Conditions: Multiple Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 76
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out what effects carfilzomib has on relapsed multiple myeloma when administered in combination with cyclophosphamide and dexamethasone.

Detailed description:
Multiple Myeloma is a cancer that affects the bone marrow where the cells in our blood system are formed. This includes the white cells, red cells, platelets and lymphoid cells. In multiple myeloma the plasma cell (one of the lymphoid cells) starts to reproduce out of control. This results in crowding of the bone marrow with abnormal production of all the cells and a malfunction of the plasma cells. They can also cause damage to the normal bone resulting in pain, fractures and other complications.

The standard or usual treatments for your disease are lenalidomide (an immunomodulatory drug) or bortezomib (a proteasome inhibitor) based treatments.

Carfilzomib is a new type of proteasome inhibitor that is approved for the treatment of relapsed multiple myeloma in the United States.

Arms:
arm 1: 20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28 day cycle plus weekly oral dexamethasone (\< 70 years, 40 mg; ≥ 70 years 20mg) and cyclophosphamide 300 mg/m2 capped at 500 mg

Interventions: intervention 1: Carfilzomib intervention 2: Cyclophosphamide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_000.pdf: 
 
PROTOCOL DATE: 2015-OCT-29 
 
TRIAL: MYX.1 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION 
 
AMENDMENT #1: 2017-JAN-31 
 
 
AMENDMENT #2: 2017-OCT-11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A SINGLE ARM PHASE II STUDY OF HIGH-DOSE WEEKLY CARFILZOMIB PLUS 
CYCLOPHOSPHAMIDE AND DEXAMETHASONE IN THE TREATMENT OF RELAPSED 
MULTIPLE MYELOMA AFTER 1-3 PRIOR THERAPIES 
 
Academic CRO Protocol Number: MYX.1 
Lead Group Protocol Number: MCRN-003 
 
 
 
STUDY CHAIR: 
Christopher Venner 
 
 
TRIAL COMMITTEE: 
Donna Reece 
 
 
Engin Gul 
 
 
SENIOR INVESTIGATOR: 
Annette Hay 
 
 
BIOSTATISTICIAN: 
Bingshu Chen 
 
 
STUDY COORDINATOR: 
Max Sherry 
 
 
REGULATORY SPONSOR: 
Academic Contract Research Organization (CRO) 
 
 
SUPPORTED BY: 
Amgen 
 
 
(For contact information of study personnel see Final Page.) 
 


 
PROTOCOL DATE: 2015-OCT-29 
 
TRIAL: MYX.1 
 
 
CONFIDENTIAL 
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CONFIDENTIAL 
TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) .......................................................................... 1 
TREATMENT SCHEMA ............................................................................................................................. 2 
1.0 
OBJECTIVES .................................................................................................................................. 3 
1.1 
Primary Endpoint ............................................................................................................................. 3 
1.2 
Secondary Endpoints ....................................................................................................................... 3 
2.0 
BACKGROUND INFORMATION AND RATIONALE ............................................................... 4 
2.1 
Multiple Myeloma ........................................................................................................................... 4 
2.2  
Proteasome Inhibitors in Myeloma .................................................................................................. 4 
2.3 
Carfilzomib in Myeloma .................................................................................................................. 5 
2.4  
Rationale for this Study ................................................................................................................... 5 
3.0 
BACKGROUND THERAPEUTIC INFORMATION .................................................................... 6 
3.1 
Carfilzomib ...................................................................................................................................... 6 
3.2 
Cyclophosphamide ........................................................................................................................... 9 
3.3 
Dexamethasone .............................................................................................................................. 12 
4.0 
TRIAL DESIGN ............................................................................................................................ 14 
5.0 
STUDY POPULATION ................................................................................................................ 15 
5.1 
Eligibility Criteria .......................................................................................................................... 15 
5.2 
Ineligibility Criteria ....................................................................................................................... 17 
6.0 
PRE-TREATMENT EVALUATION ............................................................................................ 19 
7.0 
ENTRY/REGISTRATION PROCEDURES ................................................................................. 20 
7.1 
Entry Procedures ............................................................................................................................ 20 
7.2 
Body Surface Area Calculation ..................................................................................................... 20 
7.3 
Registration .................................................................................................................................... 20 
8.0 
TREATMENT PLAN .................................................................................................................... 21 
8.1 
Chemotherapy Treatment Plan ...................................................................................................... 21 
8.2 
Patient Monitoring ......................................................................................................................... 23 
8.3 
Concomitant Therapy..................................................................................................................... 29 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT ....................................... 31 
9.1 
Evaluation During Protocol Treatment .......................................................................................... 31 
9.2 
Evaluation After Protocol Treatment ............................................................................................. 33 
10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ................................................. 34 
10.1 
Definitions ..................................................................................................................................... 34 
10.2 
Response and Evaluation Endpoints .............................................................................................. 34 
10.3 
Survival Endpoints ......................................................................................................................... 37 
10.4 
Methods of Measurement .............................................................................................................. 37 
11.0 
SERIOUS ADVERSE EVENT REPORTING .............................................................................. 38 
11.1 
Definition of a Reportable Serious Adverse Event ........................................................................ 38 
11.2 
Serious Adverse Event Reporting Instructions .............................................................................. 38 
11.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting .................... 39 
11.4 
CRO Responsibility for Reporting Serious Adverse Events to Health Canada ............................. 40 
11.5 
CRO Reporting Responsibility to AMGEN................................................................................... 41 
11.6 
AMGEN Reporting Responsibility ................................................................................................ 41 
11.7 
Reporting Safety Reports to Investigators ..................................................................................... 41 
12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ..... 42 
12.1 
Criteria for Discontinuing Protocol Treatment .............................................................................. 42 
12.2 
Therapy After Protocol Treatment is Stopped ............................................................................... 42 
13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION ....................................... 43 
13.1 
Central Radiology Review ............................................................................................................. 43 
13.2 
Central Pathology Review ............................................................................................................. 43 
14.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 44 


 
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14.1 
Objectives and Design ................................................................................................................... 44 
14.2 
Primary Endpoints and Analysis .................................................................................................... 44 
14.3 
Secondary Endpoints ..................................................................................................................... 44 
14.4 
Exploratory Endpoints ................................................................................................................... 44 
14.5 
Sample Size .................................................................................................................................... 44 
14.6 
Safety Monitoring .......................................................................................................................... 44 
15.0 
PUBLICATION POLICY ............................................................................................................. 46 
15.1 
Authorship of Papers, Meeting Abstracts, Etc. .............................................................................. 46 
15.2 
Submission of Material for Presentation or Publication ................................................................ 46 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES .............................................. 47 
16.1 
Regulatory Considerations ............................................................................................................. 47 
16.2 
Inclusivity in Research ................................................................................................................... 47 
16.3 
Obtaining Informed Consent .......................................................................................................... 48 
16.4 
Discontinuation of the Trial ........................................................................................................... 49 
16.5 
Retention of Patient Records and Study Files ................................................................................ 49 
16.6 
Centre Performance Monitoring .................................................................................................... 49 
16.7 
On-Site Monitoring/Auditing ......................................................................................................... 49 
16.8 
Case Report Forms ......................................................................................................................... 50 
17.0 
REFERENCES .............................................................................................................................. 51 
APPENDIX I - PATIENT EVALUATION FLOW SHEET ...................................................................... 53 
APPENDIX II - PERFORMANCE STATUS SCALES/SCORES ............................................................ 55 
APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL .................................................. 56 
APPENDIX IV - DOCUMENTATION FOR STUDY .............................................................................. 57 
APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ................. 59 
LIST OF CONTACTS ................................................................................................................................ 60 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 


 
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CONFIDENTIAL 
 
AMEND #1: 2017-JAN-31 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol contains information that is confidential and proprietary to Amgen.  
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, and according to Good Clinical Practice and any 
applicable local regulations. I will make a reasonable effort to complete the study within the time 
designated. I confirm that I and study personnel participating under my supervision have adequate resource 
to fulfill their responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by the academic contract 
research organization (CRO)* that is sponsoring the trial and Amgen to study personnel under my 
supervision. I will discuss this material with them to ensure that they are fully informed about the 
investigational product and the study.  
 
I understand that this trial will be registered on a public trial registry and that my contact information and 
site name will be included in the registry listing. 
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of Amgen and CRO. The foregoing shall not apply to disclosure 
required by governmental regulations or laws; however, I will give prompt notice to Amgen and CRO of 
any such disclosure. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CRO. The study may 
be terminated at any time by CRO or Amgen with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
Amgen and CRO and must be kept in confidence in the same manner as the contents of this protocol. 
 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
Protocol Number: MYX.1 
 
CENTRE: ___________________________________________ 
 
* Canadian Cancer Trials Group (CCTG) acting as the academic contract research organization. 


 
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TREATMENT SCHEMA 
 
Relapsed Multiple Myeloma Diagnosed and Patient Consented 
 
Screening labs performed 
 
REGISTRATION 
 
Begin weekly carfilzomib + cyclophosphamide + dexamethasone (wCCD) * 
 
Assess response at end of Cycle 4 
 
Continue wCCD cycles 5-12 
 
Discontinue Cyclophosphamide after 12 cycles of wCCD complete and continue weekly carfilzomib and 
dexamethasone until death, relapse or intolerance 
 
* there will be a 6 patient lead in phase where safety at 70 mg/m2 will be evaluated in real time 
 


 
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1.0 
OBJECTIVES 
 
This is a single arm phase II, investigator initiated, multicentre trial run through the Myeloma 
Canada Research Network. 
 
1.1 
Primary Endpoint 
 
To determine the overall response rate after 4 cycles of weekly high-dose carfilzomib, 
cyclophosphamide and dexamethasone in patients with relapsed multiple myeloma after 1-3 prior 
regimens. 
 
1.2 
Secondary Endpoints 
 
1.2.1 
To determine the safety and toxicity profile of the combination. 
 
1.2.2 
To determine the depth of response including rates of stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR) and partial response (PR) by current 
International Myeloma Working Group (IMWG) criteria. 
 
1.2.3 
To determine progression-free survival (PFS). 
 
1.2.4 
To determine the 2-year overall survival. 
 


 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
2.1 
Multiple Myeloma 
 
Multiple myeloma (MM) is an incurable lymphoproliferative disorder arising from clonal 
expansion of malignant plasma cells. It affects approximately 2000 Canadians annually [NCI Cancer 
Statistics 2013]. The clinical phenotype is characterized by the development of hypercalcemia, lytic 
bone disease, renal dysfunction (often due to light chain cast nephropathy, a product of the secreted 
clonal protein) and marrow suppression often resulting in anemia as well as other cytopenias. 
Treatment of the disease is focused on controlling the underlying clonal population to prevent 
further end-organ damage. Recent advances in management since the introduction of novel agents 
(NA) [Kumar 2008; Venner 2011] have resulted in long-term disease control measured in years. This is 
largely attributed to the increasing availability of effective treatment options at the time of relapse. 
Despite this the disease ultimately relapses. Moreover, due to inevitable clonal evolution and 
resistance to currently available therapies, the benefit of treatment diminishes with each subsequent 
line of therapy [Kumar 2004]. Double refractory patients have expected overall survival (OS) of less 
than 13 months [Kumar 2012a]. Thus, of particular importance is the development of regimens 
addressing patients previously exposed to NA such as proteasome inhibitors and 
immunomodulating agents; drugs now widely seen as standards in the therapy of this disease.  
 
2.2  
Proteasome Inhibitors in Myeloma 
 
Bortezomib, the first in class proteasome inhibitor, is now widely used in the treatment of this 
disease. A number of bortezomib containing combinations have been explored in the treatment of 
patients with relapsed disease. Three drug combinations have become the standard, combining the 
proteasome inhibitor with dexamethasone and either an immunomodulation agent or an alkylator 
[Reeder 2014; Richardson 2010; San Miguel 2008; Stewart 2015]. Due to its ease of use and effectiveness 
Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) has been widely adopted as a 
standard of care largely based on a small phase II trial [Reeder 2014]. This recent update from the 
initial publication in upfront patients demonstrated remarkable progression free survival (PFS) and 
OS. The dataset further described the impressive response rates showing the overall response for 
all patients (N=63) to be 89% with 62% achieving a very good partial response (VGPR) or better. 
Based on the recently published EVOLUTION trial this combination was also shown to be 
equivalent to lenalidomide, bortezomib, and dexamethasone (RVD), a potent regimen in both the 
upfront and relapsed setting, at substantially lower cost [Kumar 2012b]. Overall, this data supports 
the concept of a proteasome inhibitor in combination with the classic alkylator-steroid backbone as 
a potent standard treatment approach in the treatment on myeloma. In the relapsed setting triplet-
based combinations remain an important therapeutic option. CyborD has formally been evaluated 
by the Mayo Clinic in a series of 55 patients with progressive disease. The mean number of previous 
treatment lines was 3.3 and 36% and 82% were proteasome inhibitor and CyborD naïve 
respectively. The overall response rate (ORR) was 71% with 26% achieving greater than VGPR 
and 13% a complete response (CR). In the proteasome naïve patients the overall response rate was 
95% while in previously exposed patients it was 57% [Monge 2014]. In Canada, weekly dosing has 
become standard practice for the first-in-class proteasome inhibitor bortezomib, due to the 
documented preserved efficacy and the improved patient tolerability and convenience. Also, the 
combination of novel agents with oral weekly cyclophosphamide has been commonly utilized in 
Canada. The proposed study is designed to optimize the efficacy, tolerability, patient convenience 
and cost of a regimen based on carfilzomib, oral cyclophosphamide and dexamethasone by 
administering all agents on a weekly basis. 


 
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2.3 
Carfilzomib in Myeloma 
 
Given the potency of first-generation proteasome inhibitors the development of regimens including 
newer drugs in this class is being pursued with great interest. Carfilzomib has been examined as 
single agent and in combination with significant activity noted even in heavily pre-treated patients 
including those previously exposed to both proteasome inhibitors and immunomodulators. A triplet 
based regimen was explored in the ASPIRE trial which compared carfilzomib, lenalidomide, and 
dexamethasone versus lenalidomide and dexamethasone in relapsed patients after 1-3 prior 
regimens. The primary endpoint of the trial was progression free survival from the time of treatment 
initiation to disease progression or death. Patients were randomized to receive Carfilzomib 
20 mg/m2 on days 1 and 2 of cycle 1 only, then 27 mg/m2 on days 1,2, 8,9 and 15,16 of a 28-day 
cycle. A total of 792 patients were randomly assigned. Recently presented data demonstrates PFS 
was 26.3 months for the Carfilzomib arm versus 17.6 months with lenalidomide/dexamethasone 
alone [Stewart 2015].  
 
While this result is encouraging recent evidence suggests that the optimal dose and schedule of 
carfilzomib has not yet been defined and higher doses could prove to be more effective in myeloma. 
Higher doses, given weekly along with dexamethasone, have been reported to be well tolerated and 
also effective. In a phase II trial using a dose of 56 mg/m2 administered as a 30 minute infusion in 
relapsed and or refractory myeloma patients, 55% achieved a partial response or better [Lendvai 
2014]. This compares favourably to a previous phase I result of 23% partial response (PR) or better 
using 20 mg/m2 in cycle I followed by 27 mg/m2 as a 10 minute infusion twice weekly for 3 or 4 
weeks [Papadopoulos 2011]. The slower infusion likely results in better tolerability allowing for higher 
dosing. 
 
The dosage and scheduling of Carfilzomib was further explored in the CHAMPION study [Berenson 
2013]. Patients with relapsed or refractory MM who had received 1-3 prior regimens were treated 
with Carfilzomib as a 30 minute IV infusion on days 1, 8, and 15 of each 28-day cycle in 
combination with weekly Dexamethasone. Patients received 20 mg/m2 on day 1 of cycle 1 and in 
this dose escalation study the maximally tolerated dose was 70 mg/m2. The higher dose Carfilzomib 
had an overall response rate of 67%. Additional experience with the weekly dosing strategy has 
been explored in the recently reported Italian trial showing similar results [Palumbo 2014].  
 
2.4  
Rationale for this Study 
 
Based on the previously described potency and tolerability of a triplet-based therapy incorporating 
a proteasome inhibitor with a steroid-alkylator backbone and increased effectiveness of carfilzomib 
at higher doses we are proposing a study combining high dose weekly Carfilzomib with weekly 
Dexamethasone and a low dose of weekly Cyclophosphamide (CCD). We hypothesize that this 
combination would offer a potent yet convenient treatment option to patients with relapsed 
myeloma and would compare favourably with current trials examining the use of Carfilzomib in 
this disease. Indeed, precedent for this combination does exist. A recent open-label phase II study 
has demonstrated ORR of 95% and 2-year PFS and OS of 76% and 80% respectively [Bringhen 2014] 
albeit with the twice weekly dosing strategy. Carfilzomib has also been successfully paired with 
melphalan showing similar results [Moreau 2013]. Importantly, this regimen would be cost-effective; 
important given that the combination of carfilzomib, lenalidomide, and dexamethasone examined 
in the ASPIRE trial may be cost prohibitive, limiting widespread use in most of Europe and Canada. 


 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
3.1 
Carfilzomib 
 
3.1.1 
Name and Chemical Information 
 
Carfilzomib is a synthetic small molecule peptide bearing the chemical name (2S)-N-((S)-1-((S)-
4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-
morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. 
 
3.1.2. Chemical Structure 
 
The molecular formula is C40H57N5O7 and the molecular weight is 719.91. 
 
 
 
3.1.3 
Mechanism of Action 
 
Carfilzomib specifically functions as an inhibitor of the CT-L activity of the 20S proteasome which 
leads to the accumulation of protein substrates within the cell and induction of apoptosis. 
 
3.1.4 
Experimental Antitumour Activity 
 
Carfilzomib (formerly known as PR-171) is a tetrapeptide epoxyketone-based inhibitor of the 20S 
proteasome, primarily of the CT-L activity, and at higher concentrations, of multiple 20S 
proteolytic activities. Carfilzomib, which is structurally and mechanistically different from the 
dipeptide boronic acid proteasome inhibitor bortezomib, showed less off-target activity when 
measured against a broad panel of proteases including metallo-, aspartyl-, and serine proteases 
compared to bortezomib; the latter showed off-target inhibitory activity in the nanomolar range 
against several serine proteases [Arastu-Kapur 2011]. This selectivity may be responsible for the 
reductions in myelosuppression and neuropathy observed in non-clinical studies comparing 
carfilzomib with bortezomib. 
 
Carfilzomib primarily inhibits the CT-L activity of both the constitutive proteasome and the 
immunoproteasome [Demo 2007; Kuhn 2007]. The importance for co-inhibition of multiple proteasome 
active sites for cytotoxicity (CT-L, trypsin-like, and/or caspase-like) has been demonstrated against 
multiple myeloma cell lines [Britton 2009; Geurink 2013]. Nonclinical work supported improved 
tolerability with increased infusion time, possibly because of the reduced maximum concentration 
(Cmax) with a 30-minute IV infusion [Yang 2011]. Correlative clinical pharmacodynamics studies 
have confirmed that longer infusion times and higher doses of carfilzomib resulted in increased 
proteasome inhibition [Lee 2012; Papadopoulos 2015]. Clinical evidence for carfilzomib dose response 
has been observed in a multivariable modeling analysis comparing 20 mg/m2 with 27 mg/m2 
[Squifflet 2011], suggesting that more effective inhibition of proteasome activity may improve 
efficacy. An increased infusion time of 30 minutes enabled carfilzomib to be administered at a 
higher dose with a maximum tolerated dose (MTD) of 56 mg/m2 in Study PX-171-007 compared 
to a 27 mg/m2 over a 2 to 10 minute infusion. 


 
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3.1.5 
Phase I Trials of Higher Doses of Carfilzomib 
 
CHAMPION 1, a phase Ib/II study in subjects with relapsed multiple myeloma who had received 
1 to 3 prior therapies was initiated to investigate higher doses of carfilzomib given once-weekly in 
combination with dexamethasone, and results indicate that these modifications were well tolerated 
and active. In the phase Ib dose-escalation portion of the study all subjects received 20 mg/m2 
carfilzomib on cycle 1 day 1 and then received the cohort-assigned test dose on cycle 1 days 8 and 
15. The initial dose level evaluated was 45 mg/m2 with escalation to 56 mg/m2, 70 mg/m2, and 88 
mg/m2 in successive cohorts. Subjects received 40 mg dexamethasone on days 1, 8, 15, and 22 of 
cycles 1 through 8 and on days 1, 8, and 15 from cycle 9 onward. 
 
No dose limiting toxicities (DLTs) were observed during dose escalation at the dose levels of 
45 mg/m2, 56 mg/m2, or 70 mg/m2. At the carfilzomib dose level of 88 mg/m2, 2 DLTs were 
observed during cycle 1: 
 
Dyspnea (grade 3, days 9 to 11) 
 
Vomiting (grade 3, day 15) 
 
Per protocol, an expansion cohort of 9 additional subjects was enrolled at the 70 mg/m2 dose. There 
was 1 DLT in the 70 mg/m2 expansion cohort: Grade 3 dyspnea (days 16 to 18). The MTD of 
once-weekly carfilzomib in combination with dexamethasone was determined to be 70 mg/m2. 
 
A total of 27 subjects were enrolled in the phase I portion of the study with a median of 1 prior 
therapy. Fifteen subjects received study treatment at a dose of 70 mg/m2. The majority of the 
27 subjects (85%) received prior bortezomib and 63% of those were refractory to bortezomib. The 
ORR in the phase I population was 81% with a clinical benefit rate (CBR) of 93%. The once-
weekly treatment regimen of 70 mg/m2 showed promising activity with an ORR of 93% (95% CI: 
68.1 to 99.8%), 4 subjects achieved a complete response (CR) and the CBR was 100% (95% [CI]: 
78.2 to 100%). The median treatment duration was 8.3 months in this cohort [Berenson 2014]. Five 
serious adverse events (SAEs) were reported in the phase I part of this ongoing study: 
 
One subject at 45 mg/m2 had 2 SAEs; increased blood creatinine (grade 3) and hyponatremia 
(grade 4). 
 
One subject at 70 mg/m2 had pneumonia (grade 3). 
 
One subject at 88 mg/m2 had dyspnea (grade 3). 
 
One subject at 70 mg/m2 had chronic obstructive pulmonary disease (grade 3). 
 
All SAEs were determined to be unrelated to carfilzomib and dexamethasone except for the grade 
3 dyspnea event, a DLT in a subject receiving the 88 mg/m2 dose. 
 


 
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3.1.6 
Phase II trials of Higher Doses of Weekly Carfilzomib 
 
In the ongoing phase II portion of CHAMPION 1, 82 subjects have been enrolled at the MTD as 
of the 3 September 2014 data cutoff. The median age of subjects was 68 years with 29% of subjects 
≥ 75 years. Subjects received a median of 1 prior regimen and 40% of subjects received 2 to 3 prior 
regimens. All subjects had an Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) of 0 or 1. Most subjects (82%) had prior exposure to bortezomib; 44% were refractory to 
bortezomib. Over half (55%) received prior therapy with lenalidomide. Almost one-quarter of 
subjects had a prior transplant (27%). Subjects in the ongoing phase II expansion have received a 
median of 2.9 months (0.03 to 9.3) of treatment. Preliminary efficacy data from the Phase 2 portion 
of the study in subjects (n= 70) who were enrolled prior to 31 July 2014 demonstrate an ORR of 
63%. 
 
The most common all-grade non-hematologic AEs included fatigue (33%), nausea (22%), insomnia 
(21%), headache (20%), diarrhea (13%), dyspnea (13%), musculoskeletal chest pain (11%), and 
upper respiratory tract infection (11%). 
 
Grade 3 AEs reported in > 1 subject were; acute renal failure (5%), fatigue (5%), anemia (4%), 
thrombocytopenia (2%), neutropenia (2%), back pain (2%), musculoskeletal chest pain (2%), 
diarrhea (2%), hypoxia (2%), and atrial fibrillation (2%). A total of 34 treatment-emergent SAEs 
were reported in 19 subjects (23%). Six grade 4 SAEs were reported in 2 subjects 
(thrombocytopenia, atrial fibrillation, influenza pneumonia, respiratory failure, and septic shock 
[all occurred in 1 subject], and aphasia [1 subject]). Three grade 5 SAEs were reported in 3 subjects 
(acute renal failure, cardio-respiratory arrest, and disease progression). Four subjects (5%) 
discontinued treatment due to an AE and 6 subjects (7%) had a carfilzomib dose reduction due to 
an AE. 
 
The preliminary results from CHAMPION 1 demonstrated that once-weekly carfilzomib at 
70 mg/m2 administered as a 30-minute infusion in combination with dexamethasone in subjects 
with relapsed and refractory multiple myeloma had an acceptable safety and tolerability profile and 
promising efficacy. Ninety subjects are planned for the phase II portion of the study. 
 
3.1.7 
Pharmacokinetic Studies of High Dose Weekly Carfilzomib 
 
Pharmacokinetics (PK) and pharmacodynamics (PDn) results from CHAMPION 1 are supportive 
of the proposal to study the once-weekly 70 mg/m2 regimen as an effective alternative regimen for 
carfilzomib. 
 
Preliminary PK results from CHAMPION 1 indicated that a once-weekly 30-minute infusion of 
carfilzomib had a mean terminal half-life similar to the half-life of ≤ 1 hour following the approved 
twice-weekly dosing regimen (20/27 mg/m2 over 2 to 10 minutes). In addition, the data showed a 
dose-proportional increase in the mean Cmax and area under the curve (AUC) from 20 to 88 mg/m2, 
as indicated by the similar dose normalized values for Cmax and AUC. The AUC following a 
70 mg/m2 dose was 1045 ng●h/mL, which is higher than the total weekly AUC following the twice-
weekly of 27 mg/m2 dose (758 ng●h/mL). The mean Cmax following the 70 mg/m2 dose 
administered as a 30-minute infusion is 2640 ng/mL, which is lower than the mean Cmax of 4232 
ng/mL in Study PX-71-003 – Part 2 (A1) following the IV infusion of 27 mg/m2 over 2 to 10 
minutes. 


 
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3.1.8 
Pharmaceutical Data 
 
Supplied:  
Carfilzomib for injection is supplied as a lyophilized parenteral product in single-use vials 
packaged in multi-vial cartons. Institutional pharmacies will be supplied with open stock vials with 
full disclosure labels. Additional details are provided in the pharmacy manual. 
 
Stability: 
Once carfilzomib is reconstituted and inspected, the clear solution may be stored in a refrigerator 
(recommended) controlled temperature from 2°C to 8°C (36°F–46°F) for up to 24 hours. Once 
reconstituted, carfilzomib must be used within 4 hours if not refrigerated and within 24 hours if it 
has been stored in a light-tight refrigerator (refer to Table 1 below). 
 
Table 1: Storage Conditions of Reconstituted Carfilzomib 
 
 
Stability in hours per container 
Vial 
Syringe 
IV Bag (D5W) 
Refrigerated (2°C to 8°C; 36°F to 46°F) 
24 
24 
24 
Room temperature (15°C to 30°C; 59°F to 86°F) 
4 
4 
4 
 
Storage: 
Study treatments should be stored in a securely locked area with access limited to appropriate study 
personnel. Carfilzomib must be stored at 2°C to 8°C (36°F−46°F) in a refrigerator. Carfilzomib 
vials must be kept in cartons in order to protect from light until ready for reconstitution. 
 
Solution Preparation:  
Carfilzomib for Injection will be provided as a lyophilized powder which, when reconstituted, 
contains a 2 mg/mL isotonic solution of carfilzomib free base in 10 mM sodium citrate buffer (pH 
3.5) containing 10% (w/v) sulfobutylether-beta-cyclodextrin(SBE-CD, Captisol). 
 
Route of Administration: 
Intravenous 
 
3.2 
Cyclophosphamide 
 
For further information on cyclophosphamide please refer to the approved package insert. 
 
Other Names:  
Cytoxan, Procytox. 
 
Classification:  
Alkylating agent. 
 


 
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Mechanism of Action:  
Cyclophosphamide is a nitrogen mustard of the oxazophosphorine group. It is an alkylating agent, 
which exerts its cytotoxic effect via 3 mechanisms: 1) attachment of alkyl groups to DNA bases, 
resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated 
bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage 
via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from 
being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides 
leading to mutations. 
 
Metabolism:  
Cyclophosphamide is absorbed from the gastrointestinal tract, or can be given parenterally. It is 
biologically relatively inactive, and is activated by hepatic cytochrome p-450 to 
4-hydroperoxycyclophosphamide. This compound is in steady state with the acyclic tautomer, 
aldophosphamide; the drug and its metabolites are distributed throughout the body, including the 
brain. Cyclophosphamide is eliminated very slowly. The metabolites alkylate the target sites in 
cells in an “all-or-none” fashion, or are depleted by the formation of inactive metabolites that are 
rapidly excreted via the kidneys. The rate of metabolism of cyclophosphamide is variable among 
different individuals. The average half-life of unchanged drug is between 5 and 6.5 hours after an 
intravenous dose. The peak plasma concentrations of metabolites are proportional to the dose given, 
with peak levels achieved generally 2-3 hours after the drug is given. 
 
Route of Administration:  
Oral. 
 
Availability:  
Commercially available in 50 mg tablets. 
 
Drug interactions: 
The rate of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased 
by chronic administration of high doses of phenobarbital. Cyclophosphamide also markedly 
inhibits cholinesterase activity, and potentiates the effect of succinylcholine chloride. If a patient 
has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist 
should be alerted. 
 
Other Considerations (adrenalectomy):  
Since cyclophosphamide has been reported to be more toxic in adrenalectomized dogs, adjustment 
of the doses of both replacement steroids and cyclophosphamide may be necessary in such a patient. 
 
Side-effects 
 
Gastrointestinal:  
Nausea, vomiting, anorexia, less frequently, abdominal discomfort or pain and diarrhea may occur. 
There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring 
during therapy. 
 
Dermatologic:  
Alopecia is common; the hair usually grows back after treatment with the drug or even during 
continued drug treatment, though it may be different in texture or color. Skin rash occurs 
occasionally. Pigmentation of the skin and changes in nails can occur.  


 
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Hematologic:  
Leukopenia is related to the dose of drug, and can be used as a dosage guide. Leukopenia of less 
than 2000 cells/mm3 is common when an initial loading dose of the drug is utilized, and less 
frequent in patients maintained on smaller doses. The degree of neutropenia correlates with a 
reduction in resistance to infections. Fever without documented infection has been reported in 
neutropenic patients. Thrombocytopenia or anemia develops occasionally in patients treated with 
cyclophosphamide. These hematologic effects usually can be reversed by reducing the drug dose 
or by interrupting treatment. Recovery from leukopenia usually begins in 7 to 10 days after 
cessation of therapy. 
 
Urinary:  
Hemorrhagic cystitis, rarely, can be severe or even fatal. Fibrosis of the urinary bladder may 
develop with or without accompanying cystitis. Atypical urinary bladder epithelial cells may appear 
in the urine. Bladder injury is attributed to cyclophosphamide metabolites excreted in the urine. 
Forced fluid intake helps to achieve ample urine output, promoted frequent voiding, and reduces 
the time the exposure of the bladder to the drug and its metabolites to help prevent cystitis. 
Significant hemorrhagic cystitis typically necessitates discontinuation of cyclophosphamide. 
Rarely, hemorrhagic ureteritis and renal tubular necrosis have been reported in patients treated with 
cyclophosphamide.  
 
Genital:  
Cyclophosphamide can cause fetal harm when administered to a pregnant woman. Its interference 
with oogenesis and spermatogenesis may result in sterility, potentially irreversible, in males and 
females. 
 
Cardiac:  
Several instances of cardiac dysfunction have been described following the recommended doses of 
cyclophosphamide; however, no causal relationship has been established. Acute cardiac toxicity 
has been reported with doses as low as 2.4 g/m2 to as high as 26 g/m2, most often when given as 
part of an intensive anti-cancer multi-drug regimen or in conjunction with transplantation 
procedures. In a few instances, severe, and sometimes fatal, congestive heart failure has occurred 
after the initial dose of high doses of cyclophosphamide. Histopathologic examination has mainly 
demonstrated hemorrhagic myocarditis. Hemopericardium has occurred secondary to hemorrhagic 
myocarditis and myocardial necrosis. Pericarditis has been reported independent of any 
hemopericardium. No residual cardiac abnormalities, as evidenced by electrocardiogram or 
echocardiogram appear to be present in patients surviving episodes of apparent cardiac toxicity 
associated with high doses of cyclophosphamide. Cyclophosphamide has been reported to 
potentiate doxorubicin-induced cardiotoxicity. 
 
Respiratory:  
Interstitial pneumonitis has been reported; interstitial pulmonary fibrosis has also been described 
with prolonged cyclophosphamide use. 
 
Second Malignancies:  
Second malignancies have developed in some patients treated with cyclophosphamide used alone 
or in association with other antineoplastic drugs and/or modalities. Most frequently, they have been 
urinary bladder, myeloproliferative, or lymphoproliferative malignancies. Second malignancies 
most often were diagnosed in patients treated for primary myeloproliferative or lymphoproliferative 
malignancies or nonmalignant disease in which immune processes are believed to be involved 
pathologically. 


 
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Other:  
Anaphylactic reactions, including fatal reactions, have been reported; possible cross-sensitivity 
with other alkylating agents has been described; SIADH (syndrome of inappropriate ADH 
secretion); appearance of serious infections including Herpes zoster, Varicella zoster, fungal 
infections, Pneumocystis carinii, tuberculosis; muscle wasting; delayed wound healing. 
 
3.3 
Dexamethasone 
 
For further information on dexamethasone please refer to the approved package insert. 
 
Other Names:  
Decadron, Hexadrol, Dexameth, Dexone, DXM, others. 
 
Classification:  
Adrenal corticosteroid. 
 
Mechanism of Action:  
Dexamethasone is a potent synthetic glucocorticoid that affects almost every body system. It has 
anti-inflammatory, immunosuppressant, antineoplastic, and antiemetic properties and very little 
mineralocorticoid activity. As an antineoplastic agent, dexamethasone may bind to specific proteins 
(receptors) within the cell forming a steroid-receptor complex. Binding of the receptor-steroid 
complex with nuclear chromatin alters mRNA and protein synthesis within the cell. 
 
Storage and Stability:  
The drug is stored at room temperature in a dry place.  
 
Route of Administration:  
Oral. 
 
Availability:  
Commercially available in 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 6 mg tablets. 
 
Side Effects: 
 
Gastrointestinal:  
Nausea, vomiting, anorexia, increased appetite, weight gain; aggravation of peptic ulcers. 
 
Dermatologic:  
Rash, skin atrophy, facial hair growth, acne, facial erythema, ecchymoses. 
 
Genitourinary:  
Menstrual changes (amenorrhea, menstrual irregularities). 
 
Neurologic:  
Insomnia, euphoria, headache, vertigo, psychosis, depression, seizures, and muscle weakness. 
 
Cardiovascular:  
Fluid retention and edema, hypertension; rarely, thrombophlebitis. 
 
Ocular:  
Cataracts, increased intraocular pressure, exophthalmos. 


 
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Metabolic:  
Hyperglycemia, decreased glucose tolerance, aggravation or precipitation of diabetes mellitus, 
adrenal suppression (with Cushingoid features), hypokalemia. 
 
Hematologic:  
Leukocytosis. 
 
Other:  
Osteoporosis (and resulting back pain), appearance of serious infections including Herpes zoster, 
Varicella zoster, fungal infections, Pneumocystis carinii, tuberculosis; muscle wasting; delayed 
wound healing; suppression of reactions to skin tests 
 
Nursing / Patient Implications: 
 
When administered orally, give with food or milk. 
 
Observe for signs of hyperglycemia. 
 
Observe for subtle signs of infection (fever, pain). 
 


 
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4.0 
TRIAL DESIGN 
 
This study is an investigator initiated trial run through the Myeloma Canada Research Network 
with financial support from Amgen. It is a non-randomized, 76 patient multicenter single arm phase 
II study of carfilzomib (20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent 
doses) given on days 1, 8, and 15 of a 28 day cycle plus weekly oral dexamethasone 40 mg and 
cyclophosphamide 300 mg/m2 capped at 500 mg. This study will be restricted to patients who have 
had at least one, but not more than three, prior lines of therapy. Treatment duration will be until 
progression or intolerance, except for cyclophosphamide which will be discontinued after a 
maximum of 1 year. 
 
The study will begin with a 6 patient lead-in phase where safety at 70 mg/m2 will be evaluated in 
real time. If no safety concerns are identified, the tested dose will be expanded to add an additional 
63 patients. If safety concerns are observed in more than 1 out of 6 patients, then the carfilzomib 
dose will be administered at 56 mg/m2 (20 mg/m2 on day 1 then escalated to 56 mg/m2 for day 8 
and 15) during the first cycle in the expansion cohort and then escalated to 70 mg/m2 starting with 
cycle 2 provided that there are no related grade 2 or higher non-hematologic or grade 3 or higher 
hematologic toxicities during the first cycle. Non-evaluable patients (up to 7) will be replaced for 
a total planned accrual of approximately 76 patients. 
 
Safety Concerns are defined as: 
 
Inability to begin cycle 2 because of drug-related toxicity; 
 
Grade 2 or higher neuropathy with pain; 
 
Any drug related grade 3 or higher non-hematologic adverse event (excluding nausea, 
vomiting, diarrhea, dexamethasone-induced hyperglycemia);  
 
Any toxicity requiring dose reduction within cycle 1; 
 
Grade 4 neutropenia (ANC < 0.5 × 109/L) lasting longer than 7 days despite intervention; 
 
Febrile neutropenia (ANC < 1.0 × 109/L with fever ≥ 38°C); 
 
Grade 4 thrombocytopenia (platelets < 25 × 109/L) longer than 7 days and requiring platelet 
transfusion; 
 
Grade 3 thrombocytopenia associated with bleeding. 


 
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5.0 
STUDY POPULATION 
 
Enrolled patients must meet standard diagnostic criteria for multiple myeloma and they must have 
relapsed disease according to the International Myeloma Working group criteria [Palumbo 2009]. 
Prior autologous stem cell transplant is allowed but not required. This study will be restricted to 
patients who have had at least one, but not more than three, prior lines of therapy. Previous 
treatment with bortezomib is permitted, but refractory patients (relapsed within 60 days of last 
bortezomib dose) will be excluded. 
 
This study is designed to include women and minorities as appropriate, but is not designed to 
measure differences in intervention effects. 
 
5.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of registration. Questions 
about eligibility criteria should be addressed prior to calling for registration. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy. For the safety of the patients, as well as to ensure that the results of this study can be 
useful for making treatment decisions regarding other patients with similar diseases, it is important 
that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfill all of the following criteria to be eligible for admission to the study: 
 
5.1.1 
Disease Related 
 
5.1.1.1 Relapsed symptomatic multiple myeloma as per the International Myeloma Working group criteria 
[Palumbo 2009]. 
 
5.1.1.2 Measurable disease, as defined by one or more of the following (assessed within 21 days prior to 
registration): 
 
Serum M-protein ≥ 5 g/L (0.5g/dL) 
 
Urine Bence-Jones protein ≥ 200 mg/24 hours 
 
Involved serum free light chain (FLC) measurement ≥ 100 mg/L (10 mg/dL), provided serum 
FLC ratio is abnormal (abnormal if FLC ratio is <0.26 or >1.65) 
 
Biopsy proven plasmacytoma 
 
For IgA patients whose disease can only be reliably measured by serum quantitative 
immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL) 
 
5.1.1.3 Prior treatment with at least one, but no more than three, regimens for multiple myeloma. 
 
5.1.1.4 Documented relapse or progressive disease on or after any regimen (subjects refractory to the most 
recent line of therapy are eligible except those who are refractory to bortezomib as described in 
exclusion criteria 1). 
 
5.1.1.5 Achieved a response to at least one prior regimen (defined as ≥ 25% decrease in M-protein). 


 
PROTOCOL DATE: 2015-OCT-29 
 
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AMEND #1: 2017-JAN-31 
5.1.2 
Demographic 
 
5.1.2.1 Age ≥ 18 years. 
 
5.1.2.2 Life expectancy ≥ 3 months. 
 
5.1.2.3 ECOG performance status 0–2. 
 
5.1.3 
Laboratory Requirements (must be done within 21 days of registration):  
 
Hematology: 
 
Absolute neutrophil count (ANC) ≥ 1.0 × 109/L 
 
Hemoglobin ≥ 8 g/dL (80 g/L) (subjects may be receiving red blood cell (RBC) transfusions in 
accordance with institutional guidelines) 
 
Platelet count ≥ 50 × 109/L, independent of platelet transfusion for 7 days (≥ 30 × 109/L if 
myeloma involvement in the bone marrow is ≥ 50%) 
 
Biochemistry: 
 
ALT ≤ 3.5 x UNL 
 
Serum direct bilirubin ≤ 2 mg/dL (34 μmol/L) (only required if total bilirubin ≥ 2 mg/dL 
(34 μmol/L)) 
 
Creatinine clearance (CrCl) ≥ 30 mL/minute (Crockcroft and Gault formula) and not on dialysis 
 
5.1.4 
Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrollment in the trial to document 
their willingness to participate.  
 
5.1.5 
Patients must be accessible for treatment and follow-up. Patients registered on this trial must be 
treated and followed at the participating centre. This implies there must be reasonable geographical 
limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial. 
(Call the CRO office at 613-533-6430 if questions arise regarding the interpretation of this 
criterion.) Investigators must assure themselves the patients registered on this trial will be available 
for complete documentation of the treatment, response assessment, adverse events, and follow-up. 
 
5.1.6 
In accordance with CRO policy, protocol treatment is to begin within 2 working days of patient 
registration. 
 
5.1.7 
Women/men of childbearing potential must have agreed to use a highly effective contraceptive 
method as detailed in Section 8.2.8.  


 
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AMEND #1: 2017-JAN-31; AMEND #2: 2017-OCT-11 
5.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
5.2.1 
Disease-Related 
 
5.2.1.1  Refractory to any proteasome inhibitor therapy (bortezomib, ixazomib, etc.)  
 
Refractory disease is defined as failure to respond to the proteasome inhibitor, initial response 
followed by progression while on a proteasome inhibitor, or relapse within 60 days of stopping 
proteasome inhibitor therapy 
 
5.2.1.2 Prior carfilzomib treatment. 
 
5.2.1.3 POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin 
changes) 
 
5.2.1.4 Waldenström’s macroglobulinemia or IgM myeloma 
 
5.2.1.5 Current or previous plasma cell leukemia(defined as > 2.0 × 109/L circulating plasma cells by 
standard differential) 
 
5.2.2 
Concurrent Treatments 
 
5.2.2.1 Chemotherapy or investigational agent within 3 weeks prior to registration or antibody therapy 
within 6 weeks prior to registration 
 
5.2.2.2 Radiotherapy to multiple sites within 28 days prior to registration; localized radiotherapy to a single 
site within 7 days prior to registration 
 
5.2.2.3 Plasmapheresisis within 14 days of registration.  
 
5.2.3 
Concurrent Conditions 
 
5.2.3.1 Pregnant or lactating females. 
 
5.2.3.2 Major surgery within 21 days prior to registration. 
 
5.2.3.3 Active, uncontrolled bacterial, fungal, or viral infection 
 
5.2.3.4 Known human immunodeficiency virus infection. 
 
5.2.3.5 Active hepatitis B or C infection. 
 
5.2.3.6 Myocardial infarction within 4 months prior to registration, 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. 
 
5.2.3.7 Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to registration. 
 
 


 
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AMEND #2: 2017-OCT-11 
5.2.3.8 Concurrent amyloidosis. 
 
5.2.3.9 Other malignancy, including MDS, within the past 3 years with the exception of adequately treated 
basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix 
or breast; prostate cancer of Gleason Score 6 or less with stable prostate-specific antigen levels; or 
cancer considered cured by surgical resection or unlikely to impact survival during the duration of 
the study, such as localized transitional cell carcinoma of the bladder or benign tumours of the 
adrenal or pancreas. 
 
5.2.3.10 Significant neuropathy (≥ grade 3, or grade 2 with pain) within 14 days prior to registration. 
 
5.2.3.11 Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib). 
 
5.2.3.12 Contraindication to any of the required concomitant drugs or supportive treatments, including 
hypersensitivity antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac 
impairment. 
 
5.2.3.13 Ongoing graft-versus-host disease. 
 
5.2.3.14 Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 
days prior to registration. 
 
5.2.3.15 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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AMEND #1: 2017-JAN-31 
6.0 
PRE-TREATMENT EVALUATION 
(See Table 2 and Appendix I) 
 
Table 2: Pre-Treatment Evaluation 
 
Investigations 
Timing 
History and 
Physical Exam 
including: 
History, including: 
• diagnosis of myeloma  
• prior therapy, concurrent illness / medications  
• review of symptoms 
• demographics 
Physical Exam, including:  
• height and weight, BSA, performance status  
• vital signs 
• complete exam including neurological and plasmacytoma 
assessment (if appropriate) 
Within 21 days prior to 
registration 
Hematology 
• CBC and differential 
Biochemistry 
Full serum chemistry panel:  
• BUN 
• creatinine 
• glucose (random) 
• uric acid 
• bicarbonate 
• calcium 
• chloride 
• phosphorus 
• potassium 
• sodium 
• LDH 
• albumin 
• total protein 
• magnesium 
• total bilirubin 
• serum direct bilirubin* 
• alkaline phosphatase 
• ALT and AST 
Radiology 
• Skeletal survey (including skull, all long bones, pelvis and chest) 
Within 30 days prior to 
registration 
• Extra-medullary plasmacytomas should be assessed by either 
PET/CT scan, CT or MRI, whichever is most appropriate for the 
location of the lesion** 
Other 
Investigations 
• Serum Pregnancy test (For women of childbearing potential only) Within 72 hours prior to 
registration 
• Cytogenetic assessment of marrow plasma cells by FISH for 
t(4;14), t(14;16), del P53 to be done as per local standard*** 
Within 8 weeks prior to 
registration 
• Urinalysis including macroscopic examination (specific gravity, 
protein, pH, glucose, ketones, blood, leukocyte esterase and 
nitrite) 
• Urinalysis with microscopic examination (RBCs, WBCs, 
epithelial cells, casts, crystals, bacteria, and yeast) 
• 24-hour urine protein with urine protein electrophoresis (UPEP)♦ 
and urine immunofixation electrophoresis (UIFE) 
• Serum protein electrophoresis (SPEP) with immunofixation to 
confirm monoclonal protein sub-type 
• Serum free light chain (sFLC) 
• Serum β2-microglobulin 
• Quantitative immunoglobulins 
• 12-lead ECG with QTC interval 
Within 21 days of registration 
• Bone Marrow aspiration and biopsy for baseline assessment of 
plasma cell burden.  
Within 8 weeks prior to 
registration 
Adverse Event 
Baseline adverse event evaluation (to document residual adverse 
event from previous therapy and baseline symptoms) 
Within 21 days of registration 
* 
Only required if total bilirubin ≥ 2 mg/dL (34 μmol/L) 
** Only required if plasmacytomas are being followed 
*** Patients can be enrolled prior to cytogenetics results.  
♦ 
24 hour assessment, no substitute method is acceptable 
 
 


 
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AMEND #1: 2017-JAN-31 
7.0 
ENTRY/REGISTRATION PROCEDURES 
 
7.1 
Entry Procedures 
 
All registration will be done through the CRO web-based, password-operated Electronic Data 
Capture (EDC) system. Complete details regarding obtaining a password, accessing the system and 
registering/randomizing patients will be provided at the time of study activation and will also be 
included in the “EDC Data Management Guidebook”, posted on the MYX.1 trial specific web-site. 
If sites experience difficulties accessing the system and/or registering/randomizing patients please 
contact the help desk (link in EDC) or the MYX.1 Study Coordinator. 
 
All eligible patients enrolled on the study by the participating treatment centre will be assigned a 
serial number which must be used on all documentation and correspondence with CRO. 
 
The following information will be required: 
 
trial code (MYX.1) 
 
investigator user ID 
 
patient's initials (may be coded)  
 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
 
confirmation of the requirements listed in Section 5.0, including dates of essential tests and 
actual laboratory values 
 
body surface area (BSA), height and weight  
 
7.2 
Body Surface Area Calculation 
 
In calculating surface areas, actual heights and weights should be used, that is, there will be no 
downward adjustment to "ideal" weight. This principle applies to individuals whose calculated 
surface area is 2.2 m2 or less. Subjects with a BSA > 2.2 m2 will receive a dose based upon a 2.2 m2 
BSA. BSA calculations are based on the DuBois formula:  
BSA (m2) = (W(kg) 0.425 x H (m) 0.725) x 0.007184. 
 
7.3 
Registration 
 
Registration will be provided electronically. 
 
Note: The validity of results of the trial depends on the authenticity of and the followup of all patients 
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the participant withdraws from the trial and requests that 
data collection/submission cease from the point in time of withdrawal. 
 
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting registration. 
 
All randomized patients are to be followed until death or until sites are informed by CRO that 
further follow-up is no longer required. The follow-up requirements for ineligible patients who 
have received no protocol therapy include submission of the baseline Report. Data submission for 
ineligible participants who have received at least one dose of protocol therapy should be followed 
according to the protocol to allow for treatment and adverse event assessment. 
 
 


 
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AMEND #1: 2017-JAN-31; AMEND #2: 2017-OCT-11 
8.0 
TREATMENT PLAN 
 
Although the CRO acts as the coordinating agency for the trial, the responsibility for treatment of 
patients rests with the individual investigator. 
 
In accordance with CRO policy, protocol treatment is to begin within 2 working days of patient 
registration. 
 
8.1 
Chemotherapy Treatment Plan 
 
8.1.1 
Drug Administration 
 
Table 3. Treatment Schedule 
 
Agent(s) 
Dose 
Route 
Duration 
Schedule 
Carfilzomib 
20 mg/m2 (cycle 1, day 1 only) 
IV 
30 mins 
D1, D8, D15  
of each cycle* 
70 mg/m2 (all subsequent doses) 
Cyclophosphamide 
300 mg/m2** 
PO 
-- 
D1, D8, D15, D22  
of each cycle 
Dexamethasone 
Age < 70 years, 40 mg 
Age ≥ 70 years, 20 mg 
PO 
-- 
D1, D8, D15, D22  
of each cycle 
*  1 cycle = 28 days 
**  Capped at 500 mg, see 8.1.1.2 for further details 
 
Carfilzomib, cyclophosphamide and dexamethasone will be administered in 28-day cycles. All 
cycles will start 28 days (± 2) after the start of the prior cycle. Once-weekly carfilzomib must never 
be administered within the 5 days following a previous carfilzomib infusion. 
 
The reason for all cycle delays, missed doses, and dose interruptions will be reported. 
 
8.1.1.1 Carfilzomib will be administered as an IV infusion over approximately 30 minutes. Carfilzomib 
for Injection is supplied as a lyophilized parenteral product in single-use vials. The lyophilized 
product is reconstituted with Sterile Water for Injection (SWI), United States Pharmacopeia (USP), 
to a final carfilzomib concentration of 2.0 mg/mL prior to administration. The dose can be 
calculated using the subject’s actual body surface area (BSA) at baseline; however, dosing 
adjustments for subsequent actual BSA determinations are allowed per institutional guidelines. 
Subjects with a BSA > 2.2 m2 will receive a dose based upon a 2.2 m2 BSA. Dose adjustments must 
be made for weight gains/losses of ≥ 10% of baseline body weight. 
 
Mechanical infusion pumps are recommended but gravity-dependent infusions are permitted if the 
30-minute infusion duration can be reliably maintained. Carfilzomib infusion must occur at a 
facility capable of managing hypersensitivity reactions. Subjects will remain at the investigational 
site under observation for at least 1 hour following each infusion of carfilzomib in cycle 1. 
Carfilzomib should be administered via a dedicated IV line. If an existing IV line or permanent 
infusion device (e.g. porta-cath) is used for carfilzomib administration, the line must be flushed 
with a minimum of 20 mL of normal saline or 5% Dextrose Injection (D5W), prior to and following 
carfilzomib infusion. 


 
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AMEND #1: 2017-JAN-31; AMEND #2: 2017-OCT-11 
8.1.1.2 Cyclophosphamide tablets will be given orally at a dose of 300 mg/m2 on the days 1, 8, 15 and 22 
each cycle. The dose be rounded off to the closest 50 mg and will be capped at 500 mg total per 
week. It is recommended the dose be administered any time prior to carfilzomib administration on 
corresponding days. After 1 year (12 cycles) of therapy the cyclophosphamide will be discontinued.  
 
8.1.1.3 Dexamethasone will be taken orally. It is recommended dexamethasone be administered at least 30 
minutes (but no more than 4 hours) prior to carfilzomib infusion on days 1, 8 and 15. It will be 
given again on day 22 with cyclophosphamide.  
 
8.1.2  IV Hydration 
 
Subjects will receive IV prehydration prior to each carfilzomib infusion during cycle 1. 
Prehydration will consist of 250 mL normal saline or other appropriate IV fluid. Thereafter, 
carfilzomib prehydration should only be administered if the subject’s condition and/or risk factors 
require hydration. The total amount of prehydration will be reported and the reason for hydration 
after cycle 1 will be reported. 
 
Adequate hydration is required prior to dosing in cycle 1, especially in subjects at high risk of 
tumour lysis syndrome (TLS) or renal toxicity. All subjects should be monitored for evidence of 
volume overload and fluid requirements should be tailored to individual subject needs. The total 
volume of fluids may be adjusted as clinically indicated in subjects with baseline cardiac failure or 
who are at high risk for cardiac failure. 
 
8.1.3 
Premedication 
 
It is strongly encouraged but not required that all patients will be premedicated with ondansetron 
8-16 mg PO once daily on days 1, 8, 15, and 22 at least 30 minutes before chemotherapy 
administration.  
 
8.1.4 
Prophylactic Medications 
 
Required prophylactic medications should be initiated at least 24 hours prior to the first 
administration of carfilzomib. 
 
8.1.4.1 Antiviral Prophylaxis: Acyclovir (or an equivalent antiviral) is a required concomitant medication. 
 
Acyclovir 400 mg PO BID (or equivalent antiviral according to institutional practice), should be 
continued for the duration of study treatment. If valacyclovir is used it should be given at 
500 mg PO daily. Additional prophylaxis is at the investigator’s discretion. 
 
8.1.4.2 Gastrointestinal Prophylaxis: Lansoprazole, 15 mg PO daily, or other oral proton-pump inhibitor 
according to institutional practice to prevent peptic ulcer disease is a required concomitant 
medication throughout the duration of study treatment with dexamethasone. 
 
8.1.5 
Duration of Protocol Treatment  
 
Therapy is delivered weekly until the criteria for removal from protocol treatment have been met 
(see Section 12.0). 


 
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8.2 
Patient Monitoring 
 
Special Warnings and Precautions for Use 
 
Cardiopulmonary Disorders:  
New or worsening cardiac failure (e.g. congestive cardiac heart failure, pulmonary edema, and 
decreased ejection fraction), myocardial ischemia, and myocardial infarction have occurred 
following administration of carfilzomib. Death due to cardiac arrest has occurred within a day of 
carfilzomib administration, and fatal outcomes have been reported with cardiac failure and 
myocardial infarction. 
 
Acute Renal Failure:  
Cases of acute renal failure have been reported in subjects who received carfilzomib. Acute renal 
failure was reported more frequently in subjects with advanced relapsed and refractory multiple 
myeloma who received carfilzomib monotherapy. This risk was increased in subjects with a 
decrease in estimated creatinine clearance, calculated using Cockcroft and Gault equation, prior to 
receiving carfilzomib. 
 
Tumour Lysis Syndrome:  
Cases of tumour lysis syndrome (TLS), including fatal outcome, have been reported in subjects 
who received carfilzomib. Subjects with a high tumour burden should be considered to be at greater 
risk for TLS. Ensure that subjects are well hydrated before administration of carfilzomib in cycle 
1 and in subsequent cycles as needed. Uric acid-lowering drugs should be considered in subjects at 
high risk for TLS. Monitor for evidence of TLS during treatment, including regular measurement 
of serum electrolytes, and manage promptly. Interrupt carfilzomib until TLS is resolved. 
 
Infusion Reactions:  
Infusion reactions, including life-threatening reactions, have been reported in subjects who received 
carfilzomib. Symptoms may include fever, chills, arthralgia, myalgia, facial flushing, facial edema, 
vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These 
reactions can occur immediately following or up to 24 hours after administration of carfilzomib. 
Administer dexamethasone prior to carfilzomib either as premedication or as part of combination 
therapy to reduce the incidence and severity of reactions. 
 
Thrombocytopenia:  
Carfilzomib causes thrombocytopenia with platelet nadirs observed between day 8 and day 15 of 
each 28-day cycle with recovery to baseline platelet count by the start of the next cycle. 
 
Hepatic Toxicity:  
Cases of hepatic failure, including fatal cases, have been reported. Carfilzomib can cause elevations 
of serum transaminases. 
 
Thrombocytopenic Thrombotic Purpura / Hemolytic Uremic Syndrome:  
Cases of thrombocytopenic thrombotic purpura/hemolytic uremic syndrome (TTP/HUS) including 
those with fatal outcome have been reported in subjects who received carfilzomib. Monitor for 
signs and symptoms of TTP/HUS. The safety of reinitiating carfilzomib therapy in subjects 
previously experiencing TTP/HUS is not known. 
 


 
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AMEND #1: 2017-JAN-31 
Posterior Reversible Encephalopathy Syndrome:  
Posterior reversible encephalopathy syndrome (PRES), formerly termed reversible posterior 
leukoencephalopathy syndrome (RPLS), is a rare neurological disorder, which can present with 
seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and 
neurological disturbances, along with hypertension. The diagnosis is confirmed by neuro-
radiological imaging. If diagnosed early and treated, the symptoms of PRES may be reversed. Cases 
of PRES have been reported in subjects receiving carfilzomib. The safety of reinitiating carfilzomib 
therapy in subjects previously experiencing PRES is not known. 
 
Overdose:  
Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia, and lymphopenia have 
been reported following a dose of 200 mg of carfilzomib administered in error. There is no known 
specific antidote for carfilzomib overdose. In the event of an overdose, the subject should be 
monitored. 
 
Geriatric Use:  
Overall, the subject incidence of certain adverse events (including cardiac failure) in clinical trials 
was higher for subjects who were ≥ 75 years of age compared to subjects who were < 75 years of 
age. 
 
8.2.1 
Dose Adjustments 
 
Doses will be reduced for hematologic and other adverse events. Dose adjustments are to be made 
according to the system showing the greatest degree of toxicity. Adverse events will be graded 
using the NCI Common Terminology Criteria for Adverse Events (CTCAE) (see Appendix V). 
 
There will be no re-escalation of dose after reduction for adverse events unless otherwise specified 
in the dose modification tables below.  
 
8.2.2 
The major toxic effects which will limit the dose of carfilzomib are listed in Tables 4 and 6. The 
guidelines which follow outline dose adjustments for several of these toxic effects. If a patient 
experiences several adverse events and there are conflicting recommendations, please use the 
recommended dose adjustment that reduces the dose to the lowest level. 
 
8.2.3 
 Carfilzomib Dose Decrements 
 
Dose 
Carfilzomib Dose Decrements 
First Dose Reduction 
Dose -1 
Second Dose Reduction 
Dose -2 
Third Dose Reduction 
Dose -3 
70 mg/m2 
56 mg/m2 
45 mg/m2 
36 mg/m2 
 
8.2.4 
Hematologic Adverse Events 
 
Toxic effects will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (Appendix V). Guidelines for dose modification of carfilzomib and cyclophosphamide 
in the event of hematologic toxicities are summarized in Table 4. 


 
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AMEND #1: 2017-JAN-31 
Table 4: Dosing Guidelines for Hematologic Toxicity 
 
Hematologic Toxicity 
Recommended Action* 
Carfilzomib 
Cyclophosphamide 
Thrombocytopenia 
 
 
If platelets 10 –30 × 109/L 
without evidence of bleeding** 
Go down by one dose 
decrement*** 
Continue at 50% dose reduction 
If evidence of bleeding or platelets 
< 10 × 109/L 
Withhold dose until platelets 
return to ≥ 10 × 109/L and/or 
bleeding is controlled, then 
reduce by one dose 
decrement** 
Withhold dose until platelets 
return to ≥ 10 × 109/L, then 
resume at 50% dose reduction 
Neutropenia 
 
 
If ANC < 0.5 × 109/L 
Withhold dose until ANC 
returns to ≥ 0.5 × 109/L, then 
resume at same dose 
Withhold dose until ANC 
returns to ≥ 0.5 × 109/L, then 
resume at 50% reduction. 
ANC = absolute neutrophil count;  
* 
The maximum allowed dose interruption is 4 weeks. 
** 
Support with platelet transfusion is allowable to maintain platelets at > 20 x 109/L 
*** See Carfilzomib Dose Decrements table above. 
 
8.2.5 
Non-Hematologic Adverse Events 
 
Toxic effects will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (Appendix V). Guidelines for dose modification in the event of non-hematologic 
toxicities are summarized in Table 5. 
 
Table 5: Carfilzomib Dosing Guidelines for Non-Hematologic Toxicity 
 
Non-Hematologic Toxicity 
Recommended Action* 
Renal Dysfunction 
 
Serum creatinine equal to or 
greater than 2 × baseline, or 
CrCl < 15 mL/min (or CrCl 
decreases to ≤ 50% of baseline), 
or need for dialysis 
• Withhold dose and continue monitoring renal function (serum 
creatinine or creatinine clearance). 
• If attributable to carfilzomib, resume when renal function has 
recovered to within 25% of baseline; start at 1 dose level 
reduction. 
• If not attributable to carfilzomib, dosing may be resumed at the 
discretion of the physician. 
• If tolerated, the reduced dose may be escalated to the previous 
dose at the discretion of the physician. For patients on dialysis 
receiving carfilzomib, the dose is to be administered after the 
dialysis procedure. 
Hepatic Dysfunction 
 
≥ Grade 3 Elevation in LFTs 
(AST, ALT, or total bilirubin)** 
• Withhold dose. Resume at 1 dose decrement when toxicity has 
resolved to baseline*** 
Non-neutropenic infection 
 
Grade 3 Infection 
• Withhold carfilzomib until infection resolves. Resume 
carfilzomib at same dose. 
continued on next page … 


 
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Table 5: Carfilzomib Dosing Guidelines for Non-Hematologic Toxicity continued 
 
Non-Hematologic Toxicity 
Recommended Action* 
Cardiac toxicity 
 
Congestive heart failure 
• Any subject with symptoms of congestive heart failure, whether 
or not drug related, must have the dose held until resolution or 
return to baseline, after which treatment may continue at a 
reduced dose, or the subject may be permanently discontinued.  
• If no resolution after 4 weeks, the subject will be withdrawn 
from all study treatment. 
Left Ventricular Ejection Fraction 
Reduction: For resting LVEF 
< 40% or reduction of LVEF to 
< 55% if the drop is greater than 
20% from baseline 
Withhold until LVEF returns to > 40% or, if held due to a drop to 
< 55%, to within 15% of baseline. Resume at 1 dose decrement.*** 
Other grade 3 or 4 cardiac event 
Withhold carfilzomib until recovery. If recovery within 4 weeks 
may be restarted at one dose level reduction. If no resolution after 
4 weeks, the subject will be withdrawn from all study treatment.  
Micro-Angiopathy 
 
Thrombotic thrombocytopenic 
purpura/hemolytic uremic 
syndrome (TTP/HUS) 
• If suspected TTP/HUS, withhold carfilzomib.  
• Manage symptoms per standard of care including plasma 
exchange as clinically indicated.  
• If the diagnosis of TTP/HUS is excluded, carfilzomib 
administration may resume if clinically appropriate. 
Other 
 
Pulmonary Hypertension 
• Withhold until resolved or returned to baseline. 
• Restart at the dose used prior to the event or reduce dose by 
1 dose level (i.e. 70 mg/m2 to 56 mg/m2 for the once weekly 
schedule), at the discretion of the physician. 
• If tolerated, the reduced dose may be escalated to the previous 
dose at the discretion of the physician. 
Posterior reversible encephalopathy 
syndrome (PRES; with symptoms 
including headaches, altered mental 
status, seizures, visual loss, and 
hypertension) 
• If suspected PRES, withhold carfilzomib.  
• Consider evaluation with neuroradiological imaging for onset 
of visual or neurological symptoms suggestive of PRES.  
• If the diagnosis of PRES is excluded, carfilzomib 
administration may resume if clinically appropriate. 
Any Other Drug-Related 
Non-Hematologic Toxicity  
≥ Grade 3 
• For carfilzomib attribution, withhold dose.  
• Resume at 1 dose decrement when toxicity has resolved to 
grade 2 or less or to baseline grade. 
• If tolerated, the reduced dose may be escalated to the previous 
dose at the discretion of the physician. 
ALT =  alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase;  
CrCl =  creatinine clearance; IB = Investigator’s Brochure;  
LFTs =  liver function tests; LVEF = left ventricular ejection fraction; mL = milliliter(s);  
ULN =  upper limit of normal. 
Note:  
Carfilzomib dose schedule does not need to be adjusted for baseline renal dysfunction. 
* 
The maximum allowed dose interruption is 4 weeks. 
** 
If AST or ALT is ≥ 3 × ULN, report as serious adverse event (SAE), see section 11.1. 
*** 
Dose reduction should be attempted first to manage treatment-emergent toxicities. 


 
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8.2.6 
Dexamethasone 
 
Dose reduction levels of dexamethasone for toxicity management of individual subjects are 
provided in Table 6. 
 
Table 6: Dose Decrements for Dexamethasone 
 
Nominal Dose 
Dexamethasone Dose Decrements 
Dose -1 
Dose -2 
40 mg 
20 mg 
12 mg 
 
Dexamethasone will be permanently discontinued after 2-dose level reductions in the event of 
additional dexamethasone-related toxicities. At the investigator’s discretion, dexamethasone may 
be tapered prior to complete discontinuation according to institutional practice. Guidelines for 
dexamethasone-related toxicities are summarized in Table 7. 
 
Table 7: Treatment Guidelines for Dexamethasone-related Toxicities 
 
continued on next page … 
Symptom 
Findings 
Recommended Action 
Cardiovascular 
Edema > grade 3 
(anasarca or limiting 
function and 
unresponsive to 
therapy) 
• Diuretics as needed, and restart dexamethasone at 1 dose 
decrement; if edema persists despite above measures, decrease 
dose by another dose decrement. 
• Discontinue dexamethasone permanently if symptoms persist 
despite second reduction. 
Gastrointestinal 
Toxicity 
Dyspepsia, gastric or 
duodenal ulcer, or 
gastritis grade 1or 2 
(requiring medical 
management) 
• Continue dexamethasone at same dose and treat with therapeutic 
doses of histamine 2 (H2) blockers, or proton pump inhibitor. 
• Consider adding sucralfate or other antiulcer treatment as 
clinically indicated. 
• If symptoms persist despite above measures, decrease 
dexamethasone dose by 1 dose level. 
Dyspepsia, gastric or 
duodenal ulcer, or 
gastritis ≥ grade 3 
(requiring 
hospitalization or 
surgery) 
• Withhold dexamethasone until symptoms return to baseline.  
• Restart dexamethasone at 1 dose decrement along with 
concurrent therapy with H2 blockers, sucralfate, or omeprazole. 
• If symptoms persist despite above measures, discontinue 
dexamethasone permanently. 
Acute pancreatitis 
• Discontinue dexamethasone permanently. 
General 
Disorders 
Limb edema 
> grade 3(> 30% limb 
discrepancy in 
volume; gross 
deviation from 
normal anatomic 
contour; limiting self-
care activities of daily 
living) 
• Withhold dexamethasone until symptoms return to baseline. 
• Diuretics as needed, and restart dexamethasone at 1 dose 
decrement; if edema persists despite above measures, decrease 
dose by another dose decrement. 
• Discontinue dexamethasone permanently if symptoms persist 
despite second reduction. 
Psychiatric 
Disorders 
Confusion or mood 
alteration ≥ grade 2 
(interfering with 
function ± interfering 
with activities of 
daily living) 
• Withhold dexamethasone until symptoms return to baseline. 
• Restart dexamethasone at 1 dose decrement. 
• If symptoms persist despite above measures, reduce by another 
dose decrement. 


 
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AMEND #1: 2017-JAN-31 
Table 7: Treatment Guidelines for Dexamethasone-related Toxicities continued 
 
 
8.2.7 
Cyclophosphamide 
 
Dose reductions for cyclophosphamide will only be mandated with the development of grade 3 or 4 
non-hematologic toxicity as defined by the NCI Toxicity Grade (see Appendix V). Dose reduction 
levels of cyclophosphamide for non-hematologic toxicity are provided in Table 8. For hematologic 
toxicity guidelines please see Table 4. 
 
Table 8: Cyclophosphamide Dose Adjustments for non-hematologic toxicity 
 
Study Drug 
NCI Toxicity 
Grade 
Toxicity and Action 
Cyclophosphamide 
Grade 3 
• If, within 2 weeks, the toxicity returns to ≤ grade 2, restart the 
drug at 50% of the previous dose level. If the same toxicity 
persists, reduce dose by an additional 50%. If the patient cannot 
tolerate the 75 mg/m2 weekly dose, the patient will be taken off 
the study.  
Grade 4 
• For any toxicity of grade 4 that is deemed likely to be related to 
cyclophosphamide, study drug should be withheld and the local PI 
notified immediately. 
Patients who develop hematuria of any grade must have the study drugs held until the etiology can 
be ascertained. If the hematuria is due to a urinary tract infection and resolves with appropriate 
antibiotic treatment, the study drugs may be restarted at the previous dose levels. If the patient is 
felt to have cyclophosphamide-induced hemorrhagic cystitis, he/she will be taken off study. 
Symptom 
Findings 
Recommended Action 
Musculoskeletal 
Muscle 
weakness≥ grade 2 
(symptomatic and 
interfering with function 
± interfering with 
activities of daily living) 
• Decrease dexamethasone by 1 dose decrement. 
• If weakness persists, decrease dose by another dose 
decrement. 
• Discontinue dexamethasone permanently if symptoms 
persist. 
Metabolism and 
Nutrition 
Disorders 
Hyperglycemia ≥ grade 3 
(fasting glucose > 250 mg 
/dL) 
• Withhold dexamethasone until glucose is ≤ grade 2 
(< 250 mg/dL) and treat with insulin or other 
hypoglycemic agents as needed. 
• If uncontrolled despite above measures, decrease dose 
by 1 dose decrement until ≤ grade 2 (< 250 mg /dL). 
All Other 
Other toxicity ≥ grade 3 
felt related to 
dexamethasone 
• Withhold dexamethasone dose. Resume at 1 dose 
decrement when toxicity has resolved to ≤ grade 2. 
• If toxicity recurs, withhold dexamethasone dose until 
toxicity has resolved to ≤ grade 2 and resume 
dexamethasone dose by another dose decrement. 
• If toxicity recurs despite 2 dose decrements, discontinue 
dexamethasone permanently. 


 
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AMEND #1: 2017-JAN-31; AMEND #2: 2017-OCT-11 
8.2.8 
Pregnancy and Contraception During Dose Interruptions 
 
In women, contraception must continue during study drug dose interruption intervals until 6 months 
after the last administration of cyclophosphamide, and 30 days after the last dose of carfilzomib, 
whichever is longest. A woman is considered to be of "childbearing potential" if she has had menses 
at any time in the preceding 12 consecutive months. If a menstrual period in a Female of 
Childbearing Potential (FCBP) does not occur at the anticipated time, study drug treatment must 
be interrupted, and a serum pregnancy test must be performed locally. Study drug administration 
may resume after documentation of a non-pregnant state. 
 
Contraception for men must also continue during study drug dose interruption intervals until 6 
months after the last administration of cyclophosphamide, and 90 days after the last dose of 
carfilzomib, whichever is longest. Male subjects must agree to refrain from donating sperm during 
treatment with carfilzomib and for at least 90 days after the last dose of carfilzomib.  
 
In addition to routine contraceptive methods, "effective contraception" also includes heterosexual 
celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) 
defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy / 
vasectomized partner. However, if at any point a previously celibate patient chooses to become 
heterosexually active during the time period for use of contraceptive measures outlined in the 
protocol, he/she is responsible for beginning contraceptive measures. 
 
8.2.9 
Duration of Therapy 
 
Patients will continue all components of the regimen until relapse or intolerance for one year. After 
one year of therapy the cyclophosphamide will be discontinued but the patients will continue on 
carfilzomib and dexamethasone maintenance.  
 
8.2.10 Patient Compliance 
 
Standard assessment by study nurse will be done at each visit to assess and record patient 
compliance with both oral and infusional medications.  
 
A patient diary for cyclophosphamide and dexamethasone administration should be provided to 
patients, in order to document compliance with protocol therapy 
 
8.3 
Concomitant Therapy 
 
8.3.1 
Permitted 
 
Other supportive concomitant medications are allowed.  
 
Allopurinol (or other approved uric acid-lowering agent) in subjects at high risk for tumour lysis 
syndrome (TLS) due to high tumour burden may be prescribed at the investigator’s discretion. 
Subjects should be well hydrated to reduce the risk of TLS and decline in renal function. 
 
Mycostatin or oral fluconazole to prevent oral thrush is optional and may be given at the 
investigator’s discretion. 
 
Subjects may receive additional antiemetics and antidiarrheal agents as necessary.  
 
 


 
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AMEND #1: 2017-JAN-31 
Myeloid growth factors may be used if neutropenia occurs in accordance with local practice 
guidelines but should not be given prophylactically.  
 
Subjects may receive RBC transfusions, erythropoietic stimulating agents, or platelet transfusions 
if clinically indicated in accordance with institutional guidelines. 
 
Subjects may receive bisphosphonates.  
 
Palliative radiation for pain management is permitted with the written approval of the study medical 
monitor.  
 
Dexamethasone 40 mg for 4 days or equivalent is permitted prior to Cycle 1 Day 1, but only after 
all screening investigations including bone marrow are completed. 
 
8.3.2 
Not permitted 
 
The clinical investigator should contact the study medical monitor if concomitant use of excluded 
medications or therapies is required, to determine the appropriateness of continued study treatment 
administration. 
 
Concurrent therapy with a marketed or investigational anticancer therapeutic or radiation to large 
marrow reserves for either a palliative or therapeutic intent is prohibited.  
 
Additionally, no alternative or investigational anticancer therapy (other than that received in the 
study) is allowed prior to documentation of PD per protocol-specified disease response criteria. 
Any new anticancer therapies a subject received during the study (from registration to study 
completion or early discontinuation) must be recorded in the designated eCRF.  
 
Corticosteroids for nonmalignant conditions (e.g. asthma, inflammatory bowel disease) equivalent 
to a dexamethasone dose > 4.0 mg/day or prednisone > 20 mg/day are not permitted. Higher steroid 
doses given short term for exacerbations of nonmalignant conditions (e.g. asthma flare) are 
permitted with the approval of the study medical monitor. 
 
Subjects requiring the use of excluded concomitant medications or procedures will be withdrawn 
from study treatment.  
 
Plasmapheresis is not permitted while the subject is receiving study treatment. For subjects 
requiring plasmapheresis while on study treatment every attempt should be made to document 
disease status by IMWG criteria first, and then discontinue study treatment and monitor for survival 
and PFS.  
 
Subjects requiring plasmapheresis must have 2 serum samples (for serum protein electrophoresis 
[SPEP] and immunofixation) and at least one 24-hour urine sample (urine protein electrophoresis 
[UPEP] and immunofixation) obtained prior to the procedure. 


 
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AMEND #1: 2017-JAN-31; AMEND #2: 2017-OCT-11 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT 
 
All patients entered on study must be evaluated according to the schedule outlined in Appendix I 
with documentation submitted according to the schedule in Appendix IV. 
 
The following parameters will be required during and after protocol treatment to establish response 
as well survival endpoints.  
 
9.1 
Evaluation During Protocol Treatment 
 
Patients will be evaluated as per the schedule below (Table 9).  
 
Table 9: Schedule of Evaluation During Protocol Treatment 
 
Investigations 
During Treatment 
History and 
Physical Exam 
including: 
• weight, BSA, performance status  
• review of symptoms 
• complete exam including neurological  
and plasmacytoma assessment*  
(if appropriate). 
Day 1 of each cycle 
Hematology 
• CBC and differential 
Day 1 and 15 of cycles 1a and 2  
then day 1 of each cycle thereafter  
Biochemistry 
Full serum chemistry panel:  
• BUN  
• creatinine 
• glucose (random)** 
• uric acid 
• bicarbonate 
• calcium 
• chloride 
• phosphorus 
• potassium 
• sodium 
• LDH 
• albumin 
• total protein 
• magnesium 
• total bilirubin 
• alkaline phosphatase 
• ALT, AST 
Day 1 of cycles 1a, 2, and 3 
Abbreviated serum chemistry panel I:  
• BUN 
• creatinine 
• glucose (random) ** 
• uric acid 
• bicarbonate 
• calcium 
• chloride 
• phosphorus 
• potassium 
• sodium 
• LDH 
Days 15 of cycles 1 and 2 only 
continued on next page … 


 
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AMEND #1: 2017-JAN-31 
Table 9: Schedule of Evaluation During Protocol Treatment - continued 
 
Investigations 
During Treatment 
Biochemistry 
continued 
Abbreviated serum chemistry panel II:  
• creatinine  
• glucose (random) ** 
• calcium  
• albumin  
• bicarbonate  
• potassium  
• sodium  
• chloride  
• total protein  
• total bilirubin  
• serum direct bilirubin *** 
• alkaline phosphatase  
• ALT, AST 
Day 1 of each cycle starting with 
cycle 4 
Radiology 
To ensure 
comparability, the 
baseline exams/ 
scans and subsequent 
exams/ scans to 
assess response must 
be performed using 
identical techniques. 
• Skeletal survey (including skull, all long 
bones, pelvis and chest) 
As clinically indicated 
• Extra-medullary plasmacytomas should be 
assessed by CT, PET/CT scan or MRI 
Only required to confirm CR or better, 
or to confirm PD. 
Other 
investigations, 
including disease 
assessment 
• SPEP and immunofixation (if required to 
confirm CR) 
• Serum Free Light Chain assay (sFLC) 
• 24-hour urine protein with urine protein 
electrophoresis (UPEP) ♦ and urine 
immunofixation electrophoresis (UIFE) ♦♦ 
• Quantitative immunoglobulins 
• Serum Pregnancy test (for women of 
childbearing potential only) 
Day1 of each cycle ♦♦♦ 
• Bone marrow and aspirate 
Only required to confirm CR and sCR 
Adverse Events 
Adverse events will be recorded and graded 
according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) 
(Appendix V). 
Day1 of each cycle and then at each 
patient encounter within cycle  
Concomitant 
Medications 
• Concomitant medication evaluation  
(to document changes from previous 
therapy and study entry) 
Day1 of each cycle and then at each 
patient encounter within cycle 
α 
Not required at Day 1, Cycle 1 if blood work at screening was completed within 7 days of D1C1. 
*  
Only required to confirm CR or better, or to confirm PD. 
** If elevated perform fasting blood glucose to determine CTCAE grade and dose alterations as per Section 8. 
*** Only required if total bilirubin ≥ 2 mg/dL (34 μmol/L) 
♦ 
24 hour assessment, no substitute method is acceptable. 
♦♦ Only if UPEP ≥ 200 mg/24 hours at baseline. Please note that UPEP and immunofixation is required to be 
completed to confirm VGPR (when serum and urine M-protein are not measurable), CR and sCR even if UPEP 
< 200 mg/24 hours at baseline. See Table 11 of the protocol for more information. 
♦♦♦ Not required at Day 1, Cycle 1 if myeloma assessments at screening were completed within 7 days from D1C1. 


 
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AMEND #1: 2017-JAN-31; AMEND #2: 2017-OCT-11 
9.2 
Evaluation After Protocol Treatment 
 
All patients who have received any protocol therapy will be seen at 4 weeks after completion of 
protocol treatment (end of protocol therapy). Adverse Events deemed related to protocol therapy 
should be assessed at the 4 week post treatment visit. 
 
Patients who discontinue therapy due to toxicity in the absence of progression should be followed 
every 4 weeks until progression, or initiation of non-protocol therapy for the first 3 months after 
end of treatment.  Following 3 months after the end of treatment, patients can be followed every 3 
months. A Follow up Report should be used to capture follow-up information prior to progression.   
 
After relapse, progression or initiation of non-protocol therapy, patients will be followed every 6 
months for overall survival only and for serious, unexpected and related adverse events (as per 
Section 11.1). A Short Follow-up Report should be completed. 
 
Table 10: Schedule of Evaluation After Protocol Treatment for Patients Without Progressive 
Disease 
 
Investigations 
After Treatment 
Radiology 
To ensure comparability, the 
baseline exams/ scans and 
subsequent exams/ scans to 
assess response must be 
performed using identical 
techniques. 
• Skeletal survey (including skull, all long 
bones, pelvis and chest) 
As clinically indicated 
• Extra-medullary plasmacytomas should 
be assessed by CT, PET/CT scan or MRI 
Only required to confirm CR or 
better, or to confirm PD 
Other Investigations 
Including disease 
assessment 
• SPEP and immunofixation (if required to 
confirm CR) 
• Serum Free Light Chain assay (sFLC) 
• 24-hour urine protein with urine protein 
electrophoresis (UPEP)* and urine 
immunofixation electrophoresis 
(UIFE)** 
• Quantitative immunoglobulins 
Every 4 weeks*** 
*  
24 hour assessment, no substitute method is acceptable. 
** Only if UPEP ≥ 200 mg/24 hours at baseline. Please note that UPEP and immunofixation is required to be 
completed to confirm VGPR (when serum and urine M-protein are not measurable), CR and sCR even if UPEP 
< 200 mg/24 hours at baseline. See Table 11 of the protocol for more information. 
*** Patients who discontinue therapy due to toxicity in the absence of progression should be followed every 4 weeks 
until progression, or initiation of non-protocol therapy for the first 3 months after end of treatment.  Following 3 
months after the end of treatment, patients can be followed every 3 months. 
 


 
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AMEND #1: 2017-JAN-31 
10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
10.1 
Definitions 
 
10.1.1 Evaluable for adverse events. All patients will be evaluable for adverse event evaluation from the 
time of their first treatment. 
 
10.1.2 Evaluable for response. All patients who have received at least one cycle of therapy and have their 
disease re-evaluated will be considered evaluable for response (exceptions will be those who 
exhibit objective disease progression prior to the end of cycle 1 who will also be considered 
evaluable). Patients on therapy for at least this period and who meet the other listed criteria will 
have their response classified according to the definitions set out below. 
 
10.2 
Response and Evaluation Endpoints 
 
10.2.1 Response: Response and progression will be evaluated in this study using the International 
Myeloma Working Group Uniform Response Criteria (IMWG-URC) as summarized in Table 11 
below: 
 
Table 11:  Response According to International Myeloma Working Group Uniform Response 
Criteria 
 
 
Response 
Subcategory a 
Multiple Myeloma Response Criteria 
Stringent Complete 
Response b,c 
(sCR) 
• CR as defined below and 
• Negative immunofixation on the serum and urine and 
• Disappearance of any soft tissue plasmacytomas d and 
• < 5% plasma cells in bone marrow biopsy and 
• Normal SFLC ratio and 
• Absence of clonal cells in bone marrow d by immunohistochemistry or 
immunofluorescence. d 
Complete Response 
b,c (CR) 
• Negative immunofixation on the serum and urine and 
• Disappearance of any soft tissue plasmacytomas d and 
• < 5% plasma cells in bone marrow biopsy. 
Very Good Partial 
Response b  
(VGPR) 
• Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 
• ≥90% reduction in serum M-protein with urine M-protein level <100 mg/24 hours 
• If the serum and urine M-protein are not measureable, a ≥90% decrease in the 
difference between the involved and uninvolved FLC levels required in place of the M-
protein criteria. However, documentation of VGPR requires collection and analysis of 
24 hour urine sample for UPEP and immunofixation and confirmation to be negative. 
• If present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is also 
required. 
Partial Response b  
(PR) 
• ≥50% reduction in serum M-protein and reduction in 24-hour urinary M-protein by 
≥90% or to <200 mg/24 hours 
• If the serum and urine M-protein are not measureable, a ≥50% decrease in the 
difference between the involved and uninvolved FLC levels required in place of the M-
protein criteria.  
• If serum and urine M-protein are not measurable, and serum free light assay is also not 
measureable, ≥50% reduction in plasma cells is required in place of M-protein 
provided baseline bone marrow percentage was ≥30% 
• If present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is also 
required. 
continued on next page … 


 
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AMEND #1: 2017-JAN-31; AMEND #2: 2017-OCT-11 
Table 11 continued:  
 
Response 
Subcategory a 
Multiple Myeloma Response Criteria 
Minimal response 
(MR) 
• 25-49% reduction in serum M-protein, and 50-89% reduction in 24-hour urinary 
M-protein, if ≥ 200 mg/24 hours at baseline 
• If the serum and urine M-protein are not measureable, a decrease of 25-49% in the 
difference between the involved and uninvolved FLC levels required in place of 
the M-protein criteria 
• If present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas is 
also required. 
No change 
Stable disease b 
• Not meeting the criteria for CR, VGPR, PR or progressive disease 
Progressive Disease e 
(PD) 
Any one or more of the following: 
• Increase of ≥ 25% from lowest response value in: 
- Serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL (5 g/L)) 
- Urine M-component and/or (the absolute increase must be ≥ 200 mg/24 h) 
- 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 (0.1g/L) f 
- Bone marrow plasma cell percentages(absolute percentage must be ≥ 10%) 
• Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas g,h,i 
• Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL 
(0.115 g/L) or 2.65 mmol/L) that can be attributed solely to the plasma cell 
proliferative disorder. 
Note:  Source: [Durie 2006; Rajkumar 2011] (modified for protocol purposes). 
FLC = serum light chain; 
 
Note: Patients with measurable disease in both serum (SPEP) and urine (UPEP) at study entry are required to meet 
response criteria in both UPEP and SPEP in order to qualify for a MR or better. Conversely, it should be noted criteria 
for PD only needs to be met, and confirmed, in 1 parameter. For patients without measurable protein on UPEP at 
baseline, UPEP will need to be repeated to confirm a response. 
 
For IgA myelomas, quantitative immunoglobulin measurements are preferred for disease assessments; the same 
percentage changes applies as for serum M-protein. 
 
a  Patients with measurable disease in both serum (SPEP) and urine (UPEP) at study entry are required to meet 
response criteria in both UPEP and SPEP in order to qualify for a MR or better. Conversely, it should be noted that 
criteria for PD only needs to be met, and confirmed, in one parameter. 
b All response categories (CR, sCR, VGPR, PR) require 2 consecutive assessments made at any time before the 
institution of any new therapy, as well as no known evidence of progressive or new bone lesions if radiographic 
studies were performed. Radiographic studies are not required to satisfy these response requirements. Bone marrow, 
plasmacytoma, and skeletal survey assessments are not required to be confirmed by repeat testing. SD requires a 
duration of ≥ 6 weeks. 
c   Date of sCR or CR should be the earliest date all applicable blood and urine parameters are met, which is 
subsequently confirmed by bone marrow 
d  Presence/absence of clonal cells is based upon the kappa/lambda  ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An 
abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of > 4:1 or < 1:2. 
e  Determination of PD while on study requires 2 consecutive assessments made at any time before classification 
of PD and/or the institution of new therapy. Serum M-component increases of ≥ 1 g/dL (10 g/L) from nadir are 
sufficient to define progression if nadir M-component is ≥ 5 g/dL (50 g/dL). 
f   Free light chain (sFLC) escape is not part of IWMG response criteria used in this study but please note that we will 
be tracking sFLC escapes separately 
g  Plasmacytomas: A definite increase in the size is defined as a ≥ 50% increase as measured serially by the sum of the 
products of the cross-diameters of the measurable lesion. A plasmacytoma is considered measurable if the longest 
diameter is at least 1 cm and the product of the cross diameters is at least 1 cm2. Plasmacytomas of lesser size will 


 
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be considered non-measurable. 
h  The requirement for bi-directional measurements applies only to plasmacytomas. 
i  The plasmacytoma specifications for PD are based on Amgen’s interpretation of the IMWG-URC and practical 
considerations for study execution. 


 
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10.3 
Survival Endpoints 
 
10.3.1 Progression Free Survival 
 
PFS is the time from start of the study treatment to disease progression, death or last follow-up.  
 
10.3.2 Overall Survival 
 
OS is the time from the start of study treatment to death or last follow-up. 
 
10.4 
Methods of Measurement 
 
10.4.1 Disease response and progression assessments include (but are not limited to): SPEP, UPEP, 
immunofixation, SFLC, bone marrow sample evaluation, serum calcium, plasmacytoma 
evaluation, and skeletal survey. Multiple myeloma assessment should be based on calendar day, 
regardless of cycle delay.  
 
Extramedullary Plasmacytoma Assessment 
 
A plasmacytoma evaluation will be conducted at baseline only if a lesion is suspected 
clinically. Historical assessment for extramedullary plasmacytoma evaluation done as part of 
standard of care may be used as baseline as long as it was performed within 30 days prior to 
cycle 1 day 1 dosing. 
 
Measurable lesions must have a longest diameter of at least 1 cm and the product of cross 
diameter is at least 1 cm2. Plasmacytomas of lesser size are considered unmeasurable. 
Bidimensional lesion measurements must be performed and recorded in the designated eCRF. 
The same technique may include: palpation, ultrasound, x-ray, computed tomography (CT) 
scan, magnetic resonance imaging (MRI), positron emission tomography (PET), or other 
standard-of-care method must be employed for each measurement. 
 
Skeletal Survey 
 
Skeletal survey will include lateral radiograph of the skull, anteroposterior and lateral views of 
the spine, and anteroposterior views of the pelvis, ribs, femora, and humeri.  


 
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11.0 
SERIOUS ADVERSE EVENT REPORTING 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE.A copy 
of the CTCAE can be downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CRO SAE form. The term ‘reportable SAE’ is used in 
the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CRO.  
 
11.1 
Definition of a Reportable Serious Adverse Event 
 
 
All serious adverse events that are unexpected and related to protocol treatment must be 
reported in an expedited manner (see Section 11.2 for reporting instructions). These include 
events occurring during the treatment period (until 30 days after last protocol treatment 
administration) and at any time afterwards. 
 
Unexpected adverse events are those that are not consistent in either nature or severity with 
information contained in the Investigator’s Brochure. 
 
Adverse events considered related to protocol treatment are those for which a relationship to 
the protocol agent cannot reasonably be ruled out. 
 
A serious adverse event (SAE) is any adverse event that at any dose: 
 
results in death 
 
is life-threatening 
 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
 
results in persistent or significant disability or incapacity 
 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above.  
 
In addition, because cases of hepatic failure, including fatal cases, have been reported in patients 
taking carfilzomib, as a precaution, the following will be reported in an expedited manner in this 
study: 
 
ALT or AST ≥ 3 times the institutional upper limit of normal  
 
11.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported using a web-based Electronic Data Capture 
(EDC) system being used for this trial. For details about accessing the EDC system and completing 
the on-line SAE report form, please refer to the CRO Generic Data Management Guidebook for 
EDC Studies posted on the MYX.1 of the CRO website (www.ctg.queensu.ca). 


 
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AMEND #1: 2017-JAN-31 
Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to the 
CRO via EDC system. 
 
Within 10 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to the CRO via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
Max Sherry, MYX.1 Study Coordinator 
Fax No.: 613-533-2941 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to the CRO on the paper 
SAE Report must also be entered by the site into the EDC SAE web application.  
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE Report 
from the trial website, please phone the MYX.1 trial team (613-533-6430) to obtain a copy of the 
SAE Report by FAX. Once completed, the report must be FAXED back to as indicated above. 
Once internet connectivity is restored, the information that was FAXED to the CRO on the paper 
SAE Report must also be entered by the site into the EDC SAE web application.  
 
In cases of prolonged internet interruptions, please contact the CRO Safety Desk for further 
instructions (613-533-6430).  
 
11.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting  
 
11.3.1 Pregnancy Prevention 
 
Women of Childbearing Potential (WOCBP) and males who are enrolled in the trial must have 
agreed to use contraceptive method(s) as described in Eligibility Criterion 5.1.7. Investigators may 
wish to additionally advise the female partners of male participants about pregnancy prevention 
guidelines when appropriate and compliant with local policy.  
 
11.3.2 Pregnancy Reporting 
 
The investigator is required to report to CRO any pregnancy occurring in female participants, and 
female partners of male participants. Pregnancies occurring up to 6 months after the completion of 
cyclophosphamide treatment must be reported, as well as pregnancies that occur up to 30 days after 
completion of carfilzomib for female participants, and 90 days for female partners of male 
participants. 
 
The investigator should report the pregnancy in a timely manner, within 24 hours of learning of the 
pregnancy using the CRO Pregnancy Reporting Form available from the trial webpage. 


 
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Once informed consent has been obtained, the form should be updated to provide further pregnancy 
information and to reflect the outcome of the pregnancy. All follow-up reports must be submitted 
to CRO in a timely manner. For pregnant partner of trial participant (and pregnant participants, if 
required by local policy), a copy of the signed signature page of the pregnancy follow-up consent 
must be submitted to CRO.  
 
Documents outlined above (including updates) must be sent to the CRO safety desk (613-533-2812/ 
safety-desk@ctg.queensu.ca).  
 
If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
11.3.3 Exposure Reporting 
 
The investigator is required to report to CRO any incidence of exposure to study agent(s). Exposure 
is defined as significant, direct, contact/inhalation/consumption of agent(s) by non- study 
participant (an individual who is not otherwise participating in this clinical trial). An example of 
an exposure includes a non-study participant swallowing study medication. In addition, an exposure 
includes an infant consuming breast milk produced by either a participant, or a non-study 
participant who swallowed study medication. The investigator is responsible for determining 
significance, based on the agent to which the individual is exposed.  
 
The investigator should report the exposure in a timely manner, within 24 hours of learning of the 
exposure using the CRO Exposure Reporting Form available from the trial webpage.  
 
Once informed consent has been obtained, the form should be updated to provide further exposure 
information and to reflect the outcome of the exposure as the information becomes available upon 
appropriate follow-up of the exposed individual. All follow-up reports must be submitted to CRO 
in a timely manner. A copy of the signed exposure follow-up consent signature page must also be 
submitted to CRO.  
 
Documents outlined above (including updates) must be sent to the CRO safety desk (613-533-2812/ 
safety-desk@ctg.queensu.ca).  
 
If the exposure results in death; is life-threatening; requires inpatient hospitalization or prolongation 
of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital 
anomaly/birth defect, then an SAE report must be additionally submitted as described above.  
 
11.4 
CRO Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The CRO will provide expedited reports of SAEs to Health Canada (Office of Clinical Trials) for 
those events which meet regulatory requirements for expedited reporting, i.e. events which are 
BOTH serious AND unexpected, AND which are thought to be related to protocol treatment 
(SUSARs) (or for which a causal relationship with protocol treatment cannot be ruled out). 


 
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11.5 
CRO Reporting Responsibility to AMGEN 
 
AMGEN will be notified (using CIOMS) of all regulatory reportable serious adverse events 
(SUSARs) within 24 hours of submitting the report to Health Canada.   
 
Note: “Death, cause unknown” will be processed as a SUSAR. 
 
Pregnancies and lactation exposures reports will be provided to AMGEN within 10 days of 
becoming aware of the event.  AMGEN will be notified (using CIOMS) of SUSARs resulting from 
pregnancy or lactation exposure within 24 hours of submitting the report to Health Canada. 
 
11.6 
AMGEN Reporting Responsibility 
 
Amgen will report safety updates from non-CRO trials (Safety Updates) for carfilzomib to Health 
Canada in accordance with applicable guidelines and regulations. Amgen will provide to CRO 
updated IBs and Unanticipated Problems (safety information) which result in a change to the 
protocol or consent will be sent within 7-15 days.  
 
11.7 
Reporting Safety Reports to Investigators 
 
CRO will notify Investigators of all Safety Reports (Serious Adverse Events (SAEs) from this trial 
and Safety Updates (SUs) from other clinical trials) that are reportable to regulatory authorities in 
Canada as reported to the CRO. This includes all serious events that are unexpected and related 
(i.e. possibly, probably, or definitely) to protocol treatment. The reports will be posted to the 
MYX.1 web-based safety monitoring utility. 
 
Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes. 
The date of REB Submission for these SAEs and SUs will need to be entered into the CRO trial 
MYX.1 web based safety monitoring utility and documentation of REB submission must be 
retained in the study binder on site. The REB submission template provided by CRO can be used 
to assist with tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be filed 
in the trial files on site. 


 
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AMEND #1: 2017-JAN-31; AMEND #2: 2017-OCT-11 
12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
12.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
 
Intercurrent illness that would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
 
Unacceptable toxicity as defined in Section 8.0. 
 
Tumour progression or disease recurrence as defined in Section 10.0. 
 
Request by the patient. 
 
Completion of therapy as outlined in Section 8.0. Efforts should be made to maintain the 
investigations schedule and continue follow-up, even if patients discontinue protocol treatment 
prematurely and/or no longer attend the participating institution. 
 
12.2 
Therapy After Protocol Treatment is Stopped 
(see Section 10.0 for response definition) 
 
For all responding patients (SD or better) therapy will continue as per protocol until 
progression, intolerance or death. 
 
Patients who progress (treatment failure) will go off study at the time progression is 
documented clinically, biochemically and/or radiographically. 
 
Therapy after protocol treatment is stopped is at the discretion of the investigator. 
 
Patients who have received any protocol treatment should be followed for progression free and 
overall survival as per Section 9. 


 
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13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION 
 
13.1 
Central Radiology Review 
 
There will be no central radiology review for this study 
 
13.2 
Central Pathology Review 
 
There will be no central pathology review for this study. 


 
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14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Objectives and Design 
 
This is a phase II single arm study assessing the response rate of CCD regimen after 4 cycles of 
treatment.  
 
14.2 
Primary Endpoints and Analysis 
 
The response rate observed in the historical comparator (CyBorD) in this patient population is 
around 65%, and we expect achieve a 15% increase with the study treatment to attain an 80% ORR 
(PR or better) after 4 cycles. 
 
14.3 
Secondary Endpoints 
 
To determine the safety and toxicity profile of the combination. 
 
To determine the depth of response including rates of sCR, CR, VGPR, PR by current IMWG 
criteria. 
 
To determine progression-free survival. 
 
To determine the 2-year overall survival. 
 
Both the overall survival (OS) and progression free survival (PFS) are secondary but very 
important endpoints of this study. After the final analysis for 4 cycle response rate is performed, 
all patients will continue to be followed for an additional 1 year to have robust data for both OS 
and PFS analyses. Follow up will continue for a maximum of 36 months after the last accrual, or 
until all patients have discontinued protocol therapy, whichever is sooner. 
 
14.4 
Exploratory Endpoints 
 
To perform a descriptive cost analysis of CCD therapy in relapsed and refractory multiple 
myeloma. 
 
A descriptive analysis of costs associated with weekly carfilzomib, cyclophosphamide and 
dexamethasone treatment will be performed, from the perspective of the Canadian health care 
system.  Resource utilization for each patient will be determined from submitted electronic case 
report form data.  Unit costs will be obtained from provincial / national databases and assumed to 
be representative of costs across the country.  A mean treatment cost per cycle will be derived, and 
a range of costs for each patient over the course of their participation in the study calculated.  Costs 
will be expressed in Canadian dollars, adjusted to the year of study completion / analysis.    
 
14.5 
Sample Size 
 
Assume H0: p=0.65 and HA: p=0.80, the planned sample size is 69 evaluable patients to achieve a 
79.5% power. The two sided type I error was set at 0.05. CCD combination will be considered 
clinically valuable if 53 or more patients achieve PR or better after 4 cycles of treatment. 
Accounting for 5-10% non-evaluable patients, the total number of patients to be enrolled will be 
73 – 76. The sample size was calculated based on one proportion Clopper-Pearson Binomial exact 
method. 
 
14.6 
Safety Monitoring 
 


 
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Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigators' meetings. 


 
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15.0 
PUBLICATION POLICY 
 
15.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
15.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
 
The first author will generally be the chair of the study. 
 
A limited number of the members of the Myeloma Canada Research Network may be credited 
as authors depending upon their level of involvement in the study. 
 
Additional authors will be those who have made the most significant contribution to the overall 
success of the study. This contribution will be assessed, in part but not entirely, in terms of 
patients enrolled and will be reviewed at the end of the trial by the study chair. 
 
Dissemination of Trial Results 
MCRN will inform participating investigators of the primary publication of this trial. 
 
15.2 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by MCRN, 
Amgen and the academic CRO Senior Investigator, Senior Biostatistician, Study Coordinator, and 
approval of the Study Chair. Individual participating centres may not present outcome results from 
their own centres separately. Supporting groups and agencies will be acknowledged. 
 


 
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16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
16.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a 
result, the conduct of this trial must comply with Division 5 of the Canadian Regulations 
Respecting Food and Drugs (Food and Drugs Act). 
 
16.2 
Inclusivity in Research 
 
CRO does not exclude individuals from participation in clinical trials on the basis of attributes such 
as culture, religion, race, national or ethnic origin, colour, mental or physical disability (except 
incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, 
unless there is a valid reason (i.e. safety) for the exclusion.  
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CRO that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or 
a group to which the person belongs.  
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately.  
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CRO clinical trial under this policy but excluded by local policy, it is 
expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs.  
 
It is CRO policy that persons who cannot give informed consent (i.e. mentally incompetent persons, 
or those physically incapacitated such as comatose persons) are not to be recruited into CRO 
studies. It is the responsibility of the local investigator to determine the subject’s competency, in 
accordance with applicable local policies and in conjunction with the local REB (if applicable).  
 
Subjects who were competent at the time of enrolment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CRO will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation.  


 
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16.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in a CRO trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring that 
all local policies are followed. 
 
Additionally, in accordance with GCP 4.8.2, CRO may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential participant’s 
willingness to participate in the study.  
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. CRO 
recognizes that in many centres other personnel (as designated on the participants list) also play an 
important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified 
Investigator to delegate the responsibility for conducting the consent discussion. 
 
CRO requires that each participant sign a consent form prior to their enrollment in the study to 
document his/her willingness to take part. CRO may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during 
the course of the study. In conjunction with GCP 4.8.2, the communication of this information 
should be documented. 
 
CRO allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local centre. Centres should follow applicable local policies when procuring 
or using a translator for the purpose of obtaining informed consent to participate in a clinical trial.  
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject.  
 
16.3.1 Obtaining Consent for Pregnancy/Exposure Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner, exposed individual) should not be collected about or from them unless or until they are a 
willing participant in the research. The rights and protections offered to participants in research 
apply and consent must be obtained prior to collecting any information about or from them. If the 
main consent form adequately addresses the collection of information regarding the outcome of a 
pregnancy of a trial participant, a “Pregnancy Follow-up consent form will not be required by CRO. 
 
Trial-specific consent forms for “Pregnancy Follow-up” and “Exposure Follow-up” can be found 
on the trial webpage. The appropriate consent form must be used to obtain consent from any non-
trial participant (such as the pregnant partner or exposed individual). 
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy/exposure. Similarly, male participants 
will not be withdrawn from the main study should their partner refuse/withdraw permission. 
 
Obtaining Consent for Research on Children  
 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner or an exposed child), consent must be obtained from the parent/guardian.  


 
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For reporting an exposure, the parent/guardian is required to sign an “Exposure Follow-up” consent 
form (even if they are a participant in the main study) prior to collecting information about the 
child. 
 
16.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the CRO all centres will be notified in writing of the 
discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any potential 
risks to the health of patients participating on the trial or other persons, the CRO will provide this 
information to centres as well. 
 
If this trial is discontinued at anytime by the centre (prior to closure of the trial by the CRO), it is 
the responsibility of the qualified investigator to notify the CRO of the discontinuation and the 
reason(s) why.  
 
Whether the trial is discontinued by the CRO or locally by the centre, it is the responsibility of the 
qualified investigator to notify the local Research Ethics Board and all clinical trials subjects of the 
discontinuance and any potential risks to the subjects or other persons. 
 
16.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained as per C.05.012 and in accordance with ICH-GCP.  
 
The Qualified Investigator must ensure compliance with the Regulations and the GCP Guideline 
from every person involved in the conduct of the clinical trial at the site.  
 
Essential documents must be retained for 25 years following the completion of the trial at the centre 
(25 years post final analysis, last data collected, or closure notification to REB, whichever is later), 
or until notified by CRO that documents no longer need to be retained.  
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access.  
 
CRO will inform the investigator/institution as to when the essential documents no longer need to 
be retained.  
 
16.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI).  
 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 
 
16.7 
On-Site Monitoring/Auditing 
 
Site monitoring/auditing will be conducted at participating centres by the CRO in the course of the 
study as part of the overall quality assurance program. The monitors/auditors will require access to 
patient medical records to verify the data, as well as essential documents, standard operating 
procedures (including electronic information), ethics and pharmacy documentation (if applicable). 


 
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As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 
 
The CRO has reserved the right to audit participating centres. 
 
Audits may only be conducted after consultation with CRO. 
 
16.8 
Case Report Forms 
 
A list of forms to be submitted, as well as expectation dates, are to be found in Appendix IV. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For 
details of accessing the EDC system and completing the on-line Case Report Forms please refer to 
the “Registration/Randomization and Data Management Guidebook” posted on the MYX.1 area of 
the study web-site www.ctg.queensu.ca. 
 


 
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17.0 
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targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clinical Cancer 
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Berenson, J. R., Klein, L. M., Rifkin, R. M., & Patel, P. (2014). Results of the dose-escalation portion of a phase 
1/2 study (CHAMPION-1) investigating weekly carfilzomib in combination with dexamethasone for patients 
with relapsed or refractory multiple myeloma. J Clin Oncol 32:5s, (suppl; abstr 8594). 
Berenson, J. R., Klein, L., Rifkin, R., Patel, P., Dixon, S., Ou, Y., & Cartmell, A. (2013). A Phase 1, Dose-
Escalation Study (CHAMPION-1) Investigating Weekly Carfilzomib In Combination With Dexamethasone For 
Patients With Relapsed Or Refractory Multiple Myeloma. Blood, 122(21), 1934–1934. 
Bringhen, S., Petrucci, M. T., Larocca, A., Conticello, C., Rossi, D., Magarotto, V., et al. (2014). Carfilzomib, 
cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, 
phase 2 study. Blood, 124(1), 63–69. 
Britton, M., Lucas, M. M., Downey, S. L., Screen, M., Pletnev, A. A., Verdoes, M., et al. (2009). Selective 
inhibitor of proteasome's caspase-like sites sensitizes cells to specific inhibition of chymotrypsin-like sites. 
Chemistry & Biology, 16(12), 1278–1289.  
Demo, S. D., Kirk, C. J., Aujay, M. A., Buchholz, T. J., Dajee, M., Ho, M. N., et al. (2007). Antitumor activity 
of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Research, 67(13), 6383–6391. 
Durie, B., Harousseau, J. L., Miguel, J. S., & Blade, J. (2006). International uniform response criteria for multiple 
myeloma. Leukemia. 
Geurink, P. P., van der Linden, W. A., Mirabella, A. C., Gallastegui, N., de Bruin, G., Blom, A. E. M., et al. 
(2013). Incorporation of non-natural amino acids improves cell permeability and potency of specific inhibitors 
of proteasome trypsin-like sites. Journal of Medicinal Chemistry, 56(3), 1262–1275.  
Kuhn, D. J., Chen, Q., Voorhees, P. M., Strader, J. S., Shenk, K. D., Sun, C. M., et al. (2007). Potent activity of 
carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of 
multiple myeloma. Blood, 110(9), 3281–3290. 
Kumar, S. K., Lee, J. H., Lahuerta, J. J., Morgan, G., Richardson, P. G., Crowley, J., et al. (2012a). Risk of 
progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter 
international myeloma working group study. Leukemia, 26(1), 149–157.  
Kumar, S. K., Rajkumar, S. V., Dispenzieri, A., Lacy, M. Q., Hayman, S. R., Buadi, F. K., et al. (2008). Improved 
survival in multiple myeloma and the impact of novel therapies. Blood, 111(5), 2516–2520.  
Kumar, S. K., Therneau, T. M., Gertz, M. A., Lacy, M. Q., Dispenzieri, A., Rajkumar, S. V., et al. (2004). 
Clinical course of patients with relapsed multiple myeloma. Mayo Clinic Proceedings, 79(7), 867–874.  
Kumar, S., Flinn, I., Richardson, P. G., Hari, P., Callander, N., Noga, S. J., et al. (2012b). Randomized, 
multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, 
and lenalidomide in previously untreated multiple myeloma. Blood, 119(19), 4375–4382.  
Lee, S. J., Arastu-Kapur, S., & Kellerman, L. (2012). Potent inhibition of select proteasome subunits by 
carfilzomib in multiple myeloma and solid tumor patients is associated with patient response. Haematologica. 
Lendvai, N., Hilden, P., Devlin, S., Landau, H., Hassoun, H., Lesokhin, A. M., et al. (2014). A phase 2 single-
center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma. 
Blood, 124(6), 899–906.  
Monge, J., Kortuem, K. M., Stewart, A. K., Bergsagel, P. L., Mikhael, J. R., Reeder, C. B., et al. (2014). 
Cyclophosphamide, bortezomib, and dexamethasone (CYBORD) treatment for relapsed/refractory multiple 
myeloma. Journal of Clinical Oncology, 32(5s), 8586.  


 
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Moreau, P., Kolb, B., Hulin, C., Caillot, D., Benboubker, L., Tiab, M., et al. (2013). Carfilzomib PLUS 
Melphalan and Prednisone (CMP) Is A Promising Combination Therapy For The Treatment Of Elderly Patients 
With NEWLY Diagnosed Multiple Myeloma: Results Of A PHASE I/II Trial In 68 CASES. Blood, 122(21), 
1933–1933. 
NCI Cancer Statistics: http://seer.cancer.gov/statfacts/html/mulmy.html. (n.d.). 
http://seer.cancer.gov/statfacts/html/mulmy.html. Retrieved from 
http://seer.cancer.gov/statfacts/html/mulmy.html 
Palumbo, A., Rossi, D., Bringhen, S., Larocca, A., Gentilini, F., De Paoli, L., et al. (2014). Weekly Carfilzomib, 
Cyclophosphamide and Dexamethasone (wCCd) in Newly Diagnosed Multiple Myeloma Patients: A Phase I- II 
Study. Blood, 124(21), 175–175. 
Palumbo A, Sezer O,  Kyle R, et. al. International Myeloma Working Group guidelines for the management of 
multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell 
transplantation. Leukemia 1 -15, 2009. 
Papadopoulos, K. P., Lee, P., Singhal, S., Holahan, J. R., Vesole, D. H., Rosen, S. T., et al. (2011). A Phase 1b/2 
Study of Prolonged Infusion Carfilzomib in Patients with Relapsed and/or Refractory (R/R) Multiple Myeloma: 
Updated Efficacy and Tolerability From the Completed 20/56mg/m2 Expansion Cohort of PX-171-007. Blood, 
118(21), 2930.  
Papadopoulos, K. P., Siegel, D. S., Vesole, D. H., Lee, P., Rosen, S. T., Zojwalla, N., et al. (2015). Phase I study 
of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients 
with relapsed and/or refractory multiple myeloma. Journal of Clinical Oncology, 33(7), 732–739.  
Rajkumar, S. V., Harousseau, J. L., Durie, B., & Anderson, K. C. (2011). Consensus recommendations for the 
uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 
Reeder, C. B., Reece, D. E., Kukreti, V., Mikhael, J. R., Chen, C., Trudel, S., et al. (2014). Long‐term survival 
with cyclophosphamide, bortezomib and dexamethasone induction therapy in patients with newly diagnosed 
multiple myeloma. British Journal of Haematology, 563–565.  
Richardson, P. G., Weller, E., Lonial, S., Jakubowiak, A. J., Jagannath, S., Raje, N. S., et al. (2010). 
Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple 
myeloma. Blood, 116(5), 679–686.  
San Miguel, J. F., Schlag, R., Khuageva, N. K., Dimopoulos, M. A., Shpilberg, O., Kropff, M., et al. (2008). 
Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. The New England Journal 
of Medicine, 359(9), 906–917.  
Squifflet, P., Michiels, S., Siegel, D. S., & Vij, R. (2011). Multivariate modelling reveals evidence of a dose-
response relationship in phase 2 studies of single-agent carfilzomib.  
Stewart, A. K., Rajkumar, S. V., Dimopoulos, M. A., Masszi, T., Spicka, I., Oriol, A., et al. (2015). Carfilzomib, 
lenalidomide, and dexamethasone for relapsed multiple myeloma. The New England Journal of Medicine, 
372(2), 142–152.  
Venner, C. P., Connors, J. M., Sutherland, H. J., Shepherd, J. D., Hamata, L., Mourad, Y. A., et al. (2011). Novel 
agents improve survival of transplant patients with multiple myeloma including those with high-risk disease 
defined by early relapse (<12 months). Leukemia & Lymphoma, 52(1), 34–41.  
Yang, J., Wang, Z., Fang, Y., Jiang, J., Zhao, F., Wong, H., et al. (2011). Pharmacokinetics, pharmacodynamics, 
metabolism, distribution, and excretion of carfilzomib in rats. Drug Metabolism and Disposition: the Biological 
Fate of Chemicals, 39(10), 1873–1882.  


 
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AMEND #1: 2017-JAN-31; AMEND #2: 2017-OCT-11 
APPENDIX I - PATIENT EVALUATION FLOW SHEET 
 
Required Investigations 
Pre-study 
(within 21 days of 
registration) 
During Protocol Treatment 
After Completion of Protocol Therapy 
Day 1 of 
Cycle 1, 
2, and 3 
Day 15 
of Cycle 
1 and 2 
Day 1 of each 
cycle starting 
with cycle 4  
Every 4 weeks after end 
of therapy until 
Progressive Disease € 
Every 6 months 
after disease 
progression 
Physical 
 
 
 
 
 
 
Medical History1 
X 
 
 
 
 
 
Physical exam, including neurological 
and plasmacytoma assessment2 (if 
appropriate) 
X 
X 
 
X 
 
 
Weight, BSA 
X 
X 
 
X 
 
 
Height, Vital Signs 
X 
 
 
 
 
 
Performance Status 
X 
X 
 
X 
 
 
Survival and SAEs3 
X 
X 
X 
X 
X 
X 
Hematology* 
 
 
 
 
 
 
Complete blood count with differential 
X 
X4 
X 
X 
 
 
Biochemistry* 
 
 
 
 
 
 
Full serum chemistry panel5 
X 
X4 
 
 
 
 
Abbreviated serum chemistry panel I5 
 
 
X 
 
 
 
Abbreviated serum chemistry panel II5 
 
 
 
X 
 
 
Radiology 
 
 
 
 
 
 
Skeletal Survey** 
X 
(within 30 days) 
 
 
 
 
 
CT, PET CT or MRI 
X2 
(within 30 days) 
 
 
 
 
 
Other Investigations 
 
 
 
 
 
 
Beta2-microglobulin 
X 
 
 
 
 
 
Serum protein electrophoresis (SPEP) 
with immunofixation 
X 
X 
 
X 
X 
 
24h Urine protein with urine protein 
electrophoresis (UPEP) and urine 
immunofixation electrophoresis (UIFE)# 
X 
X 
 
X 
X 
 
Urinalysis including macroscopic 
examination (specific gravity, protein, 
pH, glucose, ketones, blood, leukocyte 
esterase and nitrite)  
X 
 
 
 
 
 
Urinalysis with  microscopic 
examination (RBCs, WBCs, epithelial 
cells, casts, crystals, bacteria, and yeast) 
X 
 
 
 
 
 
Serum free light chain assay (sFLC) 
X 
X 
 
X 
X 
 
Quantitative serum immunoglobulins 
X 
X 
 
X 
X 
 
Bone Marrow Assessment*** 
X 
(within 8 weeks prior) 
 
 
 
 
 
Cytogenetic assessment of marrow 
plasma cells by FISH 
X 
(within 8 weeks prior) 
 
 
 
 
 
12-lead ECG with QTC interval 
X 
 
 
 
 
 
Serum Pregnancy Test (For women of 
childbearing potential only) 
X 
(within 72 hours) 
X 
 
X 
 
 
Adverse Events 
 
 
 
 
 
Adverse Event Assessment 
X 
X 
X 
X 
X## 
 
footnotes on next page … 
 
 


 
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AMEND #1: 2017-JAN-31 
 
1 
Please refer to Table 6.0 for more information. 
2 
Only required if plasmacytomas are being followed. Plasmacytoma assessment required to confirm CR or better, or to 
confirm PD. 
3 
Serious, unexpected and related adverse events (as per Section 11.1). 
4 
Not required at Day 1, Cycle 1 if blood work at screening was completed within 7 days of D1C1. 
5 
Please refer to Table 6.0 and 9.0 for the full list of investigations required for biochemistry. 
* 
Bloodwork Timing: Pre-treatment blood draws may be done the day prior to treatment if necessary, and when treatment is 
to begin on a Monday, may be done on the previous Friday (maximum 72 hours prior to treatment). In order to ensure that 
nadir counts are not missed, every effort should be made to do interim blood draws within 24 hours of the day specified in 
the protocol. 
** 
Required within 30 days prior to registration and as clinically indicated throughout study. 
*** Required at screening to assess clonal disease burden with subsequent marrows only required to confirm CR if achieved by 
biochemical parameters. 
# 
Only if UPEP ≥ 200 mg/24 hours at baseline. Please note that UPEP and immunofixation is required to be completed to 
confirm VGPR (when serum and urine M-protein are not measurable), CR and sCR even if UPEP < 200 mg/24 hours at 
baseline. See Table 11 of the protocol for more information. 
## 
Required at the 4 week post treatment visit only. 
€          Patients who discontinue therapy due to toxicity in the absence of progression should be followed every 4 weeks until 
progression, or initiation of non-protocol therapy for the first 3 months after end of treatment.  Following 3 months after 
the end of treatment, patients can be followed every 3 months. 
 


 
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APPENDIX II - PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
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. 
80 
Active, but tires more quickly. 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
selfcare 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. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 


 
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APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
 
General 
 
Carfilzomib will be supplied by Amgen. 
 
Cyclophosphamide and dexamethasone for this protocol are commercially available and sourced from the 
Canadian market. 
 
 
Distribution 
 
Drug distribution will be managed through an Interactive response technology system called Endpoint. 
Please refer to the MYX.1 trial specific website for more information/instructions on carfilzomib ordering 
and distribution. 
 
 
Drug Accountability 
 
It is the responsibility of each site to maintain drug accountability logs for carfilzomib. 
 


 
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AMEND #1: 2017-JAN-31 
APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of registration and will apply to all eligible patients.  
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For details of 
accessing the EDC system and completing the on-line Case Report Forms please refer to the “CRO EDC 
Generic Data Management Guidebook” posted on the MYX.1 area of the study web-site 
www.ctg.queensu.ca. 
 
The electronic CRFs to be used in this trial, through the EDC system, are as follows: 
 
Electronic Folder 
Required at 
To be completed 
electronically 
Supporting Documentation 
Required* 
Eligibility Checklist 
 
At the time of registration 
Copies of the signed Consent 
form**, relevant pathology 
and radiology reports 
(including bone marrow 
aspirate, biopsy and 
cytogenetics), serum protein 
electrophoresis, serum free 
light chains, quantitative 
immunoglobulins, 24 hour 
urine protein electrophoresis 
reports) 
Baseline Report 
 
Within 2 weeks of 
registration 
Treatment Report 
Every 4 weeks (28 
days) after each cycle 
Within 2 weeks of the end 
of each cycle 
Bone marrow (if applicable), 
serum protein electrophoresis, 
serum free light chains, 
quantitative immunoglobulins, 
24 hour urine protein 
electrophoresis and relevant 
radiology reports 
Concomitant Medication 
Report 
Continuous running-
log folder 
 
 
End of Treatment Report 
When the patient goes 
off protocol treatment 
Within 2 weeks of the end 
of treatment 
 
Post Treatment Report 
To be completed once 
on all patients, 4 weeks 
after going off protocol 
treatment 
Due within 2 weeks after 
contact with patient 
Bone marrow (if applicable), 
serum protein electrophoresis, 
serum free light chains, 
quantitative immunoglobulins, 
24 hour urine protein 
electrophoresis and relevant 
radiology reports 
Follow-up Report 
Every 4 weeks until 
progression (following 
4 week Post Treatment 
Report) € 
Within 2 weeks of follow - 
up visit 
Bone marrow (if applicable), 
serum protein electrophoresis, 
serum free light chains, 
quantitative immunoglobulins, 
24 hour urine protein 
electrophoresis and relevant 
radiology reports  
continued on next page … 
 
 


 
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AMEND #1: 2017-JAN-31 
 
Relapse/Progression 
Report 
Upon disease 
progression 
Within 4 week of 
confirmation 
Relevant radiology, operative 
and pathology reports. Bone 
marrow (if applicable), serum 
protein electrophoresis, serum 
free light chains, quantitative 
immunoglobulins, and 24 
hour urine protein 
electrophoresis reports 
Short Follow-up Report 
Every 6 months after 
progression 
Within 2 weeks follow-up 
visit 
 
Death Report 
When patient dies 
Within 2 weeks of patient's 
death 
Autopsy/post-mortem report, 
if done 
SAE Report*** 
At the time of the event 
See Section 11 
Any relevant reports as 
requested 
* 
Supporting Documentation should be uploaded into the EDC system. 
** It is acceptable to submit only the signature page(s) of the main consent provided that the version date of the consent form 
is indicated. 
*** See Section 11.0 Serious Adverse Event Reporting for details. 
€    Patients who discontinue therapy due to toxicity in the absence of progression should be followed every 4 weeks until 
progression, or initiation of non-protocol therapy for the first 3 months after end of treatment.  Following 3 months after 
the end of treatment, patients can be followed every 3 months. 


 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
 


 
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Final Page 
CONFIDENTIAL 
 
AMEND #1: 2017-JAN-31 
LIST OF CONTACTS 
 
 
Contact 
Tel. # 
Fax # 
ELIGIBILITY CHECKLIST 
Must be completed prior to 
registration. 
Amanda Bontje 
Clinical Trials Assistant 
Email: 
 abontje@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY SUPPLIES 
Forms, Protocols 
Available on Trial Website: 
http://www.ctg.queensu.ca 
under: Clinical Trials 
 
 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Max Sherry 
Study Coordinator 
Email: 
msherry@ctg.queensu.ca 
613-533-6430 
613-533-2941 
or: 
Dr. Annette Hay 
Senior Investigator 
Email: 
ahay@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY CHAIR 
Dr. Christopher Venner 
Study Chair 
Email: 
christopherpaul.venner@albertahealthservi
ces.ca 
780-432-8757 
780-432-8888 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 11.0 for 
details of reportable events. 
Dr. Annette Hay 
Senior Investigator 
or: 
Max Sherry 
Study Coordinator 
613-533-6430 
613-533-2941 
DRUG ORDERING 
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SAP_001.pdf: 
 
 
Statistical Analysis Plan (SAP) 
Doc. No.: 
MYX.1  
Version: 
V001 
Date: 
2018-01-26 
 
1 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan for  
 
 
A SINGLE ARM PHASE II STUDY OF HIGH-DOSE WEEKLY CARFILZOMIB PLUS 
CYCLOPHOSPHAMIDE AND DEXAMETHASONE IN THE TREATMENT OF RELAPSED 
MULTIPLE MYELOMA AFTER 1-3 PRIOR THERAPIES 
 
Academic CRO Protocol Number: MYX.1 
Lead Group Protocol Number: MCRN-003 
 
 
 
 
Prepared by: 
 
Senior Statistician: Bingshu E. Chen 
 
 
Reviewed by: 
 
 
Senior Investigator: Annette Hay 
Study Chair: Chris Venner  
 
 


 
 
Statistical Analysis Plan (SAP) 
Doc. No.: 
MYX.1  
Version: 
V001 
Date: 
2018-01-26 
 
2 
 
 
Table of Contents 
1. OVERVIEW ............................................................................................................................................ 3 
1.1 Objectives ........................................................................................................................................... 3 
1.2 Timeline .............................................................................................................................................. 3 
1.3 Data Collection ................................................................................................................................... 3 
2. Results ...................................................................................................................................................... 3 
2.1 Accrual ................................................................................................................................................ 4 
2.2 Eligibility status .................................................................................................................................. 4 
2.3 Duration of follow-up ......................................................................................................................... 4 
2.4 Patient Characteristics ......................................................................................................................... 4 
2.5 Efficacy ............................................................................................................................................... 4 
2.5.1 Response rates .............................................................................................................................. 4 
2.5.2 Overall Survival (OS) .................................................................................................................. 5 
2.5.3 Progression free survival (PFS) ................................................................................................... 5 
2.6 Drug Exposure .................................................................................................................................... 6 
2.7 Toxicity ............................................................................................................................................... 6 
2.8 Off treatment ....................................................................................................................................... 7 
3. Tables and Figures .................................................................................................................................. 8 
Figure 1. KM for OS ................................................................................................................................. 8 
Figure 2. KM for PFS ............................................................................................................................... 8 
 
 
 


 
 
Statistical Analysis Plan (SAP) 
Doc. No.: 
MYX.1  
Version: 
V001 
Date: 
2018-01-26 
 
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1. OVERVIEW 
 
This document is to describe the statistical analysis plan for MYX.1, and serves as the guideline 
for the analyses generated for writing the study report of this trial. 
 
The data will be collected and cleaned by Canadian Cancer Trials Group (CCTG) according to the 
data management plan for this study. A senior biostatistician in CCTG will perform all analyses, 
and prepare a final statistical analysis report. 
 
1.1 Objectives 
 
This is a single arm phase II, investigator initiated, multicentre trial run through the Myeloma 
Canada Research Network. The primary objective is to determine the overall response rate after 4 
cycles of weekly high-dose carfilzomib, cyclophosphamide and dexamethasone (CCD regimen) in patients 
with relapsed multiple myeloma after 1-3 prior regimens. 
1.2 Timeline 
 
The clinical cut-off date of final analysis is June 15th, 2018. The database will be locked for on 
July 13, 2018 for final analysis. The results will be available for 2018 abstract submission.  
1.3 Data Collection 
 
Data are collected and entered by CCTG, Kingston, Ontario. Procedures for data collection, data 
editing and data transfer are described in the data management plan. 
 
 
2. RESULTS 
 
Analysis population: All treated patients will be included in this analysis. 
 
Baseline evaluations are those collected closest, but prior to, or on the first day of study medication, 
unless otherwise specified. 
 
When either day or month of a date is missing, the missing day and/or month will be imputed by 
the midpoints within the smallest known interval.  For example, if the day of the month is missing 
for any date used in a calculation, the 15th of the month will be used to replace the missing day.  
If the month and day of the year are missing for any date used in a calculation, the first of July of 
the year will be used to replace the missing day. 
 
All comparisons between treatment arms will be carried out using a two-sided test at an alpha level 
of 5% unless otherwise specified.  No formal adjustments will be made for the multiplicity of 
inferences for multiple clinical endpoints. 
 


 
 
Statistical Analysis Plan (SAP) 
Doc. No.: 
MYX.1  
Version: 
V001 
Date: 
2018-01-26 
 
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2.1 Accrual 
 
Number (%) of patients per study center (Table 1) (All patients). 
 
2.2 Eligibility status 
 
Number (%) of eligible and ineligible patients and reasons of ineligibility (Table 2) (All patients).  
 
2.3 Duration of follow-up 
 
Median (range) duration of followup up will be reported using inverse OS method (Table 3). 
2.4 Patient Characteristics 
 
Number (%) of patient characteristics (Table 4) (Treated patients): 
 Age (40-49, 50-59, 60-69, >=70) 
 Age (Median, Range, Q1, Q3, Mean, SD) 
 Sex 
 ECOG performance status 
 Number of prior therapy 
 Myeloma Subtype – IgA, IgG, IgD LC only  
 Stem Cell Transplant – Yes/No 
 Baseline Genetics 
 ISS stage 
 Revised-ISS stage (using most current CG data and LDH from the time of study entry) 
 % Proteosome Inhibitor exposed (either bortezomib or ixazomib) 
 % Proteosome Inhibitor refractory 
 % IMID (lenalidomide or pomalidomide or thalidomide) exposed 
 % IMID refractory 
 % of clonal plasma cells 
 Participated in the millenoium study: Yes vs No  
 
2.5 Efficacy 
 
2.5.1 Response rates 
 
All patients who have received at least one cycle of therapy and have their disease re-evaluated 
will be considered evaluable for response (exceptions will be those who exhibit objective disease 


 
 
Statistical Analysis Plan (SAP) 
Doc. No.: 
MYX.1  
Version: 
V001 
Date: 
2018-01-26 
 
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progression prior to the end of cycle 1 who will also be considered evaluable). Patients on therapy 
for at least this period and who meet the other listed criteria will have their response classified 
according to the definitions set out below. 
 
Response and progression will be evaluated in this study using the International Myeloma Working 
Group Uniform Response Criteria (IMWG-URC) as summarized in Table 11 of the study protocol. 
Response sub-category includes Stringent Complete Response (sCR), Complete Response (CR), 
Very Good Partial Response (VGPR), Partial Response (PR), Minimal Response (MR), Stable 
Disease (SD) and Progressive Disease (PD) 
 
Number and (%) of disease response (sCR/CR/VGPR/PR/MR/SD/PD) will be reported in Table 
5.  
 
Overall response rate after 4 cycles of tretment will be calculated by number of (sCR + CR + 
VGPR + PR) / number of all treated patients. The corresponding 95% confidence interval for the 
overall response rate will be calculated by Normal approximation method. 
 
Note: For patients with PD who were off treatment before cycle 4 will be considered as PD for 
cycle 4 response. Patients with other categories who off treatment before cycle 4 will be considered 
as in-evaluable for cycle 4 response.  
 
Response rates of sCR, CR, VGPR, PR, MR, SD, PD and the corresponding 95% CI will also be 
reported separately.  
 
Response rate according to baseline genetics will also be reported.   
 
Best overall response will not be reported in this analysis but will be reported in a follow-up 
analysis.  
2.5.2 Overall Survival (OS) 
 
For patients who have died, overall survival is calculated in months from the day of registration to 
date of death. Otherwise, overall survival is censored at the last day the patient is known alive 
(LKA).  
 
Two-year OS rate and the corresponding 95% CI will be estimated. KM curve of overall survival 
will be reported in Figure 1.  
 
Cause of death and reason of censoring will be listed on Table 6. 
 
2.5.3 Progression free survival (PFS) 
 
Progression free survival (PFS) is defined as from the time of registration to the time of objective 
relapse for patients who achieved sCR, CR, VGPR or PR; to the time of progression of disease for 


 
 
Statistical Analysis Plan (SAP) 
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patients who maintained SD; to the time of symptomatic relapse or progression confirmed by 
imaging and/or necessitating institution of new treatment for myeloma; or to the time of death 
from any cause, whichever comes first. For patients who have not relapsed, progressed, or died, 
PFS is censored on the date of the last disease assessment. 
 
Two-year PFS rate and the corresponding 95% CI will be estimated. KM curve of PFS will be 
reported in Figure 2.  
 
Note: PFS will not be reported in current final analysis and will be analyzed later.  
 
Type of PFS event and reason of censoring will be list on table 7. 
 
2.6 Drug Exposure 
 
Cumulative dose (mg) is the sum of each study medication doses received. 
 
Mean, SD, Median, Q1, Q3, minimum and maximum of total amount for each of three drugs will be 
reported for patients who received at least one dose of carfilzomib, cyclophosphamide and 
dexamethasone treatment (based on standard IND algorithm) (Table 8) 
 
 
Relative Dose Intensity (%) 
 
Relative Dose Intensity for cyclophosphamide = Actual total dose / planned dose  x 100% 
Note: Relative dose intensity does not apply to Carfilzomib and Dexamethasone.  
 
Mean, SD, Median, Q1, Q3, minimum and maximum of relative dose intensity, number and % of patients 
with relative dose intensity > 90% for each drug will be reported (Table 9).  
 
 
Dose reduction, modification and discontinuation 
 
The number and % of patients with at least one dose reduction, dose modification and dose 
discontinuation for each drug will be summarized for each of the three drugs (Table 10a). Reasons 
for dose reduction, dose modification and dose discontinuation for each drug will be reported. 
 
Number of dose reduction (Mean, SD, median, Q1, Q3, min, max) per patient will be report for 
each drug. (Table 10b) 
 
2.7 Toxicity 
 
Post baseline Non-Hem Adverse Events (Table 11) 
 


 
 
Statistical Analysis Plan (SAP) 
Doc. No.: 
MYX.1  
Version: 
V001 
Date: 
2018-01-26 
 
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The number and % of patients with the following vascular, thromboembolic and cardiac adverse 
events (grade 1 or higher) will be reported:  
 
 
TTP 
 
PE/DVT 
 
Stroke 
 
Hypertension 
 
MI 
 
CHF event 
 
Unexplained dyspnea 
 
Renal failure 
 
 
 
Hem Adverse Events (Table 12) 
 
Biochemical Adverse Events (Table 12) 
 
AE will be reported up to cycle 5 of treatment for this analysis.  
 
2.8 Off treatment 
 
Number (%) of patients off protocol treatment for each drug. (Table 13) 
 
Death on trial (Table 14) 
 
Number (%) of death and the reason of death (e.g, related or un-related to protocol treatment) will 
be reported.  
 
SAE (Table 15).  
Note: All SAE will be reported.  
 
 
 


 
 
Statistical Analysis Plan (SAP) 
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Version: 
V001 
Date: 
2018-01-26 
 
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3. TABLES AND FIGURES 
 
Figure 1. KM for OS 
 
Figure 2. KM for PFS