (e.g., an end date for the AE or 
laboratory values received after the report) must be documented on a follow-up MEDWATCH or 
CIOMS I form, and submitted to Onyx in the same timelines as outlined above.  The Onyx 
protocol number (IST-CAR-579) and the institutional protocol number should be included on all 
reports to Onyx.   
All other SAE’s will be sent to Onyx in real time and must be submitted on a FDA 3500A 
MEDWATCH or CIOMS I (for EU studies) form.  This form must be completed and supplied to 
Onyx in English. The report  must include the following information; patient initials, date of 
birth, sex, SAE onset date, SAE stop date, event name (term), outcome, date of first dose of study 
drug(s), date of last dose of study drug(s) prior to the event, action taken with study drug(s) the 
Investigator’s assessment of causality (relationship to carfilzomib), and the Investigator’s 
assessment of expectedness to carfilzomib.  The sponsor reserves the right to review the CRFs or 
source documents in response to any inquires by regulatory agencies that the sponsor may 
receive. 
Onyx Drug Safety and Pharmacovigilance Contact Information: 
Onyx Drug Safety Fax:    650.266.0501 or 800-783-7954 
SAE hotline:                     (650)-266-2501) 
e-mail:                     AdverseEvents@onyx.com 
 
11.5 
PREGNANCY 
If a subject or spouse or partner of a subject becomes pregnant while enrolled in this clinical trial 
or up to three months following administration of CFZ, Onyx Drug Safety must be notified 
within 24 hours of the Investigator, designee, or site personnel learning of the pregnancy (See 
Onyx Drug Safety and Pharmacovigilance Contact information above).  If the subject is pregnant, 
CFZ must be withheld.   
Subjects, spouses, or partners will be followed through the outcome of the pregnancy.  The 
Investigator will be required to report the results to Onyx Drug Safety. 

 
 
 
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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 Investigator should repeat the procedures 
for expedited reporting of SAEs as outlined above. 

 
 
 
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12 
STATISTICAL CONSIDERATIONS 
 
12.1 
STUDY DESIGN/ENDPOINTS 
This is a phase I/II, open label, non-randomized dose escalation study. The primary endpoint of 
this study is to define the recommended phase II dose of CFZ in combination with bendamustine 
and dexamethasone in patients with newly diagnosed MM. This study defines the phase II dose 
as the combination at which 20% of treated patients would be predicted to experience DLT (as 
defined in Section 11.1). The study design allows for sufficient numbers of patients to be accrued 
at a dose level near the MTD that this present study will have the power of a typical phase 2 
study. 
 
Doses will be allocated to patients using a two-stage Up-and-Down dose escalation scheme, (17) 
(Storer's schema D, with a one-patient-per-level run-in) without intra-patient dose escalation. The 
initial protocol proposed a maximum sample size of 34 patients to be accrued. As of 
18APR2017, a total of 14 evaluable (received at least 2 cycles of treatment) patients have been 
enrolled in the trial. Out of 14 patients, 4 patients were allocated to dose level 1 to 4 and 10 
patients were allocated to dose level 5 (maximum dose level). Given that none of the patients 
have yet experienced a DLT, we considered a sample size re-calculation that would shorten the 
length of the trial. Given the current trend, it is expected to see at most 1 DLT at the maximum 
dose level 5. By planning to enroll 12 additional patients at level 5, we can ensure that the 90% 
confidence interval (CI) for the DLT rate will be below the targeted DLT rate of 20%, providing 
acceptable insurance that the toxicity at this dose level is at most 20%. With 22 patients enrolled 
at dose level 5, the 90% CIs are as follows: for 0 DLT observed: (0, 0.13); for 1 DLT observed: 
(0, 0.20). We re-estimated the sample size to 26 evaluable patients, with a maximum of 2 
additional patients that might not complete the required 2 cycles of treatment. Therefore, the new 
targeted accrual is 28 patients, lower as compared to the initial 34. 
12.2 
STRATIFICATION FACTORS  
There are no planned stratification factors.   
 
12.3 
SAMPLE SIZE 
Approximately 26 evaluable subjects (men and women who are at least 18 years of age) will 
participate in this study. 
 
12.4 
ANALYSIS OF PRIMARY ENDPOINT 
The primary endpoint of this trial is DLT, defined as a dichotomous variable in Section (11.1).  
The proportion of patients at each dose level tested who experience DLT will be estimated with 
an exact 90% binomial confidence interval.  As a secondary analysis, depending on which doses 
are tested, a logistic regression model of DLT as a function of the doses of the two drugs, treated 
as continuous variables, may be fit to the data.  The up-and-down dose escalation scheme 
presents a recommended phase II dose at the end of study.   
 

 
 
 
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12.5 
ANALYSIS OF SECONDARY ENDPOINTS 
 Determine preliminary evidence of efficacy (ORR) of the combination of CFZ in 
combination with bendamustine and dexamethasone:  The proportion of responders (defined 
in Section 10.3) at each dose will be estimated along with 95% exact binomial confidence 
intervals. Fisher’s exact test (at a significance level of 0.05) will be used to test the null 
hypothesis that there is no relationship between treatment combination and response.  
Depending on which doses are tested, a logistic regression model of response as a function of 
the doses of the two drugs, treated as continuous variables, may be fit to the data.   
 
Time to progression (TTP) will be analyzed by means of a product limit (Kaplan-Meier) 
estimator of the survival function at each dose.  The median TTP will be estimated, along with 
a 95% confidence interval.  If patients are enrolled primarily at higher doses, median TTP will 
not be estimable at lower doses.  If all enrollments (after the rapid escalation phase) is at the 
upper two doses, TTP estimation will also be performed on all patients without regards to dose.   
 
Duration of response (DOR):  Analysis plan is similar to that of TTP. 
 
Progression free survival (PFS):  Analysis plan is similar to that of TTP. 
 
Overall survival (OS):  Analysis plan is similar to that of TTP. 
 
Evaluate the safety and toxicity:  In addition to the primary analysis of DLT, AEs will be 
tabulated at each dose level.  SAEs will be tabulated by dose and assessed relation to treatment 
(not related; unlikely related; possibly related; probably related; related). 
 
Stem cell collection parameters after using the protocol as induction regimen  
 
12.6 
DOSE ASSIGNMENT ALGORITHM 
The first patient will be enrolled at Level 1 (all levels correspond to Table 1).  This is the first 
stage of dose escalation.  If that patient does not experience a Grade 2 toxicity (at least possibly 
related to treatment), the second patient will be enrolled at the next higher level.  The first patient 
at each dose level must complete the first cycle prior to enrolling the next patient at the next dose 
level. Once the first Grade 2 (or worse) toxicity at least possibly related to treatment is observed, 
the dose is decremented by one level, and five patients are treated at that dose.  If 0/5 patients 
experience DLT (11.1), the next cohort of 5 is treated at the next higher level.  If 1/5 patients 
experience DLT, the next cohort of 5 is treated at the same level.  If >1/5 patients experience 
DLT, the next cohort of 5 is treated at the next lower level. If 0/5 patients in a cohort experience 
DLT at Level 4, the next cohort is treated at Level 4.  If >1/5 patients experience DLT at Level 1, 
accrual to the trial will be paused so that amendments to the treatment plan can be considered. 
This algorithm is repeated until six cohorts are completed (for a maximum accrual of 
4+65=34).(17)  The first patient will be enrolled at Level 1. 
 
Table 1.  Dose Escalation Schema 
 
Carfilzomib 
Bendamustine 
Dexamethasone 
-1  
27 mg/m2 
50 mg/m2 
20 mg 
1 
27 mg/m2 
70 mg/m2 
20 mg 
2 
36 mg/m2 
70 mg/m2 
20 mg 

 
 
 
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12.7 
JUSTIFICATION OF DESIGN 
The design of the trial is justified in terms of the primary objective.  The operating characteristics 
of the dose-allocation algorithm were investigated by Monte Carlo simulation.  It was assumed 
that the true probability of toxicity at each dose was described by Table 9. 
 
 
Table 9.  Dose-specific probabilities of DLT assumed for Monte 
Carlo simulation to assess the operating characteristics. 
 
True P(DLT) 
Dose combination 
Simulation 1 
Simulation 2 
Simulation 3 
1 
0.05 
0.07 
0.07 
2 
0.10 
0.14 
0.14 
3 
0.15 
0.21 
0.21 
4 
0.20 
0.28 
0.35 
5 
0.25 
0.35 
0.49 
 
The operating characteristics, assuming the probabilities of toxicity in Table 9, are presented in 
Figure 1. In each row, the left frame presents the percentage of simulated trial choosing a given 
dose level as the phase II recommended dose. In the top row (Simulation 1), it is seen that 85% of 
trials choose either Dose Level 3 or 4 (within 5% of the target combination, Level 4). All 
simulation scenarios control the median proportion of observed DLTs to less than 20%. In all 
three simulation sets, an average of at least 20 patients is treated within one level of the true 
target dose. 
3 
36 mg/m2 
90 mg/m2 
20 mg 
4 
45 mg/m2 
90 mg/m2 
20 mg 
5 
56 mg/m2 
90 mg/m2 
20 mg 

 
 
 
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Figure 1 Operating characteristics of design estimated from Monte Carlo simulations of trial 
design. From left to right, histograms of the phase II doses the trial selects, expected number of 
observed DLTs out of 35 patients treated, and distribution of numbers of patients treated at 
each combination. The line in the left frame indicates the true P (DLT).  From top to bottom, 
the frames represent Simulations 1, 2 and 3 of Table 9. 

 
 
 
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13 
INVESTIGATIONAL PRODUCT 
13.1 
CARFILZOMIB DESCRIPTION 
CFZ is a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-1-((S)-4-
methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-
morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide.  The molecular formula is 
C40H57N5O7 and the molecular weight is 719.91.  It specifically functions as an inhibitor of the 
chymotrypsin-like activity of the 20S proteasome which leads to the accumulation of protein 
substrates within the cell and induction of apoptosis.   
 
13.2 
FORMULATION 
CFZ for Injection will be provided as a lyophilized powder which, when reconstituted, contains 2 
mg/mL isotonic solution of CFZ Free Base in 10 mm sodium citrate buffer (pH 3.5) containing 
10% (w/v) sulfobutylether--cyclodextrin (SBE--CD, Captisol®).   
 
13.3 
STORAGE 
Lyophilized CFZ 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. 
 
13.4 
ACCOUNTABILITY 
Onyx, Inc. and the 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. 

 
 
 
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14 
CORRELATIVE STUDIES 
Multiple Myeloma is associated with increased osteoclast activity resulting in increased bone 
resorption. Concurrent myeloma cells secrete factors that inhibit the activity of osteoblast 
resulting in pure lytic lesions. The restoration of the balance between increased bone 
resorption and decreased bone formation is therefore a critical goal in the treatment of MM. 
Bisphosphonates such as zoledronic acid (ZA) have shown to inhibit osteoclast activity. 
Proteasome inhibitors such as bortezomib have been shown to be osteoblast inducers 
resulting in increased bone formation. 
 
We hypothesize that the more potent proteasome inhibitor carfilzomib induces osteoblast 
activity and subsequently bone formation. This should result in increased bone density, bone 
quality and increase of serum bone formation markers such as osteocalcin and P1NP in our 
study population. We plan to measure the bone resorption markers at baseline, day 1 of each 
cycle, andat treatment discontinuation.. The bone quality at the distal radius and tibia will be 
measured by high resolution peripheral QCT (HRpQCT) at baseline and the end of the study 
or after 1 year whichever comes first. The bone density at the hip and spine will be measured 
by DEXA scan at the same time points. This will be performed as standard of care and is 
well established in multiple myeloma treatment. The escalating dose of CFZ will give us 
information whether CFZ enhances bone formation in a dose-dependent manner. By 
HRpQCT, we expect to see increases in total and trabecular density and possibly in 
trabecular and cortical thickness, with decreases in trabecular separation. We do not 
anticipate that bendamustine has any effect on bone formation. Further most of the patients 
will receive Zoledronic Acid (ZA) that inhibits osteoclast activity and therefore only affects 
bone resorption markers such CTX and TRAP5b. We expect a decrease in osteoclast-
mediated bone resorption and thus also decrease serum bone resorption markers. 
 
 
Baseline 
Cycle X Day 
1 
Discontinuation 
visit  
Osteocalcin 
X 
X 
X 
P1NP 
X 
X 
X 
 
TRAP5b 
 
X 
 
X 
 
X 
 
Patients will be informed of these studies during the informed consent process. All 
correlative studies are optional. One gold top tube of peripheral blood (at least 5mL) should 
be drawn fasting as indicated in the table if the subject agrees to participate in the correlative 
studies. Two 0.5 ml aliquots of serum will be stored at -80°C. These sample will be de-
identified, collected and stored in the laboratory of Dr. Suzanne Lentzsch, Black Building, 8th 
Floor. After completion of the sample collection all samples will be analyzed at the 
Biomarker Core at CUMC under the leadership of Dr. Serge Cremers. The HRpQCT will be 
performed at the Metabolic Bone Diseases Program, 9th Floor of the Harkness Pavilion. We 
do not plan to send any samples to outside institutions. 

 
 
 
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15 
REGULATORY OBLIGATIONS 
 
15.1 
INFORMED CONSENT 
The investigator-sponsor will make certain that an appropriate informed consent process is in 
place to ensure that potential research subjects, or their authorized representatives, are fully 
informed about the nature and objectives of the clinical study, the potential risks and benefits of 
study participation, and their rights as research subjects. The investigator-sponsor, or a sub-
investigator(s) designated by the investigator-sponsor, will obtain the written, signed informed 
consent of each subject, or the subject’s authorized representative, prior to performing any study-
specific procedures on the subject. The date and time that the subject, or the subject’s authorized 
representative, signs the informed consent form and a narrative of the issues discussed during the 
informed consent process will be documented in the subject’s case history. The investigator-
sponsor will retain the original copy of the signed informed consent form, and a copy will be 
provided to the subject, or to the subject’s authorized representative. 
 
The investigator-sponsor will make certain that appropriate processes and procedures are in place 
to ensure that ongoing questions and concerns of enrolled subjects are adequately addressed and 
that the subjects are informed of any new information that may affect their decision to continue 
participation in the clinical study. In the event of substantial changes to the clinical study or the 
risk-to-benefit ratio of study participation, the investigator-sponsor will obtain the informed 
consent of enrolled subjects for continued participation in the clinical study 
 
15.2 
COMPLIANCE WITH LAWS AND REGULATIONS 
The study will be conducted in accordance with U.S. 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 IRB or Ethics Committee requirements. 
This study must have the approval of a properly constituted IRB or Ethics Committee.  Before 
the investigational drug is shipped to the Investigator, the 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 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 
249 East Grand Ave 
South San Francisco, CA 94080 
The Investigator is also responsible for notifying their IRB or Ethics Committee of any 
significant AEs that are serious and/or unexpected. 

 
 
 
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Onyx will provide study sites with any expedited safety reports generated from any ongoing 
studies with CFZ, changes to the Investigator’s Brochure, and any other safety information which 
changes the risk/benefit profile of CFZ during the conduct of the study, to allow him/her to fulfill 
his/her obligation for timely reporting to the IRB/Ethics Committee and other Investigators 
participating in the study. 
Upon completion of the trial, the Investigator must provide the IRB or Ethics Committee and 
Onyx with a summary of the trial’s outcome. 
 
15.3 
SUBJECT CONFIDENTIALITY 
Subject medical information obtained as part of this study is confidential, and must not be 
disclosed to third parties, except as noted below.  The subject may request in writing that medical 
information be given to his/her personal physician. 
The Investigator/Institution will permit direct access to source data and documents by 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. 

 
 
 
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16 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
 
16.1 
PROTOCOL AMENDMENTS AND STUDY TERMINATION 
The sponsor-investigator will obtain, from the CUMC IRB, prospective approval of the clinical 
protocol and corresponding informed consent form(s); modifications to the clinical protocol and 
corresponding informed consent forms, and advertisements (i.e., directed at potential research 
subjects) for study recruitment, if applicable. 
 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s). In such circumstances, the 
sponsor-investigator will promptly notify the CUMC IRB of the deviation. 
The CUMC IRB operates in compliance with FDA regulations at 21 CFR Parts 50 and 21 CFR 
56, and in conformance with applicable ICH Guidelines on GCP. 
 
In the event that the CUMC IRB requires, as a condition of approval, substantial changes to a 
clinical protocol submitted under an FDA-accepted IND application, or in the event of an 
sponsor-investigator’s decision to modify the previously accepted clinical protocol, the sponsor-
investigator will submit (i.e., in advance of implementing the change) a Protocol Amendment to 
the IND describing any change that significantly affects the safety of subjects, the scope of the 
investigation, or the scientific quality of the study. Examples of protocol changes requiring the 
submission of a Protocol Amendment include: 
 Any increase in drug dosage or duration of exposure of individual subjects to the 
investigational drug beyond that described in the current protocol, or any significant 
increase in the number of subjects under study. 
 Any significant change in the design of the protocol (such as the addition or deletion of a 
control group). 
 The addition of a new test or procedure that is intended to improve monitoring for, or 
reduce the risk of, a side effect or AE; or the dropping of a test intended to monitor the 
safety of the investigational drug. 
 
16.2 
ETHICAL AND SCIENTIFIC CONDUCT OF THE CLINICAL STUDY 
The clinical study will be conducted in accordance with the current IRB-approved clinical 
protocol; ICH Guidelines on Guidelines on GCP; and relevant policies, requirements, and 
regulations of the CUMC IRB and applicable federal agencies. 
 
16.3 
STUDY DOCUMENTATION AND ARCHIVE 
16.3.1 Data Recording/Case Report Forms 
Case Report Forms will be completed for each subject enrolled into the clinical study.  It is the 
investigator/sponsor’s responsibility for ensuring that all clinical and laboratory data entered on 
the CRFs are complete, accurate and authentic. 
 
 
16.3.2 Record Maintenance and Retention 
The sponsor-investigator will maintain records in accordance with GCP guidelines; to include: 

 
 
 
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 FDA correspondence related to the IND and clinical protocol, including copies of 
submitted Safety Reports and Annual Reports 
 IRB correspondence (including approval notifications) related to the clinical protocol; 
including copies of AE reports and annual or interim reports 
 Current and past versions of the IRB-approved clinical protocol and corresponding IRB-
approved consent form(s) and, if applicable, subject recruitment advertisements 
 Signed FDA Form 1572 Statements of Investigator (i.e., for the sponsor-investigator and 
all identified sub-investigators) 
 Financial disclosure information (sponsor-investigator and clinical protocol sub-
investigators) 
 Curriculum vitae (sponsor-investigator and clinical protocol sub-investigators) 
 Certificates of required training (e.g. human subject protections, GCP, etc.) for sponsor-
investigator and listed sub-investigators 
 Listing of printed names/signatures of sponsor-investigator and listed sub-investigators 
 Normal value(s)/range(s) for medical/laboratory/technical procedures or tests included in 
the clinical protocol 
 Laboratory certification information 
 Instructions for on-site preparation and handling of the investigational drug(s), study 
treatment(s), and other study-related materials (i.e., if not addressed in the clinical 
protocol) 
 Signed informed consent forms 
 Completed CRFs; signed and dated by sponsor-investigator 
 Source Documents or certified copies of Source Documents 
 Monitoring visit reports 
 Copies of sponsor-investigator correspondence to sub-investigators, including 
notifications of safety information 
 Subject screening and enrollment logs 
 Subject identification code list 
 Investigational drug accountability record, including documentation of drug disposal. 
 Final clinical study report 
 
Subject identity on study records will be indicated by a case number rather than by name, and the 
information linking the case numbers with the subject’s identity will be kept separate from the 
research records. All records related to this research study will be stored in a locked file cabinet. 
 
The sponsor-investigator will retain the specified records and reports for up to 2 years. 
16.4 
DATA SAFETY AND MONITORING COMMITTEE 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every subject who receives treatment on 
this protocol for toxicity. This protocol and all CUMC investigator-initiated protocols will 
adhere to the policies of the HICCC Data and Safety Monitoring Plan (DSMP) dated July 31, 
2013, which is in accordance with NCI and CUMC-IRB policy and guidelines.  The committee 
is led by Dr. J. Gregory Mears and consists of HICCC faculty and staff with expertise in 
oncology, research pharmacy, research nursing, and data management. The DSMC convenes 
twice a month to review patient safety and conduct. The PI will submit data and safety 

 
 
 
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monitoring reports to the DSMC at a frequency to be determined based on risk to the subjects. 
 
At the time of renewal, the study team will submit the most recent DSMC approval letter for 
safety review to the CUMC IRB. Any modifications that are required by the DSMC to ensure 
patient safety will be submitted to the IRB. All protocol deviations, violations, and eligibility 
waivers will be submitted to and approved by the DSMC prior to being reported to the IRB 
and all other designated regulatory agencies as required. All study data reviewed and discussed 
during these meetings will be kept confidential. Any breaches in research subject 
confidentiality will be immediately reported to the IRB. 
16.5 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by the CPDM Compliance Core on behalf of the HICCC DSMC.  Additionally, the 
Compliance Oversight Committee of the IRB at Columbia University Medical Center may audit 
the study at any time per institutional policies and procedures. 
 
The investigator-sponsor and Columbia University Medical Center will permit direct access of 
the study monitors and appropriate regulatory authorities to the study data and to the 
corresponding source data and documents to verify the accuracy of this data. 
 
1. A risk-based approach will be used by the Compliance Core to determine the 
frequency, number of subject charts, and data elements to be monitored. The 
Compliance Coordinator will review the study status and summarize enrollment, 
toxicities, SAEs/UPs, dose escalation, statistical endpoints (e.g., stopping rules), etc. 
for the full DSMC membership at the regularly scheduled meetings.  The Compliance 
Coordinator will also monitor for applicable regulatory compliance and research 
pharmacy compliance (if applicable) and communicate any deficiencies as 
appropriate. 

Title: Phase I/II study of carfilzomib in combination with bendamustine and dexamethasone in 
patients with newly diagnosed multiple myeloma 
 
 
 
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17 
REFERENCES 
 
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Siegel DSd, Martin T, Wang M, Vij R, Jakubowiak AJ, Jagannath S, et al. Results of PX-
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Sonneveld P, Hacker E, Zweegman S, Kersten MJ, Vellenga E, van Marwijk-Kooy M, et al. 
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Kolb B, Hulin C, Caillot D, Benboubker L, Tiab M, Blin L, et al. Phase I/II study of 
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Berdeja JG, Savona MR, Essell J, Murphy P, Chu L, Boccia RV, et al. Bendamustine, 
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Knop S SC, Haen M,. The efficacy and toxicity of bendamustine in recurrent multiple 
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Title: Phase I/II study of carfilzomib in combination with bendamustine and dexamethasone in 
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10. 
Ponisch W, Mitrou PS, Merkle K, Herold M, Assmann M, Wilhelm G, et al. Treatment of 
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Lentzsch S, O’Sullivan A, Kennedy R, Gill N, Andreas C, Gardner D, et al. Combination of 
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Dubbelman AC, Rosing H, Darwish M, D'Andrea D, Bond M, Hellriegel E, et al. 
Pharmacokinetics and Excretion of (14)C-Bendamustine in Patients with Relapsed or 
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Fenk R, Michael M, Zohren F, Graef T, Czibere A, Bruns I, et al. Escalation therapy with 
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Papadopoulos K, Siegel DS, Singhal SB, Infante JR, Sausville EA, Gordon MS, et al. Phase 
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Blood (ASH Annual Meeting Abstracts) 2010; 116: Abstract 3024. 
 
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Badros AZ, Vij R, Martin T, Zonder JA, Woo T, Wang Z, et al. Phase I Study of Carfilzomib 
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Berenson JR, Yellin O, Bessudo A, Boccia R, Gravenor DS, Noga SJ, et al. An Open-Label 
Phase 1/2 Trial of Bendamustine Combined with Bortezomib for Patients with 
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Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood 2011 May 5; 117(18): 4691-
4695. 
 

Title: Phase I/II study of carfilzomib in combination with bendamustine and dexamethasone in 
patients with newly diagnosed multiple myeloma 
 
 
 
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19. 
Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, et al. Criteria for 
evaluating disease response and progression in patients with multiple myeloma treated by 
high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the 
EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998 Sep; 
102(5): 1115-1123. 
20.       Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al.    
            International Myeloma Working Group Updated Criteria for the diagnosis of Multiple   
            Myeloma. Lancet Oncol. 2014 Nov;15(12):e538-48. 
 
 
 
 
 
 
 
 
 
 

Title: Phase I/II study of carfilzomib in combination with bendamustine and dexamethasone in 
patients with newly diagnosed multiple myeloma 
 
 
 
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APPENDIX A.  STAGING OF MYELOMA: DURIE-SALMON SYSTEM AND 
INTERNATIONAL STAGING SYSTEM 
 
The staging system most widely used since 1975 has been the Durie-Salmon system, in which 
clinical stage of disease (stage I, II, or III) is based on four measurements: levels of M protein, the 
number of lytic bone lesions, hemoglobin values, and serum calcium levels. Stages are further 
divided according to renal function. There is somewhat of an overlap between the various myeloma 
categories and stages. For example, both patients with smoldering myeloma and patients with Stage I 
disease do not require immediate treatment, and patients with Stage II and III disease have active, 
symptomatic myeloma. Increasingly, physicians are relying less on the Durie-Salmon staging system 
and more on biologically relevant markers as prognostic indicators when making treatment choices. 
 
A new, simpler, more cost-effective alternative is the International Staging System (ISS). The ISS is 
based on the assessment of two blood test results, beta 2-microglobulin (ß2-M) and albumin, which 
together showed the greatest prognostic power for MM. This system has only recently been 
developed, but has already been proven more sensitive in discriminating between three stages of the 
disease, which indicate different levels of projected survival and suggest increasingly more 
aggressive treatment strategies. The following table summarizes the staging criteria. 
 
Stage 
Durie-Salmon Criteria 
ISS Criteria 
I 
All of the following: 
 Hemoglobin value >10 g/dL 
 Serum calcium value normal or =12 mg/dL 
 Bone x-ray, normal bone structure (scale 0) or 
solitary bone plasmacytoma only 
 Low M-component production rate - IgG value <5 
g/dL; IgA value <3 g/dL 
 Bence Jones protein <4 g/24 h 
β2-M < 3.5 mg/dL and 
albumin ≥3.5 g/dL 
II 
Neither stage I nor stage III 
β2-M < 3.5 mg/dL and 
albumin < 3.5 g/dL; or β2-
M ≥ 3.5 and < 5.5 
III 
One or more of the following: 
 Hemoglobin value <8.5 g/dL 
 Serum calcium value >12 mg/dL 
 Advanced lytic bone lesions (scale 3) 
 High M-component production rate - IgG value >7 
g/dL; IgA value >5 g/dL - Bence Jones protein >12 
g/24 h 
β2-M ≥ 5.5 mg/dL 
Durie-Salmon sub classifications (either A or B) 
A: Relatively normal renal function (serum creatinine value <2.0 mg/dL 
B: Abnormal renal function (serum creatinine value =2.0 mg/dL 
 
 

Title: Phase I/II study of carfilzomib in combination with bendamustine and dexamethasone in 
patients with newly diagnosed multiple myeloma 
 
 
 
Page 69 of 71 
Investigator-sponsored Protocol 26FEB2018 
 
APPENDIX B. INTERNATIONAL MYELOMA WORKING GROUP DIAGNOSTIC 
CRITERIA 
 
The International Myeloma Working Group developed new diagnostic criteria in 2003 for MM 
emphasizing clinical characteristics of PD associated with active myeloma known as “CRAB” 
features. The intent is to distinguish between active myeloma and smoldering (asymptomatic) 
myeloma that does not typically require systemic therapy. 
 
Smoldering (Asymptomatic) Myeloma 
Serum M-protein 3.0 g/L 
AND/OR 
Bone marrow plasma cells 10% 
No related organ tissue impairment (ROTI) 
Symptomatic MM 
M-protein in serum and/or urine 
Bone marrow clonal plasma cells or plasmacytoma 
ROTI 
C Calcium elevation in blood (>11.5 g/dL) 
R Renal insufficiency (serum creatinine 
>2mg/dL) 
A Anemia (Hgb <10 g/dL or 2g<normal) 
B Lytic bone lesions or osteoporosis 
OR  
Any one or more of the following diagnostic 
criteria 
According to new International Myeloma working 
group (20) 
1. Clonal bone marrow plasma cell percentage 
≥60% 
2. Involved/uninvolved serum free light chain ratio 
≥100 
3. >1 focal lesions on MRI studies 
 
 
 
 
 
 
 
 
 

Title: Phase I/II study of carfilzomib in combination with bendamustine and dexamethasone in 
patients with newly diagnosed multiple myeloma 
 
 
 
Page 70 of 71 
Investigator-sponsored Protocol 26FEB2018 
 
APPENDIX C:  NCI-CTCAE VERSION 4.0 
 
Common Terminology Criteria for Adverse Events (CTCAE) of the  
National Cancer Institute v4.0 
 
Publish Date:  September 15, 2009 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_5x7.pdf 
 
 
 
 

Title: Phase I/II study of carfilzomib in combination with bendamustine and dexamethasone in 
patients with newly diagnosed multiple myeloma 
 
 
 
Page 71 of 71 
Investigator-sponsored Protocol 26FEB2018 
 
APPENDIX D:  PERFORMANCE STATUS CRITERIA 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead.