A Phase 3, Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Pomalidomide, Bortezomib and Low-Dose Dexamethasone Versus Bortezomib and Low-Dose Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma
Phase: PHASE3
Conditions: Multiple Myeloma
Sponsor: Celgene

Protocol for 
 
Official Title of Study 
A PHASE 3, MULTICENTER, RANDOMIZED, OPENLABEL 
STUDY TO COMPARE THE EFFICACY AND 
SAFETY OF POMALIDOMIDE, BORTEZOMIB AND 
LOW-DOSE DEXAMETHASONE VERSUS 
BORTEZOMIB AND LOW-DOSE DEXAMETHASONE 
IN SUBJECTS WITH RELAPSED OR REFRACTORY 
MULTIPLE MYELOMA 
 
NCT01734928 
 
June 14, 2017 

EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 Jun 2017
TITLE PAGE
A PHASE 3, MULTICENTER, RANDOMIZED, OPEN-
LABEL STUDY TO COMPARE THE EFFICACY AND 
SAFETY OF POMALIDOMIDE, BORTEZOMIB AND 
LOW-DOSE DEXAMETHASONE VERSUS
BORTEZOMIB AND LOW-DOSE DEXAMETHASONE 
IN SUBJECTS WITH RELAPSED OR REFRACTORY 
MULTIPLE MYELOMA
INVESTIGATIONAL PRODUCT (IP):
Pomalidomide (CC-4047) for US;
Pomalidomide (CC-4047) and 
Dexamethasone for Japan; 
Pomalidomide (CC-4047), 
Bortezomib, and Dexamethasone for 
ex-US
PROTOCOL NUMBER:
CC-4047-MM-007
DATE FINAL:
15 Oct 2012
AMENDMENT #1:
27 Mar 2014
AMENDMENT #2:
14 Nov 2014
AMENDMENT #3:
16 Oct 2015
AMENDMENT #4
09 Dec 2015
AMENDMENT #5
14 Jun 2017
EudraCT NUMBER:
2014-000268-17
IND NUMBER:
066188
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.
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Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 Jun 2017
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information: 
Name: 
Title: Clinical Research Physician/Sr. Medical Monitor
Address: Celgene Europe, Route de Perreux 1, 2017 Boudry, Switzerland
Phone: 
Mobile: 
E-mail: 
BACK-UP MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION
Contact Information:
Name:  
Title: Clinical Research Physician/ Medical Monitor
Address: Celgene Europe, Route de Perreux 1, 2017 Boudry, Switzerland
Mobile : 
E-mail: 
Note: The back-up 24 hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24 Hour Global Emergency Contact Call Center: 
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Pomalidomide (CC-4047)
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Celgene Corporation
Confidential and Proprietary
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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{Please see appended electronic signature page.}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.
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Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 Jun 2017
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, ICH Good Clinical Practices 
Guidelines, and local regulations governing the conduct of clinical studies.
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Celgene Corporation
Confidential and Proprietary
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COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 Jun 2017
PROTOCOL SUMMARY
Study Title
A Phase 3, Multicenter, Randomized, Open-label Study to Compare the Efficacy and Safety of 
Pomalidomide (POM), Bortezomib (BTZ) and Low-Dose Dexamethasone (LD-DEX) versus
Bortezomib and Low-Dose Dexamethasone in Subjects with Relapsed or Refractory Multiple 
Myeloma (MM)
Indication
Relapsed or Refractory MM
Study Objectives
To compare the efficacy of POM + BTZ + LD-DEX with BTZ + LD-DEX in subjects with 
relapsed or refractory MM 
Secondary Objectives:
To evaluate the safety and additional efficacy of POM + BTZ + LD-DEX versus BTZ + LD-
DEX in subjects with relapsed or refractory MM.
Exploratory Objectives:
!
To evaluate the differences in clinical benefits of POM + BTZ + LD-DEX versus 
BTZ + LD-DEX in subjects with relapsed or refractory MM
!
To evaluate the differences in key efficacy variables of POM + BTZ + LD-DEX 
versus BTZ + LD-DEX within defined subgroups 
!
To evaluate the differences in health-related quality of life of POM + BTZ + LD-
DEX versus BTZ + LD-DEX in subjects with relapsed or refractory MM
!
To evaluate Minimal Residual Disease (MRD), genomic, molecular/mechanistic and 
immune biomarkers and their correlation to clinical outcome measures for only those 
subjects who give their consent (Optional)
Study Design Overview
This study is a multicenter, randomized, open-label, phase 3 study comparing the efficacy and 
safety of POM + BTZ + LD-DEX (Treatment Arm A) versus BTZ + LD-DEX (Treatment Arm 
B) in subjects with relapsed or refractory MM. 
For Treatment Arm A (POM + BTZ + DEX), the dose was based on the results from the CC-
4047-MM-005 (MM-005) Phase 1 dose escalation MTD study in which bortezomib was 
administered via IV infusion.  In the MM-005 study, the maximum planned dose (MPD), POM 
(4 mg) + IV BTZ (1.3 mg /m2) and DEX (20 mg subjects ≤ 75 years old/10 mg subjects > 75 
years old) was reached without any DLTs. Considering an early POM single agent MTD study 
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Confidential and Proprietary
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 Jun 2017
(Richardson, 2013) as well as the findings in MM-005, the MPD was determined to be the 
optimal dose for the triple combination therapy.  With the optimal dose determined, MM-007 
was initiated using the MPD dose for the combination of POM + BTZ + LD-DEX (with IV 
BTZ).
During the conduct of the MM-005 study, subcutaneous (SQ) BTZ was approved as an 
alternative administration method for BTZ (23 Jan 2013).  The SQ BTZ was reported to have a 
decreased incidence of neurotoxicity versus the IV BTZ (Velcade® Prescribing Information, 
2014).  To explore the SQ route of BTZ administration in combination with POM and DEX, the 
MM-005 protocol was amended to add a cohort of 6 subjects at the MPD/optimal dose for the 
combination of POM + BTZ + LD-DEX with BTZ administered via SQ injection.  Based on the 
safety, efficacy and PK data for this SQ BTZ cohort (see Section 1.4) and general adoption in 
medical practice of SQ BTZ as standard of care due to decreased neurotoxicity, BTZ 
administration is now to be SQ for both arms in the MM-007 study (Treatment Arm A and B).
Subjects who consented to the original MM-007 protocol can continue with IV BTZ or switch to 
SQ BTZ at the discretion of the treating physician.  Subjects randomized into MM-007 under IV 
BTZ treatment will not be replaced.
Approximately 544 subjects will be randomized equally (1:1 ratio) into the two treatment arms 
(272 subjects in each arm).
Based on the primary endpoint progression-free survival (PFS), at 2-sided significance level of 
5%, with one interim analysis for futility only, an estimated total of 381 progression/death events 
are required to detect a 33% increase in median PFS in the POM treatment arm (Arm A; median 
= 12 months) compared to that in the comparator arm (Arm B; median = 9 months) with 80% 
power. In order to obtain PFS events from approximately 70% of the study ITT population for 
the final PFS analysis, a total of 544 randomized subjects are required to test the hypothesis.  The 
interim analysis on PFS will take place when approximately 50% PFS information (191 events) 
has occurred. The interim results will be examined for futility only with the pre-specified type II 
error spending functions described in Section 10.9.
Celgene amended the protocol in Amendment 5 to perform the final PFS analysis earlier than 
originally planned (381 PFS events).  Recently published data from a number of Phase 3 studies 
revealed that the PFS of the bortezomib with low-dose dexamethasone (BTZ+LD-DEX) arm on 
this study CC-4047-MM-007 (OPTIMISMM), that requires prior treatment with lenalidomide as 
per Protocol Inclusion Criteria #7 (Section 7.2), is expected to be shorter than the original 
OPTIMISMM protocol statistical assumption of 9 months (relevant median PFS data from Phase
3 ENDEAVOR, PANORAMA-1, and CASTOR studies ranging from 7 to 8 months) (Moreau, 
2017; Palumbo, 2016; San-Miguel, 2014).
Subsequently, if the assumption for the pomalidomide, bortezomib and low-dose dexamethasone 
(POM+BTZ+LD-DEX) arm and other study assumptions remain unchanged, the number of PFS 
events required for the final analysis would be less than originally planned. The data cutoff date 
for the revised final PFS analysis will be October 2017, by which time approximately 320 PFS 
events are projected to be reached, representing an approximate 57% event rate (out of 559 
randomized subjects). This would allow for 80% power to test a median PFS of 12 months in 
Arm A versus 8.8 months in Arm B, corresponding to an estimated hazard ratio of 0.73.
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Celgene Corporation
Confidential and Proprietary
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Overall survival (OS) will be tested if PFS and overall response rate (ORR) results are 
significant (see Section 10.10). With one planned interim analysis OS at the time of the final PFS 
analysis (estimated to be at approximately 50% OS information [190 deaths]), at a 2-sided 
significance level of 5%, a total of 379 deaths are required to detect a 33% increase in median 
OS in Treatment Arm A (40 months) compared with Treatment Arm B (30 months) with 75% 
power. 
The OS assumption for the control arm (Treatment Arm B) are based on the published results of 
SUMMIT and APEX trials in relapsed MM treated with bortezomib (Richardson, 2003; 
Richardson, 2007c).  Considering that LD-DEX will be given in combination with BTZ in this 
study (as opposed to the SUMMIT trial where LD-DEX was added later on to subjects under 
BTZ single agent therapy with suboptimal response) as well as published observational data of 
OS in patients receiving combination therapy of BTZ plus DEX (Ionita, 2009), the estimated 
median OS in the control arm (Treatment Arm B) using BTZ plus LD-DEX is 30 months. This is 
also supported by more recent data in the ENDEAVOR and PANORAMA-1 studies, where the 
OS ranged from 24.3 to 35.8 months (Moreau, 2017; San-Miguel, 2014). 
Except for pregnancy test and urinalysis, all laboratory assessments will be performed centrally; 
however, tests that may result in dose interruption and/or modification should also be performed 
locally to allow for treatment related decisions during subject visits.  All abnormal results from 
local laboratories used in treatment decisions or adverse event reporting must be entered into an 
unscheduled visit on the eCRF. An Independent Response Adjudication Committee (IRAC) will 
be set up for this trial to review efficacy data in a blinded manner. The IRAC will determine the 
tumor response to therapy and to confirm the time of disease progression (PD) (if disease 
progressed) at scheduled or unscheduled visits for each subject. 
The safety and efficacy of the study will be monitored by an independent data monitoring 
committee (IDMC) who are not involved in the trial conduct. The IDMC will meet up and 
review unblinded trial data at pre-specified intervals throughout the trial.  At time of the interim 
analysis, the IDMC will review the study data for futility assessment. In addition to the IDMC 
review, safety data will be monitored by the Celgene Medical Monitor and Safety Physician on 
an ongoing basis throughout the study. In the event when a significant safety issue is identified, 
the IDMC will be convened to make a recommendation as to the future conduct of the study.
The study will be conducted globally.
Screening
Potential study subjects will sign an informed consent prior to undergoing any study-related 
procedure.  Subjects need to complete screening for protocol eligibility within 28 days of 
randomization, as outlined in Table 1, Table of Events.  Subjects may have the choice to 
participate in an optional biomarker study conducted at selected clinical sites (where 
operationally and logistically feasible).  If a subject chooses to participate in the biomarker study, 
he/she must give consent for the optional biomarker study.
Subjects must have discontinued anti-myeloma therapies at least 14 days prior to randomization
(wash-out period). Subjects with myeloma-associated bone lesion may receive bisphosphonate 
therapy prior to study entry, unless such therapy is contraindicated.
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Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 Jun 2017
Subjects who fail screening as a result of severe neutropenia or anemia will not be permitted to 
use growth factors or platelet/blood transfusion to become eligible.
Randomization
Subjects who meet all eligibility criteria will be randomized to either Treatment Arm A (POM 
+ BTZ + LD-DEX) or Treatment Arm B (BTZ + LD-DEX) with equal probability (1:1 
randomization ratio).
 
 The 
randomization procedure will be accomplished by a validated IVRS/IWRS, stratified by the 
following factors: 1) age (≤ 75 years old vs. > 75 years old); 2) number of prior anti-MM 
regimens (1 vs. >1); 3) Beta-2 microglobulin (β2M) at screening (< 3.5 mg/L vs. ≥ 3.5 mg/L - ≤ 
5.5 mg/L vs. > 5.5 mg/L). A randomization authorization number is needed to initiate the 
IVRS/IWRS prior to subject enrollment.
Study Treatment Phase
Study treatment for each subject begins on the same day as, or within 4 days following 
randomization.  Study visits with serial measurements of safety and efficacy will be performed 
as outlined in Table 1, Table of Events.
 
  
 
Tumor response, including progressive disease (PD), will be assessed according to the 
International Myeloma Working Group (IMWG) uniform response criteria (Durie, 2006); an 
exploratory assessment of response using the European Group for Blood and Marrow 
Transplantation (EBMT) (Bladé, 1998) response criteria will also be performed. All treatment 
decisions will be made by treating physicians based on response as assessed using the IMWG 
criteria. 
The severity of AEs will be graded according to the National Cancer Institute Common Toxicity 
Criteria for Adverse Events (NCI CTCAE) version 4.0 or higher.
Thromboembolism prophylaxis during the study treatment is required for subjects in Treatment 
Arm A. Low-dose aspirin, low molecular weight heparin, or other equivalent antithrombotic or 
anti-coagulant will be given to all subjects assigned to Treatment Arm A as well as Treatment 
Arm B subjects who have a prior history of deep vein thrombosis (DVT) or pulmonary embolism 
(PE).  At the discretion of the treating physician, other Treatment Arm B subjects may also 
receive antithrombotic therapy.  Subjects who develop symptomatic DVT under study treatment 
will be assessed and diagnosed objectively by Doppler ultrasonography or a comparable method.  
Diagnostic algorithms will be provided in Appendix A.
Herpes Zoster Prophylaxis should be considered for all study subjects receiving bortezomib.  
Oral acyclovir or equivalent antiviral therapy per institutional guidelines is acceptable for herpes 
zoster prophylaxis. 
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Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 Jun 2017
During the study, subjects with myeloma-associated bone lesion may receive bisphosphonate 
therapy.
Radiation therapy to a pathological fracture site or to treat bone pain is permitted throughout the 
study. 
The use of hematopoietic growth factors is permitted (the use of myeloid growth factors is 
encouraged when the absolute neutrophil count is less than 1,000/μL) at the discretion of the 
treating physician.  Platelet and red blood cell transfusions are also permitted during the study.  
However, subjects who fail absolute neutrophil count (ANC), hemoglobin or platelet eligibility 
criteria at screening CANNOT be re-tested for the study after being treated with growth factors 
or platelet/blood transfusion. However, subjects who meet the ANC, hemoglobin and platelet 
eligibility criteria due to growth factor treatment or platelet/blood transfusion received prior to 
screening are acceptable and are not considered as screening failures.
Drugs known to prolong QT corrected (QTc) interval should be avoided unless deemed 
medically necessary. See Appendix G for link to a comprehensive list of drugs which are known 
to prolong QTc.  A thorough QT study (CC-4047-CP-010) was conducted in healthy subjects 
according to the E14 Guidance to assess the potential of pomalidomide (POM) to delay cardiac 
re-polarization, especially as prolongation of the QT interval.  The result of the QT prolongation 
assessment was observed to be negative, indicating a low risk of POM-associated QT 
prolongation.
Study Treatment Discontinuation 
Subjects will continue study treatment until PD or unacceptable toxicity.  An active treatment 
discontinuation visit should occur for all subjects at the time of permanent discontinuation from 
study treatment.  The reason for discontinuation from study treatment will be documented in the
electronic case report forms (eCRFs) for all subjects. 
Progression-free Survival follow-up Phase
To ensure accuracy and completeness for the primary efficacy endpoint assessment of 
progression-free survival, subjects who permanently discontinued study treatment prior to PD 
will continue to be followed up in the PFS follow-up phase until PD. During this PFS follow-up 
period, efficacy assessments for response and PD per the IMWG uniform response criteria will 
be performed every 21 days (see Table 1, Table of Events). Subjects are not expected to start any 
other anti-myeloma therapy during the PFS follow-up phase prior to PD.  Subjects are expected
to have a visit at the time of discontinuation from the PFS follow-up period.
Long-term Follow-up Phase
All subjects will be followed in the long-term follow-up phase until death or for at least 5 years 
after the last subject is randomized into the study, or longer if clinically indicated (unless the 
follow-up is shorter due to withdrawal of consent, loss to follow-up, or death).  Long-term 
follow-up will occur 4 times per year (every 3 months) after the 28 days post treatment 
discontinuation visit or PFS follow-up phase discontinuation visit, as applicable.  During long-
term follow-up the following information will be collected: survival, subsequent anti-myeloma 
regimens, date of progression and reason for progression based on the IMWG uniform response 
criteria, if available, for subjects who did not have PD during the study treatment or PFS follow-
up period, and second primary malignancies (SPM).
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Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 Jun 2017
Study Population
The study population comprises of relapsed or refractory MM subjects who had at least one but 
no more than three prior anti-myeloma regimens, and who have had received at least 2 
consecutive cycles of lenalidomide treatment. Subjects who have received prior bortezomib 
therapy (either IV or subcutaneous) can enter the study. However, those who have received prior 
bortezomib therapy must not have had PD during therapy or within 60 days of their last dose of 
the bortezomib-containing regimen under the 1.3 mg/ m2/dose twice weekly dosing schedule.
See Section 7 of the protocol for a detailed description of the study population.
Length of Study
The study will consist of the following consecutive phases: Screening, Treatment, PFS follow-up
(if applicable), and Long-term follow-up.  The screening period may not exceed a 28-day
window prior to start of study treatment (Cycle 1 Day 1). Subjects may continue on study 
treatment until PD or unacceptable toxicity. Subjects who discontinue treatment prior to PD
should remain in the PFS follow-up phase of the study and be assessed for efficacy until PD.  
Once discontinued from the study treatment or the PFS follow-up period, subjects will enter the 
long-term follow-up phase and will be contacted every 3 months for at least 5 years after the last 
subject is randomized into the study, or longer if clinically indicated (unless the follow-up is 
shorter due to withdrawal of consent, loss to follow-up, or death).
Study Treatments
Pomalidomide will be provided to all sites by Celgene Corporation as an investigational product.
Investigative sites in the United States and Japan will use commercially available bortezomib 
(Velcade®) for this study and will dispense this drug to subjects via prescription.  For 
investigative sites outside of the United States and Japan, bortezomib supplies will be provided 
by Celgene Corporation as commercial material labeled appropriately as Investigational Product 
(IP).
Investigative sites in the United States will use commercially available dexamethasone for this 
study and will dispense this drug to subjects via prescription.  For investigative sites outside of 
the United States, dexamethasone supplies will be provided by Celgene Corporation as 
commercial material labeled appropriately as Investigational Product (IP).  
Subjects will be randomized to Treatment Arm A or Treatment Arm B at a 1:1 ratio.
Treatment Arm A: Subjects randomized to Treatment Arm A (POM + BTZ + LD-DEX) will 
receive the following medications by 21-day treatment cycle:
!
Oral POM 4 mg/day on Days 1 to 14 of each 21-day treatment cycle
!
BTZ 
∀
For Cycles 1 – 8: 1.3 mg/m2/dose on Days 1, 4, 8, and 11 of a 21-day cycle
∀
For Cycles 9 onwards: 1.3 mg/m2/dose on Days 1 and 8 of a 21-day cycle
!
Oral DEX
∀
For Cycles 1 to 8, 20 mg/day (≤ 75 years old) or 10 mg/day (> 75 years old) on 
Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle.
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Celgene Corporation
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∀
For Cycles 9 and onward, 20 mg/day (≤ 75 years old) or 10 mg/day (> 75 years 
old) on Days 1, 2, 8, and 9 of a 21-day cycle.
Treatment Arm B: Subjects randomized to Treatment Arm B (BTZ + LD-DEX) will receive
the following medications by 21 -day treatment cycle:
!
BTZ 
∀
For Cycles 1 – 8:  1.3 mg/m2/dose on Days 1, 4, 8, and 11 of a 21-day cycle
∀
For Cycles 9 onwards:  1.3 mg/m2/dose on Days 1 and 8 of a 21-day cycle
!
Oral DEX
∀
For Cycles 1 to 8, 20 mg/day (≤ 75 years old) or 10 mg/day (> 75 years old) on 
Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle.
∀
For Cycles 9 and onward, 20 mg/day (≤ 75 years old) or 10 mg/day (> 75 years 
old) on Days 1, 2, 8, and 9 of a 21-day cycle.
Overview of Efficacy Assessments
!
Myeloma paraprotein (M-protein)
!
Serum immunoglobulins
!
Serum Free Light Chain
!
Corrected serum calcium
!
Bone marrow aspiration/biopsy
!
Radiographic assessments of lytic bone lesions (skeletal survey)
!
Extramedullary plasmacytoma (EMP) assessments
Overview of Safety Assessments
!
Complete physical examination including vital signs
!
Clinical laboratory evaluations (hematology, serum chemistry, urinalysis)
!
Venous thromboembolism (VTE) monitoring
!
Pregnancy testing / counseling
!
Electrocardiogram (ECG)
!
Concomitant medications and procedures
!
AEs
!
Second primary malignancies will be monitored as events of interest and should be 
included as part of the assessment of adverse events throughout the course of the 
study. Investigators are to report any second primary malignancies as serious adverse 
events regardless of causal relationship to study treatment (pomalidomide, 
bortezomib or dexamethasone), occurring at any time from the time of signing the 
informed consent up to and including the long-term follow-up period.
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Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 Jun 2017
Overview of Other Assessments
!
Eastern Cooperative Oncology Group (ECOG) performance status
!
Cytogenetics
!
Beta-2 microglobulin (β2M)
!
!
Hospital / Emergency department utilization
!
Quality of Life (QoL) questionnaires (if permitted by local regulations)
∀
The European Organization for Research and Treatment of Cancer QoL 
Questionnaire for Patients with Multiple Myeloma (EORTC QLQ-MY20) 
Module
∀
The European Organization for Research and Treatment of Cancer QoL 
Questionnaire for Patients with Cancer (EORTC QLQ-C30) Module
∀
The descriptive system of the EQ-5D
!
Bone marrow and blood samples for Minimal Residual Disease (MRD), genomic, 
molecular/mechanistic and immune biomarkers at sites permitted by local regulations, 
where operationally and logistically feasible, and only for subjects who consent to 
participate in the optional biomarker study (Optional)
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Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................21
1.1.
Treatment Options for Relapsed or Refractory Multiple Myeloma ..........................21
1.2.
Bortezomib in Relapsed or Refractory Multiple Myeloma ......................................22
1.3.
Pomalidomide (CC-4047).......................................................................................23
1.4.
Experience with IMiDs® in Combination with Bortezomib in Relapsed 
and/or Refractory Multiple Myeloma......................................................................26
1.4.1.
Pre-clinical .............................................................................................................26
1.4.2.
Clinical...................................................................................................................26
1.4.2.1.
Lenalidomide and Bortezomib................................................................................26
1.4.2.2.
Pomalidomide With Bortezomib.............................................................................27
2.
STUDY OBJECTIVES...........................................................................................29
2.1.
Primary Objectives .................................................................................................29
2.2.
Secondary Objectives .............................................................................................29
2.3.
Exploratory Objectives ...........................................................................................29
3.
STUDY ENDPOINTS............................................................................................30
3.1.
Primary Endpoint....................................................................................................30
3.2.
Secondary Endpoints ..............................................................................................30
3.3.
Exploratory Endpoints............................................................................................30
4.
OVERALL STUDY DESIGN ................................................................................31
4.1.
Study Design ..........................................................................................................31
4.2.
Study Design Rationale ..........................................................................................32
4.3.
Study Duration .......................................................................................................37
4.4.
End of Trial ............................................................................................................39
5.
TABLE OF EVENTS.............................................................................................40
6.
PROCEDURES......................................................................................................48
6.1.
Study Entry.............................................................................................................48
6.1.1.
Screening................................................................................................................48
6.1.2.
Wash-out................................................................................................................48
6.1.3.
Randomization........................................................................................................48
6.2.
Safety Assessments.................................................................................................49
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6.2.1.
Adverse Events.......................................................................................................49
6.2.1.1.
Serious Adverse Events ..........................................................................................49
6.2.1.2.
Second Primary Malignancies.................................................................................49
6.2.2.
Prior and Concomitant Medications and Procedures ...............................................50
6.2.3.
VTE Monitoring .....................................................................................................50
6.2.4.
Complete Physical Exam and Measurement of Vital Signs, Height, and 
Weight....................................................................................................................50
6.2.5.
Electrocardiogram ..................................................................................................50
6.2.6.
Laboratory Assessments for Safety Parameters.......................................................50
6.2.7.
Pregnancy Counseling (males and females) ............................................................51
6.2.8.
Contraception and Pregnancy Testing Requirements...............................................52
6.3.
Efficacy Assessments .............................................................................................52
6.3.1.
Laboratory Assessments for Efficacy Parameters....................................................53
6.3.2.
Bone Marrow Aspiration and/or Biopsy and Cytogenetics ......................................53
6.3.3.
Skeletal Survey.......................................................................................................54
6.3.4.
Extramedullary Plasmacytoma Assessments...........................................................54
6.3.5.
Assessment of Response.........................................................................................54
6.3.5.1.
Investigators’ Assessment for Tumor Response ......................................................54
6.3.5.2.
IRAC Assessment for Tumor Response ..................................................................54
6.3.6.
Overall Survival and Subsequent Anti-MM Therapies ............................................55
6.4.
Other Assessments..................................................................................................55
6.4.1.
ECOG Performance Status......................................................................................55
6.4.2.
Serum Beta-2 Microglobulin (β2M)........................................................................55
6.4.3.
Healthcare Resource Utilization..............................................................................55
6.4.4.
Quality of Life (QoL) .............................................................................................55
6.4.6.
Exploratory Biomarker Sampling............................................................................56
6.4.6.1.
Minimal Residual Disease (MRD), Genomic, Molecular/Mechanistic 
Biomarkers .............................................................................................................57
6.4.6.2.
Immune Biomarkers ...............................................................................................57
7.
STUDY POPULATION.........................................................................................58
7.1.
Number of Subjects and Sites .................................................................................58
7.2.
Inclusion Criteria....................................................................................................58
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7.3.
Exclusion Criteria...................................................................................................59
8.
DESCRIPTION OF STUDY TREATMENTS........................................................62
8.1.
Description of Investigational Product(s)................................................................62
8.2.
Treatment Administration and Schedule .................................................................63
8.2.1.
Treatment Arm A: (POM + BTZ + LD-DEX).........................................................63
8.2.2.
Treatment Arm B: (BTZ + LD-DEX) .....................................................................64
8.3.
Overdose ................................................................................................................64
8.4.
Dose Modification and Interruption ........................................................................64
8.4.1.
Dose Modification Instructions for Pomalidomide ..................................................65
8.4.2.
Dose Modification Instructions for Bortezomib ......................................................67
8.4.3.
Dose Modification Instructions for Low-Dose Dexamethasone...............................68
8.5.
Method of Treatment Assignment...........................................................................69
8.6.
Packaging and Labeling..........................................................................................69
8.7.
Investigational Product Accountability and Disposal ..............................................69
8.8.
Investigational Product Compliance........................................................................71
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................72
9.1.
Permitted Concomitant Medications and Procedures...............................................72
9.2.
Prohibited Concomitant Medications and Procedures..............................................72
9.3.
Required Concomitant Medications and Procedures................................................73
10.
STATISTICAL ANALYSES..................................................................................74
10.1.
Overview................................................................................................................74
10.2.
Study Population Definitions ..................................................................................74
10.3.
Sample Size and Power Considerations...................................................................74
10.4.
Background and Demographic Characteristics........................................................75
10.5.
Subject Disposition.................................................................................................75
10.6.
Efficacy Analysis....................................................................................................75
10.6.1.
Primary Endpoint: Progression Free Survival (PFS)................................................75
10.6.2.
Secondary Endpoints ..............................................................................................77
10.6.2.1.
Overall Survival .....................................................................................................77
10.6.2.2.
Response Assessment by the IMWG Criteria..........................................................77
10.6.2.3.
Duration of Response .............................................................................................78
10.7.
Safety Analysis.......................................................................................................78
10.8.
Exploratory Endpoints............................................................................................79
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10.8.2.
Exploratory Efficacy Analysis ................................................................................79
10.8.2.1.
Response using the EBMT Criteria.........................................................................79
10.8.2.2.
Time to Progression and Time to Response.............................................................79
10.8.2.3.
Time to Treatment Failure ......................................................................................80
10.8.2.4.
Progression-free Survival 2 (PFS2).........................................................................80
10.8.2.5.
Sub-group Analysis ................................................................................................80
10.8.3.
Clinical Benefits.....................................................................................................80
10.8.4.
Quality of Life (QoL) .............................................................................................81
10.8.5.
Healthcare Resource Utilization..............................................................................81
10.8.6.
Exploratory Biomarker Analysis.............................................................................81
10.9.
Interim Analysis .....................................................................................................82
10.10.
Statistical Approaches for Control of Alpha and Other Considerations....................82
11.
ADVERSE EVENTS..............................................................................................83
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................83
11.2.
Evaluation of Adverse Events.................................................................................83
11.2.1.
Seriousness.............................................................................................................83
11.2.2.
Severity / Intensity..................................................................................................85
11.2.3.
Causality ................................................................................................................85
11.2.4.
Duration .................................................................................................................86
11.2.5.
Action Taken..........................................................................................................86
11.2.6.
Outcome.................................................................................................................86
11.3.
Abnormal Laboratory Values..................................................................................86
11.4.
Pregnancy...............................................................................................................87
11.4.1.
Females of Childbearing Potential: .........................................................................87
11.4.2.
Male Subjects.........................................................................................................87
11.5.
Reporting of Serious Adverse Events......................................................................87
11.5.1.
Safety Queries ........................................................................................................88
11.6.
Expedited Reporting of Adverse Events..................................................................88
12.
DISCONTINUATIONS .........................................................................................90
13.
EMERGENCY PROCEDURES.............................................................................91
13.1.
Emergency Contact.................................................................................................91
13.2.
Emergency Identification of Investigational Products .............................................91
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14.
REGULATORY CONSIDERATIONS...................................................................92
14.1.
Good Clinical Practice............................................................................................92
14.2.
Investigator Responsibilities ...................................................................................92
14.3.
Subject Information and Informed Consent.............................................................92
14.4.
Confidentiality........................................................................................................93
14.5.
Protocol Amendments.............................................................................................93
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................93
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................94
14.8.
Closure of the Study ...............................................................................................94
15.
DATA HANDLING AND RECORDKEEPING.....................................................95
15.1.
Data/Documents.....................................................................................................95
15.2.
Data Management...................................................................................................95
15.3.
Record Retention....................................................................................................95
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................97
16.1.
Study Monitoring and Source Data Verification......................................................97
16.2.
Audits and Inspections............................................................................................97
17.
PUBLICATIONS ...................................................................................................98
18.
REFERENCES.......................................................................................................99
19.
APPENDICES......................................................................................................103
Appendix A:
VTE Algorithms..............................................................................................103
Appendix B:
International Myeloma Working Group Response Criteria...............................107
Appendix C:
European Group for Blood and Marrow Transplantation Criteria .....................109
Appendix D:
Skeletal (Bone) Survey Films ..........................................................................111
Appendix E:
ECOG Performance Status Scale......................................................................112
Appendix F:
Cockcroft-Gault Estimation Of Creatinine Clearance (CrCl) ............................113
Appendix G:
QT Drugs by Risk Group.................................................................................114
Appendix H:
Staging Systems for Multiple Myeloma ...........................................................115
Appendix I:
Quality of Life Questionnaires ..........................................................................116
Appendix J:
List of Abbreviations ........................................................................................121
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LIST OF TABLES
Table 1:
Table of Events.......................................................................................................40
Table 2:
Dose Modification Instructions for Pomalidomide (Treatment Arm A only) ...........66
Table 3:
Pomalidomide Dose Reduction Steps......................................................................67
Table 4:
Bortezomib Dose Modification...............................................................................67
Table 5:
Bortezomib Dose Reduction Levels........................................................................68
Table 6:
Dose Reductions for Low-Dose Dexamethasone Related Toxicities........................68
Table 7:
Low-Dose Dexamethasone Dose Reduction Steps ..................................................69
Table 8:
Censoring Rules for PFS.........................................................................................76
Table 9:
Staging Systems for Multiple Myeloma ................................................................115
Table 10:
List of Abbreviations............................................................................................121
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LIST OF FIGURES
Figure 1: Study Schema ............................................................................................................36
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1.
INTRODUCTION
Multiple myeloma (MM) is a rare and incurable progressive neoplastic disease that accounts for 
10% of all hematological malignancies.  It was estimated in 2010 that 20,180 new cases and 
10,650 deaths from the disease occurred in the United States (US) (Jemal, 2010). 
Significant progress has been made in the treatment of newly diagnosed MM with different 
combinations of melphalan, prednisone, dexamethasone, doxorubicin, thalidomide, lenalidomide
and proteasome inhibitors (bortezomib) or autologous stem cell transplant following high-dose 
chemotherapy in appropriate patients (National Comprehensive Cancer Network [NCCN]
Clinical Practice Guidelines in Oncology for MM, 2012; Child, 2003; Fermand, 2005). In recent 
years, innovative therapies such as proteasome inhibitors and immunomodulators have improved 
the prognosis for previously treated MM subjects (Kumar, 2008). However, the disease follows a 
relapsing course in the majority of patients, regardless of treatment regimen or initial response to 
treatment.  MM remains incurable using conventional treatments, with median survival duration 
of approximately 5 years (Richardson, 2007a).  Therefore, there is a need for more effective 
therapeutic options for the treatment of relapsed or refractory multiple myeloma.
1.1.
Treatment Options for Relapsed or Refractory Multiple Myeloma
The treatment options approved for use in relapsed and/or refractory MM currently include:
Panobinostat:  Panobinostat in combination with bortezomib and dexamethasone, is indicated 
for the treatment of patients with multiple myeloma who have received at least 2 prior regimens 
including bortezomib and an immunomodulatory agent.
Lenalidomide plus dexamethasone: Lenalidomide in combination with dexamethasone for the 
treatment of patients with MM who have received at least one prior therapy (Revlimid
Prescribing Information 2013).
Bortezomib:  Bortezomib monotherapy for the treatment of patients with relapsed MM
(Velcade® Prescribing Information, 2014).
Pegylated doxorubicin-liposomal plus bortezomib: Pegylated liposomal doxorubicin (PLD) 
in combination with bortezomib for the treatment of patients with MM who have not previously 
received bortezomib and have received at least one prior therapy (Velcade® Prescribing 
Information, 2014).
Carfilzomib:  Carfilzomib for the treatment of multiple myeloma in patients who have received 
at least 2 prior therapies including bortezomib and an immunomodulatory agent and have 
demonstrated disease progression on or within 60 days of completion of the last therapy 
(Kyprolis® Prescribing Information, 2012).
Pomalidomide plus dexamethasone:  Pomalidomide is a thalidomide analogue indicated, in 
combination with dexamethasone, for patients with multiple myeloma who have at least two 
prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease 
progression on or within 60 days of completion of the last therapy (Pomalyst® / Imnovid®
Prescribing Information, 2015).
Other options that may be considered for salvage therapy in MM patients include thalidomide 
alone or in combination with dexamethasone or other agents, lenalidomide monotherapy, 
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lenalidomide in combination with bortezomib and dexamethasone, or lenalidomide or 
bortezomib in combination with cyclophosphamide and dexamethasone (NCCN Clinical Practice 
Guidelines in Oncology for Multiple Myeloma, 2012).
The main considerations for choosing an appropriate treatment for relapsed MM are: risk level, 
prior therapy, duration of response to prior therapy, residual toxicity, age, physical condition, and 
whether or not the patient is a candidate for allogeneic stem cell transplantation (NCCN Clinical 
Practice Guidelines in Oncology for Multiple Myeloma, 2012; Kastritis, 2009).
1.2.
Bortezomib in Relapsed or Refractory Multiple Myeloma
Bortezomib (Velcade®) was approved for the treatment of relapsed or refractory MM based on 
the results of a Phase 3 trial (APEX Trial) comparing bortezomib to high dose dexamethasone as 
salvage therapy.  In an updated efficacy analysis of the APEX trial, the response rate was 43% 
with bortezomib vs. 18% for dexamethasone and the overall survival (OS) was 30 months with 
bortezomib vs. 23.7 months with dexamethasone (Richardson, 2007c).
The benefits of the adding dexamethasone to bortezomib therapy were shown in the SUMMIT 
trial in which 202 relapsed or refractory MM subjects were enrolled (Richardson, 2003).  In this 
phase 2 study, patients received 1.3 mg/m2 of bortezomib for up to eight cycles.  In patients with 
a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after 
bortezomib administration) was added to the regimen.  Seventy-eight patients who had either 
stable or progressive disease (PD) while receiving bortezomib alone subsequently received 
dexamethasone in combination with bortezomib.  Of these 78, a total of 74 patients could be 
evaluated for a response to this combination, and 13 of these patients (18 percent) had a minimal 
or partial response. In 6 of these 13 patients, the disease had previously been refractory to 
corticosteroid therapy.  Bortezomib in combination with dexamethasone is therefore included in 
the NCCN clinical practice guidelines as a category 2A recommendation for salvage therapy in 
MM patients (NCCN Clinical Practice Guidelines in Oncology for MM, 2012).
The approval of Doxil® (doxorubicin HCl) in combination with bortezomib has led to more 
treatment options for relapsed or refractory MM.  The approval of this regimen was based on a 
Phase 3 study in 646 patients showing a significant increase in median time to disease
progression in Doxil plus bortezomib arm compared to bortezomib monotherapy arm (9.3 vs. 6.5 
months, respectively).  Starting from the 2010 NCCN clinical practice guidelines for Multiple 
Myeloma, this combination was recommended as superior over bortezomib monotherapy for 
relapsed / refractory MM.  However, no data were submitted in support of the effectiveness of 
this combination treatment in patients who had received bortezomib previously (Orlowski,
2007).
Recently published data from a number of Phase 3 studies has revealed that the progression free 
survival (PFS) of the bortezomib with dexamethasone (BTZ+LD-DEX) arm on this study CC-
4047-MM-007 (OPTIMISMM), that requires prior treatment with lenalidomide as per protocol 
Inclusion Criteria #7 (Section 7.2), is expected to be shorter than the original OPTIMISMM 
Protocol statistical assumption of 9 months (relevant median PFS data from Phase 3
ENDEAVOR, PANORAMA-1 and CASTOR studies ranging from 7 to 8 months) (Moreau, 
2017; Palumbo, 2016; San Miguel 2014).
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Subcutaneous (SQ) versus Intravenous (IV) bortezomib 
The total system exposure after repeat dose administration (AUC last) was shown to be similar 
following IV or SQ administration of BTZ.  In addition, findings from an open-label, 
randomized, phase 3 non-inferiority study comparing the efficacy and safety of SQ versus IV 
administration of bortezomib supported the substitution of SQ administration for IV with a 
similar efficacy and safety profile and a decreased incidence of peripheral neuropathy (Velcade®
Prescribing Information, 2014).
1.3.
Pomalidomide (CC-4047)
Pomalidomide (CC-4047, 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione) is a novel 
immunomodulatory drug under development for the treatment of MM.  Pomalidomide was first 
approved in the United States (US) on 08 Feb 2013 under the trade name Pomalyst®, and most 
recently has received full approval for the combination of pomalidomide with dexamethasone on 
23 Apr 2015. Pomalidomide was approved in the European Union (EU) (Imnovid®, originally 
Pomalidomide Celgene®) on 05 Aug 2013 through the centralized authorization procedure.  
Pomalidomide shares a number of the beneficial pharmacologic properties of thalidomide and 
lenalidomide.  An in vitro model of anti-tumor necrosis factor (TNF) activity has shown that 
pomalidomide has an IC50 of approximately 0.013 μM (13 nM) against TNF produced by 
lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMC).  
Thalidomide and lenalidomide, by comparison, have an IC50 of ~194 μM and 0.10 μM (100 nM), 
respectively (Corral, 1999; Muller, 1999).  In LPS-stimulated human whole blood, IC50 for 
pomalidomide is 0.025 μM (25 nM) (Muller, 1999).  In addition, pomalidomide has 
demonstrated a 10-fold higher potency for T cell co-stimulation than lenalidomide (Corral 1999, 
Teo 2005).  Pomalidomide also augmented the activity of natural killer (NK) cells and enhanced 
antibody-dependent cell-mediated cytotoxicity (ADCC) of targeted tumor cells in combination 
with therapeutic antibodies to tumor-specific surface antigens (Hayashi, 2005; Hernandez-
Ilizaturri, 2005).  Moreover, pomalidomide is also a potent inhibitor of the proliferation of MM 
cell lines in vitro.  Concentrations of 2.73 to 27.3 ng/mL (0.01 to 0.1 μM) achieved a 50% 
inhibition of MM.1S and Hs Sultan cell proliferation.  In contrast, at concentrations of 25.8 
μg/mL (100 μM), thalidomide inhibited the proliferation of MM.1S and Hs Sultan cells by only 
15% and 20%, respectively.  Pomalidomide is also more potent than thalidomide or lenalidomide 
in inducing G1 growth arrest and apoptosis in MM cell lines and in patient MM cells that are 
resistant to melphalan, doxorubicin, and dexamethasone as well as in enhancing the anti-MM 
activity of dexamethasone (Hideshima, 2000).  However, pomalidomide does not inhibit the 
proliferation of normal B cells but rather protects them from apoptosis, suggesting an additive 
property of this compound in helping the repopulation of the normal blood cells (Verhelle, 
2007).
Of potential relevance to the refractory MM setting, pomalidomide appears to retain anti-
proliferative activity against H929 and KMS-12-BM MM cells that have increased resistance to 
acute lenalidomide treatment following chronic exposure to lenalidomide (Adams, 2009; 
Rychak, 2011).  Pomalidomide and dexamethasone were also synergistic at inhibition of cell 
proliferation in lenalidomide-resistant cell lines.  Preliminary results from an in vitro experiment 
performed by the Celgene Research group (Adams, 2009; Rychak, 2011) demonstrate that MM 
cells treated long-term with lenalidomide plus dexamethasone and with pomalidomide plus 
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dexamethasone became resistant to lenalidomide/dexamethasone but retained their sensitivity to 
pomalidomide/dexamethasone.  This suggests that the combination of pomalidomide plus 
dexamethasone may be useful in the treatment of MM that is refractory to lenalidomide plus 
dexamethasone. Experience with Pomalidomide in Relapsed and/or Refractory MM
The clinical experience with pomalidomide in relapsed and/or refractory MM is limited to 2 
Celgene-sponsored trials and 2 investigator-initiated trials. 
Celgene Phase 1b Study (CDC-407-00-001 / CC-4047-MM-001; Completed): This was a 
phase 1b single-center, ascending dose (1, 2, 5, and 10 mg), open-label study to identify the 
maximum tolerated dose (MTD) and evaluate the safety and efficacy of pomalidomide given 
continuously (cohort 1; Schey, 2004) or on alternate days (cohort 2; Streetly, 2008) in 45 
subjects with MM who were considered refractory to treatment after at least two cycles of 
treatment or who relapsed after previous treatment.  The MTD was 2 mg continuously and 5 mg 
on alternate days; the most common dose limiting toxicity (DLT) was grade 4 neutropenia.  The 
most common AEs were neutropenia, thrombocytopenia, pharyngitis, cough, dyspnea, and 
hypoesthesia.  Overall, 23 (51%) of 45 subjects had PR or better, including 6 CR and 12 VGPR.  
In cohort 1, the progression free survival (PFS) was 9.75 months and OS was 22.5 months; in 
cohort 2, the PFS was 10.5 months and OS was 35.9 months.
Celgene Phase 1b/2 Study (CC-4047-MM-002; Enrollment completed): This was a phase 
1b/2 multicenter, randomized, open-label, dose escalation (2, 3, 4, and 5 mg) study to evaluate 
the MTD of pomalidomide alone (Phase 1) and the safety and efficacy of pomalidomide alone 
using a cyclic regimen (21 of 28 days) and in combination with low-dose dexamethasone (Phase 
2) using a cyclic regimen (21 of 28 days) in subjects with relapsed and refractory MM who had 
received ≥ 2 prior anti-MM regimens. All subjects must have received prior treatment that 
included lenalidomide and bortezomib. In the phase 1b segment of the study, 38 subjects were 
enrolled.  The MTD was 4 mg which was the dose selected for the phase 2 part of the study.  The 
safety profile was similar across cohorts except for grade 4 neutropenia, which was the DLT and 
was experienced at the highest rate in the 5 mg cohort. A total of 221 subjects were enrolled in 
phase 2 (POM+LD-DEX n = 113; POM n = 108); 219 received ≥ 1 cycle of study treatment and 
191 subjects were evaluable for response. Baseline characteristics were comparable between the 
two arms with a median of 5 (range 2–13) prior therapies in both arms; 74% of subjects in 
POM+LD-DEX and 76% of subjects in POM alone had prior autologous stem-cell 
transplantation (ASCT). The remaining subjects were elderly (aged > 75 yrs) or ineligible for 
ASCT; all subjects were exposed to corticosteroids and 84% in the POM+LD-DEX and 95% in 
POM alone arms were exposed to alkylators. Subjects were refractory to LEN (POM+LD-DEX 
77% and POM alone 79%), BTZ (73% and 69%), or both drugs (61% and 59%). Among 
subjects who were randomized to receive POM alone, 61 (56%) subsequently went on to receive 
POM+LD-DEX due to progressive disease (PD) per protocol. A median of 5 (range 1–17) 
treatment cycles were received by subjects in both arms. Median treatment duration was 5.0 mos.  
Response of ≥ PR was seen in 34% of subjects in the POM+LD-DEX arm and 13% in the POM 
alone arm, including 1% complete response (CR) in each arm; ≥ MR was 45% vs. 29%, 
respectively. Median DOR was 7.7 months with POM+LD-DEX and 8.3 months with POM 
alone, and median PFS was 4.6 and 2.6 months, respectively. Median OS was comparable for 
both arms (14.4 and 13.6 months). Results from independent adjudication were similar, with ≥ 
PR in 30% of subjects in the POM+LD-DEX arm and 9% in the POM alone arm, including 1% 
and 0% CR, respectively, in each arm. ≥ MR was achieved with POM+LD-DEX in 45% and 
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with POM alone in 25%; PFS was 3.8 and 2.5 months, respectively. In the subgroup of subjects 
refractory to both lenalidomide and bortezomib, 30% and 16% of subjects treated with 
POM+LD-DEX or POM alone, respectively, achieved ≥ PR; ≥ MR was 45% and 30%, 
respectively. Median PFS was 3.8 months for POM+LD-DEX and 2.0 months for POM alone; 
median OS showed a similar trend (13.5 and 10.8 months, respectively). The main reason for 
treatment discontinuation was PD in both arms (POM+LD-DEX 51%; POM alone 44%); 
discontinuations due to adverse events (AEs) were 7% and 12%, respectively. Grade 3/4 AEs in 
POM+LD-DEX vs. POM alone, respectively, were: neutropenia 38% and 47%; febrile 
neutropenia 2% and 2%; thrombocytopenia 19% and 21%; anemia 21% and 17%; pneumonia 
19% and 8%; and fatigue 10% and 8%. All grades of peripheral neuropathy, deep vein 
thrombosis, and renal failure occurred in 7% and 10%, 2% and 1%, and 2% and 1% of subjects 
for POM+LD-DEX vs. POM alone, respectively (Richardson, 2011a).
Investigator Initiated Phase 2 Study at the Mayo Clinic (PO-MM-PI-0010; Enrollment 
completed): This is a phase 2 open-label study of pomalidomide (2 mg continuous) plus low-
dose dexamethasone (40 mg/day on days 1, 8, 15, and 22) in subjects with relapsed or refractory 
MM who had received 1-3 prior regimens (Lacy, 2009a).  A total of 60 subjects were initially 
enrolled into this study.  Thirty-eight (63%) of the 60 subjects had confirmed response including 
3 CR and 17 VGPR.  Responses were seen in 8 of 12 (66.7%) lenalidomide-refractory subjects, 6 
of 16 (37%) thalidomide-refractory subjects, and 6 of 10 (60%) bortezomib refractory subjects. 
The most common Grade 3/4 hematological toxicity was neutropenia, and the most common 
non-hematological Grade 3/4 toxicities were fatigue and pneumonia. 
Since responses were observed in some patients who were refractory to lenalidomide in the 
initial cohort of 60 subjects, an additional cohort of 34 subjects, who were refractory to prior 
lenalidomide therapy, was enrolled from November 2008 to April 2009.  The overall response 
rate (≥PR) was 32% for this cohort of 34 subjects.  The most common Grade 3/4 hematologic 
toxicity was neutropenia (29%) and the most common Grade 3/4 non-hematologic toxicity was 
fatigue (9%), which was consistent with that observed in the initial cohort of 60 subjects (Lacy, 
2010b).
Based on experience of Richardson, et al (Richardson, 2009a) where the MTD of pomalidomide 
was determined to be 4 mg, a phase 2 study was initiated by Lacy, et al to compare the two 
different dosing regimens in MM subjects who were refractory to both lenalidomide and 
bortezomib.  Pomalidomide was given orally 2 mg/day or 4 mg/day, on Days 1 to 28 of a 28-day 
cycle, with dexamethasone 40 mg daily on Days 1, 8, 15 and 22.  A total of 70 subjects were 
enrolled (35 in the 2 mg cohort and 35 in the 4 mg cohort).  The most common Grade 3/4 
hematologic toxicity was neutropenia, and the most common non-hematologic toxicity was 
fatigue.  The overall response rate (≥ PR) was 25% and 29% for the 2 mg and 4 mg cohorts,
respectively (Lacy, 2010c).
Investigator Initiated Phase 2 Study (PO-MM-PI-0024; Enrollment completed): This is a 
phase 2, multicenter, randomized, open-label study of pomalidomide plus dexamethasone in 
subjects with relapsed and refractory MM who have received bortezomib and lenalidomide, 
conducted by Intergroupe Français du Myelome (IFM).  Subjects received a 4 mg dose of 
pomalidomide, given either in a continuous (28-day) or a cyclic (21-day out of 28-day cycles) 
regimen in combination with low-dose dexamethasone.  The primary endpoint is the response 
rate, and the secondary endpoints are safety, time to response, time to disease progression, and 
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OS.  Eighty-four subjects were enrolled into this study, 43 in the 4 mg 21/28 days arm (Cohort 
A) and 41 in the 4 mg 28/28 days arm (Cohort B).  At the cut-off of 01 Mar 2011, overall 
response rate (ORR) was 34.9% in Cohort A and 34.1% in Cohort B, including 4.7% and 7.3% 
≥VGPR, respectively. Overall, 40 (47.6%) subjects had stable disease (including minor 
response) and 3 subjects reached CR. The median PFS was 6.3 (4.1-9.1) months in either arm, 
and the median duration of response was 11.4 (3.7-13.6) months and 7.9 (4.0- not reached) 
months in Cohort A and in Cohort B, respectively. The median PFS was 4.2 (3.3-6.9) months for 
subjects with stable disease (SD) as compared to 12.6 (9.9-14.8) months in subjects that had a 
response.  The primary toxicity was myelosuppression and was similar in both treatment arms 
(Leleu, 2011a).
The results of studies conducted thus far indicate that pomalidomide has activity in patients with 
relapsed and/or refractory MM, including patients who are refractory to lenalidomide and 
bortezomib. Confirmed response rates range between 30% and 60% at pomalidomide doses of 
between 2 and 4 mg/day in combination with dexamethasone.  Notably, pomalidomide produces 
responses in subjects who are refractory to lenalidomide, another IMiDs® compound, aligning 
with the non-clinical results observed in lenalidomide-resistant cells (Adams, 2009; Rychak, 
2011).  The most common hematological toxicity experienced by these subjects is neutropenia 
(non-febrile), which can be managed by dose reductions or interruptions.  The most common 
non-hematological toxicities are fatigue and pneumonia.
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of 
pomalidomide.
1.4.
Experience with IMiDs® in Combination with Bortezomib in 
Relapsed and/or Refractory Multiple Myeloma
1.4.1.
Pre-clinical 
Preclinical studies have shown that both thalidomide and lenalidomide potentiate the activity of 
bortezomib in combination of dexamethasone (Mitsiades, 2002; Hideshima, 2000).  
Lenalidomide and dexamethasone have been shown to trigger myeloma cell apoptosis via 
caspase-8 and caspase-9, respectively. Bortezomib can activate both of these pathways and also 
can counteract the inhibitory effect of nuclear factor–kappa B (NF- κB) on the antimyeloma 
activity of dexamethasone. These molecular events potentiate the induction of a dual caspase-8 
and caspase-9–mediated apoptotic cascade with poly(ADP-ribose) polymerase (PARP) cleavage, 
leading to enhanced antimyeloma activity.
1.4.2.
Clinical 
1.4.2.1.
Lenalidomide and Bortezomib
The combination of an immune modulator (lenalidomide) with bortezomib, has shown promising 
efficacy as frontline and salvage treatment in MM patients.  As frontline therapy, the 
combination of lenalidomide (25 mg), bortezomib (1.3 mg/m2), and low-dose dexamethasone
generated high response in a phase 1/2 study (Richardson, 2010c). This combination has also 
been shown to be well-tolerated and active in heavily pretreated relapsed / refractory MM 
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patients, including patients with prior treatment with lenalidomide, bortezomib, and/or 
thalidomide, and with prior stem cell transplantation (Richardson 2009a).  In the phase I, dose-
escalation study in relapsed/refractory MM, patients received lenalidomide on Days 1 through 14 
and bortezomib on Days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone was added for PD
after two cycles. Thirty-eight patients were enrolled across 6 dose cohorts. The MTD was 
lenalidomide 15 mg/day plus bortezomib 1 mg/m2/dose. Dose-limiting toxicities (n = 1 for each) 
were Grade 3 hyponatremia and herpes zoster reactivation, and Grade 4 neutropenia. The most 
common treatment-related, Grades 3 to 4 toxicities included reversible neutropenia, 
thrombocytopenia, anemia, and leukopenia. Of the 36 efficacy evaluable patients, 61% achieved 
≥ MR. Of the 18 patients who had dexamethasone added, 83% achieved ≥ SD. Based on the 
promising results in the Phase 1 study, a Phase 2 study of lenalidomide, bortezomib, and 
dexamethasone in relapsed / refractory subjects was initiated.  The updated efficacy and safety 
data for after more than 2 years of follow-up for the Phase 2 study were reported at the ASH 
2010 annual meeting (Richardson, 2010).  Sixty-four subjects were treated in the study, 78% 
achieved ≥ MR, 64% achieved ≥ PR, and 25% achieved CR / near CR.  The most common 
toxicities were peripheral neuropathy (64%), fatigue (48%), neutropenia (30%) and 
thrombocytopenia (22%).
1.4.2.2.
Pomalidomide With Bortezomib
In the Celgene-sponsored CC4047-MM-005 (MM-005) study, the dose escalation to determine 
the dose for the combination of POM+BTZ+DEX was performed using intravenous (IV) BTZ, 
as only the IV BTZ formulation was approved at the time the trial was initiated.  In the first 4 
cohorts of MM-005, the POM dose was escalated from 1 mg to 4 mg with the IV BTZ at 1
mg/m2, and in the last dose-escalation cohort the POM dose was 4 mg with IV BTZ at 1.3
mg/m2. An additional 7 subjects were enrolled into an expansion cohort to further confirm the 
safety and preliminary efficacy of the 4 mg POM + 1.3 mg/m2 IV BTZ + LD-DEX dose.  The 
combination of POM+ IV BTZ+DEX was generally well tolerated in this RRMM population 
which had progressed on or within 60 days after their last lenalidomide therapy and had prior 
proteasome inhibitor exposure.  There were no DLTs in the first cycle and no discontinuations 
due to treatment-related AEs. The most common grade 3/4 toxicities were neutropenia (36%) 
and thrombocytopenia (27%).  Promising activity in this population was also shown with an 
ORR of 71% and 38% ≥ VGPR (Richardson, 2013a).
Due to the approval of SQ BTZ with safety data showing a decreased incidence of peripheral 
neuropathy compared to IV BTZ (Velcade® Prescribing Information, 2014), the MM-005 
protocol was amended in April 2013 to include an additional cohort of 6 subjects to explore the 
combination of 4 mg POM + 1.3 mg/m2 BTZ + LD-DEX with BTZ administered subcutaneously 
(SQ).  As of January 2014, all 6 subjects have been enrolled in the SQ BTZ cohort and have 
completed at least 3 cycles on study treatment.  There were no DLTs during the first cycle and 
no discontinuations due to treatment-related toxicities.  Only one subject discontinued after 
Cycle 3 due to non-treatment related cardiac arrest.  The following Grade 3 toxicities were 
reported to in 1 subject each: insomnia, memory impairment, asthenia, fatigue, blood phosphorus 
decreased, nephrolithiasis, blood creatine phosphokinase increased.  No Grade 4 toxicities have 
been reported.  Currently, the ORR is 67% (1 CR, 2 VGPR, 1 PR, 2 SD) (data on file at 
Celgene).
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2.
STUDY OBJECTIVES
2.1.
Primary Objectives
To compare the efficacy of POM + BTZ + LD-DEX with BTZ + LD-DEX in subjects with 
relapsed or refractory MM 
2.2.
Secondary Objectives
To evaluate the safety and additional efficacy of POM + BTZ + LD-DEX versus BTZ + LD-
DEX in subjects with relapsed or refractory MM.
2.3.
Exploratory Objectives
 
!
To evaluate the differences in clinical benefits of POM + BTZ + LD-DEX versus 
BTZ + LD-DEX in subjects with relapsed or refractory MM
!
To evaluate the differences in key efficacy variables of POM + BTZ + LD-DEX 
versus BTZ + LD-DEX within defined subgroups
!
To evaluate the differences in health-related quality of life of POM + BTZ + LD-
DEX versus BTZ + LD-DEX in subjects with relapsed or refractory MM
!
To evaluate Minimal Residual Disease (MRD), genomic, molecular/mechanistic and 
immune biomarkers and their correlation to clinical outcome measures for only those 
subjects who give their consent (Optional)
Data from exploratory objectives may not be included in the Clinical Study Report, but will be 
reported in a separate biomarker analysis report at the completion of the study.
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3.
STUDY ENDPOINTS
3.1.
Primary Endpoint
!
Progression-Free Survival (PFS)
3.2.
Secondary Endpoints
!
Overall Survival (OS)
!
Safety (type, frequency, seriousness and severity of AEs, and relationship of AEs to 
study drug or comparator)
!
Overall response rate (ORR) (using the International Myeloma Working Group 
Uniform [IMWG] response criteria)
!
Duration of response
3.3.
Exploratory Endpoints
!
ORR (using the European Group for Blood and Marrow Transplantation [EBMT] 
criteria)
!
Time to response
!
Time to progression (TTP)
!
Efficacy analysis in subgroups
!
Progression-free survival after next-line therapy (PFS2) 
!
!
Clinical benefits (improvement in hemoglobin value, improvement in renal function, 
improvement of ECOG performance status, improvement in hypercalcaemia, 
improvement in non-myeloma immunoglobulins)
!
The European Organization for Research and Treatment of Cancer QoL 
Questionnaire for Patients with Multiple Myeloma (EORTC QLQ-MY20) Module, 
the Cancer QoL Questionnaire for Patients with Cancer (EORTC QLQ-C30) Module, 
and the descriptive system of the EQ-5D 
!
Minimal Residual Disease (MRD), genomic, molecular/mechanistic and immune 
biomarkers for only those subjects who give their consent (Optional)
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4.
OVERALL STUDY DESIGN
4.1.
Study Design
This study is a multicenter, randomized, open-label, phase 3 study comparing the efficacy and 
safety of POM + BTZ + LD-DEX (Treatment Arm A) versus BTZ + LD-DEX (Treatment Arm 
B) in subjects with relapsed or refractory MM. 
For Treatment Arm A (POM + BTZ + DEX), the dose was based on the results from the CC-
4047-MM-005 (MM-005) Phase 1 dose escalation MTD study in which bortezomib was 
administered via IV infusion.  In the MM-005 study, the maximum planned dose (MPD), POM 
(4 mg) + IV BTZ (1.3 mg /m2) and DEX (20 mg subjects ≤ 75 years old/10 mg subjects > 75 
years old) was reached without any DLTs. Considering an early POM single agent MTD study 
(Richardson, 2013) as well as the findings in MM-005, the MPD was determined to be the 
optimal dose for the triple combination therapy.  With the optimal dose determined, MM-007 
was initiated using the MPD dose for the combination of POM + BTZ + LD-DEX (with IV 
BTZ).
During the conduct of the MM-005 study, subcutaneous (SQ) BTZ was approved as an 
alternative administration method for BTZ (23 Jan 2013).  The SQ BTZ was reported to have a 
decreased incidence of neurotoxicity versus the IV BTZ (Velcade® Prescribing Information, 
2014).  To explore the SQ route of BTZ administration in combination with POM and DEX, the 
MM-005 protocol was amended to add a cohort of 6 subjects at the MPD/optimal dose for the 
combination of POM + BTZ + LD-DEX with BTZ administered via SQ injection.  Based on the 
safety, efficacy and PK data for this SQ BTZ cohort (see Section 1.4) and general adoption in 
medical practice of SQ BTZ as standard of care due to decreased neurotoxicity, BTZ 
administration is now to be SQ for both arms in the MM-007 study (Treatment Arm A and B).
Subjects consented to the original MM-007 protocol can continue with IV BTZ or switch to SQ 
BTZ at the discretion of the treating physician.  Subjects randomized into MM-007 under IV 
BTZ treatment will not be replaced.
Approximately 544 subjects will be randomized equally (1:1 ratio) into the two treatment arms 
(272 subjects in each arm).
An Independent Response Adjudication Committee (IRAC) will be set up for this trial to review 
efficacy data in a blinded manner. The IRAC will determine the tumor response to therapy and to 
confirm the time of disease progression (PD) (if disease progressed) at scheduled or unscheduled 
visits for each subject. 
The safety and efficacy of the study will be monitored by an independent data monitoring 
committee (IDMC) who are not involved in the trial conduct. The IDMC will meet up and 
review unblinded trial data at pre-specified intervals throughout the trial.  At the time of the 
interim analysis, the IDMC will review the study data for futility assessment. In addition to the 
IDMC review, safety data will be monitored by the Celgene Medical Monitor and Safety 
Physician on an ongoing basis throughout the study. In the event when a significant safety issue 
is identified, the IDMC will be convened to make a recommendation as to the future conduct of 
the study.
The study will be conducted in sites globally.
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4.2.
Study Design Rationale
Randomization
Randomization is recognized as an appropriate means to minimize bias in subject selection for 
efficacy and safety assessments in clinical trials of 2 or more treatment groups. The study will 
utilize a centralized randomization procedure that will be accomplished by a validated interactive 
voice and web response system (IVRS/IWRS). 
Stratification
To minimize potential imbalances between treatment groups in subject characteristics that may 
impact on study outcomes, randomization will be stratified by the following baseline factors: 1) 
age (≤ 75 years old vs. > 75 years old); 2) number of prior regimens of anti-MM therapies (1 vs. 
>1); 3) β2M at screening (< 3.5 mg/L vs. ≥ 3.5 mg/L - ≤ 5.5 mg/L vs. > 5.5 mg/L).
Multicenter
This study will be conducted in sites globally.  The multicenter nature of the study provides 
reassurance to the generalizability of the study results. 
Blinding
This is an open-label study. The study center staff and the enrolled subjects will not be blinded 
for treatment assignment. To objectively assess efficacy outcomes, an IRAC will be set up to 
review all efficacy data in a blinded manner.  Any review of aggregate study data by Celgene 
personnel will also be performed in a blinded manner.
Study population
The study population includes relapsed or refractory MM subjects with at least one but no more 
than three prior anti-myeloma treatment regimens. APEX Trial, a Phase 3 trial that led to the 
approval of BTZ (Velcade®) for the treatment of relapsed or refractory MM, also included a 
similar subject population with 1 to 3 prior anti-MM therapies. All subjects must have been 
exposed to at least 2 consecutive cycles of a lenalidomide-containing prior anti-myeloma 
therapy. Subject who have received bortezomib-containing prior anti-myeloma therapy may be 
included. However, as subjects may be receiving BTZ+LD-DEX treatment (Treatment Arm B), 
they must not have had PD during therapy or within 60 days of the last dose of bortezomib-
containing therapy under the 1.3 mg/m2/dose twice weekly dosing schedule.
Comparator arm (bortezomib + low-dose dexamethasone)
Bortezomib (Velcade®) was approved for the treatment of relapsed or refractory MM based on 
the results of a phase 3 trial (APEX Trial) comparing bortezomib to high dose dexamethasone as 
salvage therapy (Richardson, 2005; Richardson, 2007). The addition of dexamethasone to 
bortezomib therapy was shown to add treatment benefit in the phase 2 SUMMIT Trial 
(Richardson, 2003; Richardson, 2006a).  In a recent retrospective analysis, salvage therapy using 
dexamethasone in combination with bortezomib have demonstrated respectable PFS and OS 
outcomes in the MM patients received at least one prior therapy (Ionita, 2009). 
In the recent update of NCCN Clinical Practice Guidelines in Oncology for MM, single agent 
bortezomib and bortezomib plus dexamethasone are Category 1 and Category 2A 
recommendations for MM salvage therapy, respectively (NCCN Clinical Practice Guidelines in 
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Oncology for MM, 2012 v1). Considering the clinical evidence of bortezomib, and recent data of 
bortezomib plus dexamethasone, a treatment regimen of bortezomib in combination with low-
dose dexamethasone is consistent with the current standard of care in this previously treated MM 
patient population.
Therefore, the choice of therapy for the comparator arm in this study will be using bortezomib 
plus low-dose dexamethasone for this relapsed or refractory multiple myeloma (RRMM)
population.
Treatment arm (pomalidomide + bortezomib + low-dose dexamethasone)
Pre-clinical data have shown synergistic anti-myeloma activity between thalidomide/
lenalidomide and bortezomib (Mitsiades, 2002; Hideshima, 2000).
The tolerability and promising activity of the combination of lenalidomide (an 
immunomodulator) and bortezomib (a proteasome-inhibitor) and dexamethasone have also been 
shown promising results in both the front-line and relapsed/refractory MM setting from Phase 1 
and Phase 2 clinical studies (Richardson 2009a; Richardson 2010; Richardson 2010c).
Pomalidomide is a potent immunomodulatory drug in the same class as lenalidomide /
thalidomide and has shown anti-myeloma activity in relapsed/refractory MM patients as a single 
agent and in combination with low-dose dexamethasone (see Section 1.3).
The results of clinical studies conducted thus far indicated that pomalidomide has activity in 
patients with relapsed/refractory MM, including patients whose disease has progressed after 
treatment with lenalidomide, bortezomib, or both. Confirmed overall response rate reached 47% 
in pomalidomide treated patients even at a dose of 2 mg/day (Lacy, 2010c).  Notably, 
pomalidomide produces respectable response rates in subjects who are refractory to 
lenalidomide, or both lenalidomide and bortezomib, aligning with the non-clinical results 
observed in lenalidomide-resistant cells (Adams, 2009).
Based on the pre-clinical and clinical data, the addition of pomalidomide to bortezomib plus low-
dose dexamethasone could be a promising combination regimen in relapsed/refractory MM, and 
therefore, is chosen to be further investigated in this Phase 3 confirmatory trial.
Treatment duration
In clinical studies where novo agents were investigated in subjects with relapsed or refractory 
malignant diseases, it is a common practice to continue investigational therapy until PD or 
development of unacceptable toxicity. Subjects in this trial will receive study treatment until PD 
or unacceptable toxicity.  Subjects who discontinued study treatment prior to PD will be 
followed until PD.  All subjects will be followed up for survival, subsequent anti-myeloma 
therapies, and second primary malignancies for at least 5 years after the last subject is 
randomized into the study or longer if clinically indicated (unless the follow-up is shorter due to 
withdrawal of consent, loss to follow-up, or death).
Dose
For Treatment Arm A (POM + BTZ + DEX), the dose was based on the results from the CC-
4047-MM-005 (MM-005) Phase 1 dose escalation MTD study in which bortezomib was 
administered via IV infusion.  In the MM-005 study, the MPD, POM (4 mg) + IV BTZ (1.3 mg 
/m2) and DEX (20 mg subjects ≤ 75 years old/10 mg subjects > 75 years old) was reached 
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without any DLTs. Considering an early POM single agent MTD study (Richardson 2013) as 
well as the findings in MM-005, the MPD was determined to be the optimal dose for the triple 
combination therapy.  With the optimal dose determined, MM-007 was initiated using the MPD 
dose for the combination of POM + BTZ + LD-DEX (with IV BTZ).
During the conduct of the MM-005 study, subcutaneous (SQ) BTZ was approved as an 
alternative administration method for BTZ (23 Jan 2013).  The SQ BTZ was reported to have a 
decreased incidence of neurotoxicity versus the IV BTZ (Velcade® Prescribing Information, 
2014).  To explore the SQ route of BTZ administration in combination with POM and DEX, the 
MM-005 protocol was amended to add an additional cohort of 6 subjects at the MPD/optimal 
dose for the combination of POM + BTZ + LD-DEX with BTZ administered via SQ injection.  
Based on the safety, efficacy and PK data for this SQ BTZ cohort (see Section 1.4) and general 
adoption in medical practice of SQ BTZ as standard of care due to decreased neurotoxicity, BTZ 
administration is now changed to SQ for both arms in the MM-007 study (Treatment Arm A and 
B).
For Treatment Arm B, the dose of BTZ will be the approved dose and schedule for relapsed or 
refractory MM (Velcade® Prescribing Information, 2014).
Subjects consented to the original MM-007 protocol can continue with IV BTZ or switch to SQ 
BTZ at the discretion of the treating physician.  Subjects randomized into MM-007 under IV 
BTZ treatment will not be replaced.
The DEX dose will be the same in both treatment arms.
Efficacy
Tumor response, including progressive disease (PD), will be assessed according to the IMWG 
uniform response criteria (Durie, 2006); an exploratory assessment of response using the EBMT 
(Bladé, 1998) response criteria will also be performed. All treatment decisions will be made by 
the treating physicians based on response as assessed using the IMWG criteria. 
An IRAC will conduct blinded assessment for tumor response (including assessment of SD and 
of PD) incrementally during the study.  The IRAC adjudicated response data will be used for the
efficacy analysis of the study in all interim and final study reports.
To ensure consistency across centers, tumor response assessments will be based on lab reports 
from central laboratories in this study.
Exploratory Biomarkers
The following assessments will be explored in subjects at selected clinical sites (where 
operationally and logistically feasible) who consent to participate in the optional exploratory 
biomarker study.
MRD and Clonal Heterogeneity
The assessment of tumor response to therapy in MM has long been based on serum and/or urine 
electrophoresis and serum/urine immunofixations.  With recent therapies, the CR rates have 
increased dramatically.  Currently, the most recent results using combination therapies in 
relapsed MM patients are showing CR rates from 30 to 50%. Many patients are expected to 
reach deeper response than CR. Assessment of Minimal Residual Disease would allow us to 
understand how the combination therapy affects the clinical outcome in the patients enrolled in 
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this study. The second aspect of interest for us is to explore how disease clones evolve within the 
patients. By using Next-generation Sequencing-based tests, we will investigate the prevalence 
and progression of clonal heterogeneity in the patients. Finally, we will compare two separate 
MRD measurement tests and determine their sensitivity and specificity.
Mechanistic Biomarkers
Recent research on the mechanism of action of lenalidomide, pomalidomide and thalidomide 
suggest that in tumor cells and T cells, cereblon, a component of E3 ubiquitin ligase complexes, 
is a target for binding by these compounds. These studies showed that the loss of cereblon
(CRBN) or a binding partner, such as DDB1, decreases or eliminates the anti-tumor and 
immunomodulatory activity of lenalidomide and pomalidomide respectively (Ito, 2010; Zhu, 
2011; Lopez-Girona, 2012).  A number of recent studies have reported correlation between 
baseline (pre-treatment level of cereblon measured by gene expression or by 
immunohistochemical methods) to clinical outcomes in subjects treated with regimens 
containing lenalidomide, pomalidomide or thalidomide. These studies have not used validated 
assays for the measurement of cereblon by either method.  In addition, the measurement of 
cereblon (and other potential biomarkers) in the maintenance setting is an open scientific 
question. Thus, we would like to use validated assays for both gene expression and 
immunohistochemical methods and measure baseline and on treatment cereblon levels to 
investigate whether there is any potential correlation of cereblon level to clinical outcomes.  
Recently, Aiolos and Ikaros have been identified as two substrates of CRBN. Together with 
CRBN, assessment of these proteins can also help us understand mechanistic as well as 
diagnostic aspect of the IMiD-based therapies.
In some subjects, we will also quantify subsets of immune cells and may assay their functions 
from whole blood samples (at baseline and during treatment) to explore whether and how during 
therapy, immune functions are modulated by the two arms of therapy. 
Genomic Biomarkers
Genomic translocations, mutations and chromosomal copy number alterations define myeloma at 
diagnosis and its natural history of progression. Therefore, understanding the molecular events 
through genomic analysis would provide us with a deeper understanding of disease biology and 
its interaction with therapeutic interventions.  In this study we will employ multiple techniques to 
understand how the myeloma genomic and epigenomic alternations contribute to clinical 
outcomes following the therapies.
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
36
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
Figure 1: Study Schema
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
4.3.
Study Duration 
Screening
Potential study subjects will sign an informed consent prior to undergoing any study-related 
procedure.  Subjects need to complete screening for protocol eligibility within 28 days of 
randomization, as outlined in Table 1, Table of Events.
Subjects must have discontinued anti-myeloma therapies at least 14 days prior to randomization
(wash-out period).
Subjects with myeloma-associated bone lesion may receive bisphosphonate therapy prior to 
study entry, unless such therapy is contraindicated.
Subjects who failed screening as a result of neutropenia or anemia will not be permitted to use 
growth factors to become eligible.  
Subjects who failed screening will be permitted to be rescreened for eligibility.
Randomization
Subjects who meet all eligibility criteria will be randomized to either Treatment Arm A (POM 
+ BTZ + LD-DEX) or Treatment Arm B (BTZ + LD-DEX) with equal probability (1:1 
randomization ratio).
 
 The
central randomization procedure will be accomplished by a validated IVRS/IWRS, stratified by 
the following baseline factors: 1) age (≤ 75 years old vs. > 75 years old); 2) number of prior anti-
myeloma regimens (1 vs. >1); 3) β2M at screening (< 3.5 mg/L vs. ≥ 3.5 mg/L - ≤ 5.5 mg/L vs. > 
5.5 mg/L).
Study Treatment Phase
Study treatment for each subject begins on the same day as or within 4 days following
randomization.  Study visits with serial measurements of safety and efficacy will be performed 
as outlined in Table 1, Table of Events.
 
 
 
Tumor response, including progressive disease (PD), will be assessed according to the IMWG 
uniform response criteria (Durie, 2006); an exploratory assessment of response using the EBMT 
(Bladé, 1998) response criteria will also be performed. All treatment decisions will be made by 
treating physicians based on response as assessed using the IMWG criteria. 
The severity of AEs will be graded according to the NCI CTCAE version 4.0 or higher.
Thromboembolism prophylaxis during the study treatment is required for subjects in Treatment 
Arm A. Low-dose aspirin, low molecular weight heparin, or other equivalent antithrombotic or 
anti-coagulant will be given to all subjects assigned to Treatment Arm A as well as Treatment 
Arm B subjects who have a prior history of DVT or PE.  At the discretion of the treating 
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
38
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
physician, other Treatment Arm B subjects may also receive antithrombotic therapy.  Subjects 
who develop symptomatic DVT under study treatment will be assessed and diagnosed 
objectively by Doppler ultrasonography or a comparable method.  Diagnostic algorithms will be 
provided in Appendix A.
Herpes Zoster Prophylaxis should be considered for all study subjects receiving bortezomib. Oral
acyclovir or equivalent antiviral therapy per institutional guidelines is acceptable for herpes 
zoster prophylaxis. 
During the study, subjects with myeloma-associated bone lesion may receive bisphosphonate 
therapy.
Radiation therapy to a pathological fracture site or to treat bone pain is permitted throughout the 
study. 
The use of hematopoietic growth factors is permitted (the use of myeloid growth factors is 
encouraged when the absolute neutrophil count is less than 1,000/μL) at the discretion of the 
treating physician.  Platelet and red blood cell transfusions are also permitted during the study.
However, subjects who fail absolute neutrophil count (ANC), hemoglobin or platelet eligibility 
criteria at screening CANNOT be re-tested for the study after being treated with growth factors 
or platelet/blood transfusion. However, subjects who meet the ANC, hemoglobin and platelet 
eligibility criteria due to growth factor treatment or platelet/blood transfusion received prior to 
screening are acceptable and are not considered as screening failures.
Drugs known to prolong QT corrected (QTc) interval should be avoided unless deemed 
medically necessary. See Appendix G for link to a comprehensive list of drugs which are known 
to prolong QTc. A thorough QT study (CC-4047-CP-010) was conducted in healthy subjects 
according to the E14 Guidance to assess the potential of Pomalidomide (POM) to delay cardiac 
re-polarization, especially as prolongation of the QT interval.  The result of the QT prolongation 
assessment was observed to be negative, indicating a low risk of POM-associated QT 
prolongation.
Study Treatment Discontinuation
Subjects will continue study treatment until PD or unacceptable toxicity.  An active treatment
discontinuation visit should occur for all subjects at the time of permanent discontinuation from 
study treatment.  The reason for discontinuation from study treatment will be documented in the 
eCRFs for all subjects.
Progression-free Survival (PFS) follow-up Phase
To ensure accuracy and completeness for the primary efficacy endpoint assessment of PFS, 
subjects who permanently discontinued study treatment prior to PD will continue to be followed 
up in the PFS follow-up phase until PD. During this PFS follow-up period, efficacy assessments 
for response and PD using the IMWG criteria should be performed every 21 days (see Table 1,
Table of Events). Subjects are not expected to start any other anti-MM therapy during the PFS 
follow-up phase prior to PD.  Subjects are expected to have a visit at the time of discontinuation 
from the PFS follow-up period.
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
39
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
Long-term Follow-up Phase
All subjects will be followed in the long-term follow-up phase for at least 5 years after the last 
subject is randomized into the study, or longer if clinically indicated (unless the follow-up is 
shorter due to withdrawal of consent, loss to follow-up, or death).  Long-term follow-up will 
occur 4 times per year (every 3 months) after the 28 days post treatment discontinuation visit or 
PFS follow-up phase discontinuation visit, as applicable.  During long-term follow-up the 
following information will be collected: survival, SPM, subsequent anti-myeloma regimens, date 
of progression and reason for progression based on the IMWG uniform response criteria, if 
available, for subjects who did not have PD during the study treatment or PFS follow-up period.
4.4.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary and/or exploratory analysis, whichever is the later date as pre-specified in the 
protocol and/or the Statistical Analysis Plan.
Approved
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
40
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
5.
TABLE OF EVENTS
Table 1:
Table of Events
Screening
Day -28 to 
Day -1
Active Treatment
(each 21-day cycle)
Active 
Treatment 
Discontinuation
(± 3 Days)
Follow-up visit 
(28 days post 
active treatment 
discontinuation)
a
(± 3 Days)
PFS Follow-up 
Phase (every 21 
days)
b
(± 3 Days)
PFS Follow-up 
Phase 
Discontinuation
(± 3 Days)
Long-term 
follow-up 
every 3 
months 
(± 2 weeks)
Day 1
c
Day 4
d
(Cycles 1-
8 only)
Day 8d
Day 11d
(Cycles 
1-8 only)
Informed Consent 
X
--
--
--
--
--
--
--
--
--
Inclusion/Exclusion 
Criteria
X
--
--
--
--
--
--
--
--
--
Demographics
X
--
--
--
--
--
--
--
--
--
Medical History
X
--
--
--
--
--
--
--
--
--
Prior anti-myeloma 
therapies, radiotherapy, 
surgeries
X
--
--
--
--
--
--
--
--
--
Disease Diagnosis
e
X
Randomization
f
--
X
(Cycle 1 
only)
--
--
--
--
--
--
--
--
Safety Assessments
Physical Exam 
X
X
--
--
--
X
--
--
--
--
Vital Signs
g
X
X
X
X
X
X
--
--
--
--
Height
X
--
--
--
--
--
--
--
--
--
Weight
X
X
X
X
X
X
--
--
--
--
Body Surface Area (BSA) 
calculation
h
--
X
X
X
X
--
--
--
--
--
VTE Monitoring
--
X
X
X
X
X
--
--
--
--
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
41
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
Table 1:
Table of Events (Continued)
Screening
Day -28 to 
Day -1
Active Treatment
(each 21-day cycle)
Active 
Treatment 
Discontinuation
(± 3 Days)
Follow-up visit 
(28 days post 
active treatment 
discontinuation)a
(± 3 Days)
PFS Follow-up 
Phase (every 21 
days)b
(± 3 Days)
PFS Follow-up 
Phase 
Discontinuation
(± 3 Days)
Long-term 
follow-up 
every 3 
months 
(± 2 weeks)
Day 1c
Day 4d
(Cycles 1-
8 only)
Day 8d
Day 11d
(Cycles 
1-8 only)
12-Lead 
Electrocardiograph (ECG)
i
X
Xi
--
--
--
X
--
--
--
--
Hematology
j, k
X
X
l
X
X
X
X
--
X
m
Xm
--
Serum Chemistry
n, k
X
X l
X
X
X
X
--
X
o
Xo
--
C-Reactive Protein (CRP) 
and Creatine Kinase
X
X l
--
--
--
X
--
--
--
--
Urinalysis
p
X
X l
--
--
--
X
--
--
--
--
Estimation of Renal 
Function
q, k
X
X l
--
--
--
X
--
--
--
--
Pregnancy Counseling
X
X
--
--
--
X
--
--
--
--
Pregnancy Test for FCBP 
s
X s
X s
--
X s, 
(Cycle 
1 and 2 
only)
--
X s
X s
X s
--
--
Adverse Events
X
u
--
Monitoring of Second 
Primary Malignancies
X
v
Prior/Concomitant 
Medications and 
Procedures
After signing the ICD and until 28 days after discontinuation from treatment.
--
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
42
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
Table 1:
Table of Events (Continued)
Screening
Day -28 to 
Day -1
Active Treatment
(each 21-day cycle)
Active 
Treatment 
Discontinuation
(± 3 Days)
Follow-up visit 
(28 days post 
active treatment 
discontinuation)a
(± 3 Days)
PFS Follow-up 
Phase (every 21 
days)b
(± 3 Days)
PFS Follow-up 
Phase 
Discontinuation
(± 3 Days)
Long-term 
follow-up 
every 3 
months 
(± 2 weeks)
Day 1c
Day 4d
(Cycles 1-
8 only)
Day 8d
Day 11d
(Cycles 
1-8 only)
Efficacy Assessments
Bone Marrow Aspiration 
and/or Biopsy and 
cytogenetics
w
X
--
--
--
--
--
--
--
--
--
Quantitative Serum 
Immunoglobulin Levels
x
X
X l
--
--
--
X
--
X
X
--
Serum protein 
electrophoresis (sPEP) and 
24-hour Urine 
electrophoresis (uPEP)
y
X
X l
--
--
--
X
--
X
X
--
Serum and urine 
immunofixation
z
Xz
Xz, l
--
--
--
Xz
--
Xz
Xz
--
Serum free light-chain 
(FLC) assay
aa
X
X l
--
--
--
X
--
X
X
--
Skeletal Survey (by x-ray)
bb
X
--
--
--
--
--
--
--
--
--
Extramedullary 
Plasmacytoma (EMP) 
Assessments
cc
X
X
--
--
--
X
--
X
X
--
Assessment of Response
dd
--
X
(starting at 
Cycle 2)
--
--
--
X
--
X
X
--
Survival
--
--
--
--
--
--
--
--
--
X
Subsequent Myeloma 
Regimens
--
--
--
--
--
--
--
--
--
X
Progression data (date and 
reason)
ee
--
--
--
--
--
--
--
--
--
X
Approved
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Approved
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
43
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
Table 1:
Table of Events (Continued)
Screening
Day -28 to 
Day -1
Active Treatment
(each 21-day cycle)
Active 
Treatment 
Discontinuation
(± 3 Days)
Follow-up visit 
(28 days post 
active treatment 
discontinuation)a
(± 3 Days)
PFS Follow-up 
Phase (every 21 
days)b
(± 3 Days)
PFS Follow-up 
Phase 
Discontinuation
(± 3 Days)
Long-term 
follow-up 
every 3 
months 
(± 2 weeks)
Day 1c
Day 4d
(Cycles 1-
8 only)
Day 8d
Day 11d
(Cycles 
1-8 only)
Study Treatment
Dispensation
Oral Pomalidomide 
accountability / 
dispensation
ff
--
X
--
--
--
--
--
--
--
--
Oral Dexamethasone 
dispensation
gg
--
X
--
--
--
--
--
--
--
--
SQ Bortezomib 
administration 
hh
--
X
X
X
X
--
--
--
--
--
Other Assessments
ECOG Performance Status
ii
X
X
--
--
--
X
--
X
X
--
Serum Beta-2 
Microglobulin
jj
X
--
--
--
--
--
--
--
--
--
Quality of Life
kk
--
X
--
--
--
X
--
--
--
--
Healthcare resource 
utilization
ll
--
X
--
--
--
--
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
44
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
Table 1:
Table of Events (Continued)
Screening
Day -28 to 
Day -1
Active Treatment
(each 21-day cycle)
Active 
Treatment 
Discontinuation
(± 3 Days)
Follow-up visit 
(28 days post 
active treatment 
discontinuation)a
(± 3 Days)
PFS Follow-up 
Phase (every 21 
days)b
(± 3 Days)
PFS Follow-up 
Phase 
Discontinuation
(± 3 Days)
Long-term 
follow-up 
every 3 
months 
(± 2 weeks)
Day 1c
Day 4d
(Cycles 1-
8 only)
Day 8d
Day 11d
(Cycles 
1-8 only)
Bone marrow aspirate and 
blood sample for MRD, 
genomic and 
molecular/mechanistic 
biomarkers studies
nn,oo
X
--
--
--
--
X
--
--
--
--
Blood samples for immune 
biomarker studies
pp
X
--
--
X
(Cycle 
1 and 3 
only)
--
--
--
--
--
--
a The follow-up visit 28 days post-active treatment discontinuation is only required for subjects who do not enter the PFS follow-up phase.
b To ensure appropriate follow-up for the primary endpoint of progression-free survival, subjects who discontinue from active treatment prior to PD will continue to be followed in 
the PFS follow-up period until PD.
c At Cycle 1 all assessments must be performed within ± 1 day of Day 1.  For Cycle 2 onwards, all assessments must be performed within ±3 days of Day 1.  If the start of a new 
cycle is delayed > 7 days from the protocol-defined 21-day dosing cycle, an unscheduled visit must be performed for efficacy assessments prior to initiation of the next cycle or 
if the delay is greater than 21 days, these efficacy assessments must be performed every 21 days (±3 days) until a new cycle can begin.  For subsequent cycles following a 
delayed cycle, efficacy assessments should be performed at the start of each new cycle.  These efficacy assessments include:  ECOG performance status, myeloma paraprotein 
protein electrophoresis and immunofixation, serum immunoglobulins, serum free light chain assay, serum hematology (for hemoglobin), serum chemistry (for corrected serum 
calcium and creatinine), and if applicable, clinical and/or radiological extramedullary plasmacytoma assessment, skeletal survey, and bone marrow aspirate/biopsy. 
d For Treatment Arm A (POM+BTZ+LD-DEX), if a subject permanently discontinues BTZ, the Day 4, 8 and 11 visits/assessments are no longer required for that subject, with the 
exception of any required pregnancy testing.
e Date of confirmed initial diagnosis and, if available, the myeloma stage at time of initial diagnosis per the Salmon-Durie Criteria and/or the International Staging System (ISS) 
(Appendix H) will be collected as part of the disease diagnosis assessment.
f Once a subject is randomized, study treatment must be initiated within 4 days.
g Vital signs include blood pressure, temperature, respiratory rate and heart rate.
h The body surface area (BSA) used to determine the bortezomib dose will be collected.  If local pharmacy SOP requires subject weight to be used from Day 1 of the current 
treatment cycle, this will be acceptable unless the physician feels there is a clinically significant change in the subject’s weight that would require modification to the bortezomib
total dose.
i All ECGs will be performed and reviewed locally.  During the study treatment phase ECGs will be performed at Cycle 3 Day 1, then every third cycle thereafter (Cycle 6 Day 1, 
Cycle 9 Day 1, etc.).  Subjects with QT or borderline QT prolongation but otherwise non-clinically significant will require more frequent ECG monitoring at the discretion of the 
investigator.
j Assessment of hematology includes: white blood cell count with differential, ANC, ALC, hemoglobin, hematocrit, platelet count, and mean corpuscular volume.
k These assessments will be performed by the central laboratory; however, tests that may result in dose interruption and/or modification should also be performed locally to allow 
for treatment related decisions during subject visits. At Study Day 1 subject must meet eligibility criteria based on local or central lab results prior to initiating study therapy.  All 
abnormal results from local laboratories used in treatment decisions or adverse event reporting must be entered into an unscheduled visit on the eCRF. 
Approved
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9.0
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Approved
1.0
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
45
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
l If screening visit laboratory tests were done ≤ 7 days prior to randomization, these laboratory assessments are not required to be repeated at Cycle 1 Day 1, except for those test 
related to protocol exclusion (ANC, platelets, hemoglobin, corrected calcium, SGOT/AST or SGPT/ALT, total bilirubin, creatinine clearance) and the screening results were 
within 10% range of the exclusion criteria.  A 24-hour urine sample obtained as a standard of care assessment prior to informed consent can be utilized for this study if it was 
performed ≤ 7 days prior to the Screening Visit and meets the protocol requirements for collection and analysis.
m Only hemoglobin will be assessed during the PFS follow-up phase visits and at the PFS follow-up phase discontinuation visit.
n Assessment of serum chemistry includes: total protein, albumin, corrected serum calcium, phosphorous, glucose, uric acid, total bilirubin, direct bilirubin (only when total 
bilirubin is increased), alkaline phosphatase, AST/SGOT, ALT/SGPT, GGT, sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, lactate dehydrogenase, 
magnesium.  If a PD is noted based on corrected serum calcium level, a repeat serum chemistry test should be performed as soon as possible to confirm PD.
o Only corrected serum calcium and serum creatinine will be assessed during the PFS follow-up phase visits and at PFS follow-up phase discontinuation visit.
p Assessment of urinalysis includes: specific gravity, pH, glucose, bilirubin, protein, ketones, blood and, if feasible, microscopic analysis [casts, bacteria, RBCs, and WBCs].  This 
assessment will be performed by the local laboratory only and as per local practice.
q Estimation of renal function will be assessed using the creatinine clearance (CrCl) calculated based on the Cockcroft-Gault formula (Appendix F) or the CrCl directly calculated 
from the 24-hour urine collection method.  Cockcroft-Gault formula: CrCl (mL/min) = (140 – age) (weight [kg]) / 72 (serum creatinine [mg/dL]); for females, the formula is 
multiplied by 0.85.
s FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting study treatment.  The first pregnancy test must be performed within 10-14 days 
prior to the start of study treatment and the second pregnancy test must be performed within 24 hours prior to the start of study treatment.  The subject may not receive study 
treatment until the study doctor has verified that the results of these pregnancy tests are negative. FCBP with regular or no menstrual cycles must agree to have pregnancy tests 
every 7 days (weekly) for the first 4 weeks of study participation (Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 8) and then every 3 weeks (starting at Cycle 3 
Day 1) while on study, at treatment discontinuation, and 4 weeks following treatment discontinuation. If menstrual cycles are irregular, the pregnancy testing must occur weekly 
for the first 4 weeks and then every 2 weeks starting with Cycle 3 Day 1 while on study, at treatment discontinuation, and at 2 weeks and 4 weeks following treatment 
discontinuation.  For FCBP entering the PFS follow-up phase following treatment discontinuation, the post treatment discontinuation pregnancy testing must still be performed at
4 weeks following treatment discontinuation for FCBP with regular or no menstrual cycles or at 2 weeks and 4 weeks following treatment discontinuation for FCBP irregular 
menstrual cycles.
u All AEs will be recorded by the Investigator from the time the subject signs informed consent (IC) to at least 28 days after the last dose of study treatment (pomalidomide, 
bortezomib or dexamethasone) for subjects not continuing in the PFS follow-up Phase. Only study/protocol related AEs will be recorded by the Investigator for subjects who 
continue in the PFS follow-up phase of the study.  AEs that lead to study treatment discontinuation should be followed until resolution or stabilization.  SAEs, regardless of 
relationship to the study treatment (pomalidomide, bortezomib, and/or dexamethasone), that occur from the time the subject signs informed consent to at least 28 days after the 
last dose of study drug (Pomalidomide, bortezomib, or dexamethasone), and those made known to the Investigator at any time thereafter that are suspected of being related to 
study treatment (Pomalidomide, bortezomib and/or dexamethasone) must be reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event.
v Screening for synchronous malignancies will be performed during the screening visit.  Second Primary Malignancies (SPMs) will be monitored as events of interest and must be 
reported as serious adverse events regardless of the treatment arm the subject is in. This includes any SPM, regardless of causal relationship to study treatment (pomalidomide, 
bortezomib or dexamethasone), occurring at any time from the time of signing the informed consent up to and including the long-term follow-up period. Events of SPM are to 
be reported using the SAE report form and must be considered an “Important Medical Event” even if no other serious criteria apply; these events must also be documented in the 
appropriate page(s) of the eCRF and subject’s source documents. Documentation on the diagnosis of the SPM must be provided at the time of reporting as a serious adverse 
event (eg, any confirmatory pathology, histology or cytology results, cytogenetics, flow cytometry, X-rays, CT scans, etc.). For all subjects who develop SPMs, all corresponding 
diagnostic reports (eg, pathology, cytogenetics, flow cytometry) from the MM diagnosis confirmation performed at screening, and if applicable, from any subsequent bone 
marrow assessments performed during the treatment or PFS follow-up phase of the study (for confirmation of CR or other clinical reason) and from the diagnostic tumor samples 
obtained at SPM determination, will be required for secondary malignancy confirmation.
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Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
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w At screening, a bone marrow aspirate (and biopsy if necessary) is required and must be obtained within 28 days prior to randomization/enrollment to obtain a current estimate of 
the % plasma cells in the marrow.  Analysis for % plasma cells in the marrow will be performed locally.  A portion of the bone marrow aspirate will be submitted to a central 
laboratory for cytogenetic studies via fluorescent in situ hybridization [FISH] analyses.  After screening, a bone marrow aspirate (or biopsy if necessary) must be performed to 
confirm a CR, and may otherwise be repeated as clinically indicated at the discretion of the treating physician.  Celgene may request a redacted copy of the pathology reports for 
post-baseline bone marrow biopsies and/or aspirates.
x Quantitative immunoglobulin assessment includes IgG, IgA, IgM for all subjects, IgE or IgD only for subjects with the respective myeloma sub-type (IgE or IgD). Quantitative 
immunoglobin assessment should be repeated at time of CR confirmation.  This assessment will be performed by the central laboratory.
y Serum and 24-hour urine protein electrophoresis (sPEP/uPEP) assessments will be performed by a central laboratory.  Investigator evaluation of disease response should be 
based solely on the central laboratory results, not local results. If a response or PD is noted based on sPEP and/or uPEP results, a repeat test should be conducted as soon as 
possible to confirm the response or PD.
z Serum and urine immunofixation tests (IFE) are performed at screening to identify the immunoglobulin subtype of MM. Thereafter, the IFE assays are triggered to be performed
whenever M-protein is undetectable by sPEP and uPEP to confirm CR.  This assessment will be performed by the central laboratory.  Investigator evaluation of disease response 
should be based solely on the central laboratory results.
aa Serum FLC assay should be repeated at the time of CR confirmation.  This assessment will be performed by the central laboratory.
bbA skeletal survey by x-ray will be performed at screening and thereafter when clinically indicated.  All skeletal survey films and analyzed locally by the site 
investigator/radiologist.  If a skeletal survey was performed within 60 days prior to the start of Cycle 1, it may be used for the screening assessment. 
cc If EMPs are clinically assessable, clinical assessment will be performed at screening, at every Cycle Day 1, at treatment discontinuation, every 21 days during the PFS follow-up 
phase, at PFS follow-up phase discontinuation, and when clinically indicated to confirm a response (≥ PR).  If EMPs are only assessable radiographically (x-ray and/or 
conventional [spiral] CT/MRI scan), scans are required at screening, at Cycle 3 Day 1, every 3 cycles thereafter (Cycle 6 Day 1, Cycle 9 Day 1, etc.) during treatment, at 
treatment discontinuation, every 63 days during the PFS follow-up phase, at PFS follow-up phase discontinuation, and when clinically indicated to confirm a response (≥ PR).  
The radiographic modality used at screening (eg, x-ray) must be repeated at each assessment time point throughout the study.  All scans will be reviewed locally only. The 
individual EMPs (both clinically and radiographically assessable) must be consistently labeled using the same numerical and descriptive values (eg, EMP#1 left rib, EMP #2 
liver) throughout the study at the specified time points requested by the protocol.
dd Response will be assessed using the IMWG criteria (Appendix B). All treatment decisions will be made by the treating physicians based on response as assessed using the 
IMWG criteria.
ee The date of progression and reason for progression based on the IMWG uniform response criteria, if available, will be collected during long-term follow-up for subjects who did 
not have PD during the active treatment or the PFS follow-up phase if applicable.
ff
Subject will take oral dose of POM on Days 1 to 14 of each 21-day cycle.  For additional details, see Section 6.4.5.
ggSubject will take oral dexamethasone on Days 1, 2, 4, 5, 8, 9, 11, and 12 of Cycles 1 to 8, and on Days 1, 2, 8 and 9 for of each 21-day cycle from Cycle 9 and onward.
hh Bortezomib doses must be at least 72 hours apart.  Missed doses cannot be made up.
ii See Appendix E for the ECOG Performance Status Scale.
jj The serum β2M test will be performed centrally at the screening visit only.  The test result should be available prior to randomization to allow for appropriate stratification.
kk Quality of Life (QoL) instruments (EORTC QLQ-MY20 and EORTC QLQ-C30) and the descriptive system of the EQ-5D will be provided to each subject to complete on the 
first day of every cycle (including Cycle 1) at the beginning of the Cycle Day 1 visit prior to any study treatment (POM, BTZ, DEX) administration and at treatment 
discontinuation.  If the collection of such information is prohibited per local regulations or is not operationally or logistically feasible, such assessments will not be considered as 
mandatory.  See Appendix I for QoLs.
ll Information for hospitalizations or emergency department visits that occur during the active treatment period will be collected.
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Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
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nnThe biomarker sampling will only be performed at sites where such sampling is permitted per local regulations, operationally and logistically feasible, and only for subjects who 
give their consent.  For investigative sites where biomarker sampling will be performed, if an assessment is not done due to insufficient sample or subject non-compliance with 
the sampling requirement it will not be considered a deviation from the protocol.  All biomarker samples will be destroyed 5 years after completion of the study or earlier if 
required by law.
ooBone marrow aspirate and a whole blood sample for MRD, genomic and molecular/mechanistic biomarkers studies will be submitted to a central laboratory at the following 
timepoints:  at screening (if sufficient bone marrow aspirate material is available after samples are prepared for the local pathology analysis and central cytogenetic analysis); at 
time of CR confirmation and at treatment discontinuation (if sufficient bone marrow aspirate material is available after samples are prepared for the local pathology analysis); at 
time of PD or treatment discontinuation (only if a bone marrow aspirate is performed for a subject as part of standard of care and sufficient material is available after samples are 
prepared for the local pathology analysis).  Sampling will only be performed at sites where such sampling is permitted per local regulations, operationally and logistically 
feasible, and only for subjects who give their consent.
ppBlood samples for immune biomarkers studies will be collected and submitted to a central laboratory at the following timepoints:  screening, Cycle 1 Day 8, and Cycle 3 Day 8.  
Sampling will only be performed at sites where such sampling is permitted per local regulations, operationally and logistically feasible, and only for subjects who give their 
consent.
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Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
6.
PROCEDURES
6.1.
Study Entry
6.1.1.
Screening
Prior to screening, subject must sign an informed consent.  All screening assessments must be 
completed within 28 days prior to start of Cycle 1, with the exception of the skeletal survey, for 
which previous results (if the survey was done within 60 days prior to randomization) can be 
used as baseline assessments. 
Confirmation of diagnosis, medical and surgical history, and review of concomitant medications 
should be documented during the screening period as well.  All prior radiotherapy, surgeries, and 
anti-myeloma therapies must be recorded in the eCRF, including approximate dates for each 
therapy and the date of progression for each regimen.  Date of confirmed initial diagnosis and, if 
available, the myeloma stage at time of initial diagnosis per the Salmon-Durie Criteria and/or the 
International Staging System (ISS) (Appendix H) will be collected as part of the disease 
diagnosis assessment.  See Table 1 for all the required assessments during screening.
If screening visit laboratory tests were done ≤ 7 days prior to enrollment/randomization, these 
laboratory assessments are not required to be repeated at Cycle 1 Day 1, except for those test 
related to protocol exclusion (ANC, platelets, hemoglobin, corrected calcium, SGOT/AST or 
SGPT/ALT, total bilirubin, creatinine clearance) for which screening results were within 10% 
range of the exclusion criteria.
The start of study treatment dosing is designated as Cycle 1 Day 1.  All assessments should be 
performed on Day 1 (± 1 Day) in Cycle 1 and within a ± 3 days window for other required visits 
during the active treatment and PFS follow-up phase.  Long-term follow-up will be performed 
every 3 months (± 2 weeks).
6.1.2.
Wash-out
Subjects’ most recent systemic anti-myeloma drug therapy must be discontinued at least 14 days 
prior to randomization. For those who used investigational anti-myeloma agents, a minimum 
wash-out of 28 days or 5 half-lives (whichever is longer) of treatment is required.
6.1.3.
Randomization 
This study will utilize centralized randomization by IVRS/IWRS.  A set of randomization 
authorization number will be pre-loaded in the IVRS/IWRS system prior to the study initiation. 
Celgene trial staff will review and verify specific eligibility criteria for all subjects prior to 
allowing randomization of subjects via the IVRS/IWRS.  Celgene trial staff will be required to 
activate a subjects in the IVRS/IWRS before site staff may randomize and obtain the treatment 
assignment via IVRS/IWRS.  Once a subject is randomized, study treatment must be initiated 
within 4 days.
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Celgene Corporation
Confidential and Proprietary
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
Designated research personnel at each investigational sites will be assigned password protected, 
coded identification numbers which gives them the access to call into IVRS/IWRS to enroll 
subjects.
6.2.
Safety Assessments
For Treatment Arm A (POM+BTZ+LD-DEX), if a subject permanently discontinues BTZ, the 
Day 4, 8 and 11 visits/assessments are no longer required for that subject, with the exception of 
any required pregnancy testing.
6.2.1.
Adverse Events 
All Adverse Events (AEs) will be recorded by the Investigator from the time the subject signs 
informed consent to at least 28 days after the last dose of study drug (pomalidomide, bortezomib, 
or dexamethasone) for subjects not continuing in the PFS follow-up Phase. Only study/protocol 
related AEs will be recorded by the Investigator for subjects who continue in the PFS follow-up 
phase of the study. AEs that lead to study discontinuation should be followed until resolution or 
stabilization. 
6.2.1.1.
Serious Adverse Events
Serious Adverse Events (SAEs), regardless of relationship to study treatment (ie, pomalidomide, 
bortezomib, and/or dexamethasone), that occur from the time the subject signs informed consent 
to at least 28 days after the last dose of study drug (pomalidomide, bortezomib, or 
dexamethasone), and those made known to the Investigator at any time thereafter that are 
suspected of being related to study treatment (pomalidomide, bortezomib and/or dexamethasone) 
must be reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the 
event.
6.2.1.2.
Second Primary Malignancies
Screening for synchronous malignancies will be performed during the screening visit.
Second Primary Malignancies (SPMs) will be monitored as events of interest and must be 
reported as serious adverse events regardless of the treatment arm the subject is in. This includes 
any SPM, regardless of causal relationship to study treatment (pomalidomide, bortezomib or 
dexamethasone), occurring at any time from the time of signing the informed consent up to and 
including the long-term follow-up period. Events of SPM are to be reported using the SAE 
report form and must be considered an “Important Medical Event” even if no other serious 
criteria apply; these events must also be documented in the appropriate page(s) of the eCRF and 
subject’s source documents. Documentation on the diagnosis of the SPM must be provided at 
the time of reporting as a serious adverse event (eg, any confirmatory pathology, histology or 
cytology results, cytogenetics, flow cytometry, X-rays, CT scans, etc.). For all subjects who 
develop SPMs, all corresponding diagnostic reports (eg, pathology, cytogenetics, flow 
cytometry) from the MM diagnosis confirmation performed at screening, and if applicable, from 
any subsequent bone marrow assessments performed during the treatment or PFS follow-up 
phase of the study (for confirmation of CR or other clinical reason) and from the diagnostic 
tumor samples obtained at SPM determination, will be required for secondary malignancy 
confirmation.
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
50
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
6.2.2.
Prior and Concomitant Medications and Procedures
All prior and concomitant therapies (prescription and non-prescription) taken and any procedures 
performed after the subject signs the informed consent, during the course of the treatment, and 
28 days after treatment discontinuation will be collected and recorded on the subject’s eCRF. 
Drugs known to prolong QT corrected (QTc) interval should be avoided unless deemed 
medically necessary. See Appendix G for link to a comprehensive list of drugs which are known 
to prolong QTc. 
6.2.3.
VTE Monitoring
All prior venous thrombotic events (VTE) and pulmonary embolisms that occurred will be 
collected with complete medical history during the screening period.  Clinical review of 
sign/symptoms for possible VTEs will be performed at every scheduled visit during study 
treatment, and at treatment discontinuation.  Subjects who develop symptomatic DVT will be 
assessed and diagnosed objectively by Doppler ultrasonography or a comparable method per 
institutions standard of care. See Appendix A for DVT and PE diagnostic algorithms.
6.2.4.
Complete Physical Exam and Measurement of Vital Signs, Height, and Weight
A complete physical exam (skin, nasal cavities, eyes, ears, respiratory, cardiovascular, 
gastrointestinal, neurological, lymphatic, and musculoskeletal systems) will be performed at 
screening, on Day 1 of every cycle starting at Cycle 1, and at treatment discontinuation.
Measurement of vital signs (blood pressure, temperature, heart rate, and respiration rate) will be 
performed at screening, at every scheduled visit during study treatment, and at treatment 
discontinuation.
Measurement of height will be performed at screening only.  Measurement of weight will be 
performed at screening, at every scheduled visit during study treatment, and at treatment 
discontinuation.
Body Surface Area used to calculate each BTZ dose will be collected in the eCRFs.
Investigators are to report any clinically significant abnormal findings as adverse events.
6.2.5.
Electrocardiogram
12-lead electrocardiogram (ECG) monitoring will be performed at screening, on Cycle 3 Day 1 
and on Day 1 of every third cycle thereafter (Cycle 6 Day 1, Cycle 9 Day 1, etc.) during 
treatment, and at treatment discontinuation. Subjects with QT or borderline QT prolongation but 
otherwise non-clinically significant will require more frequent ECG monitoring at the discretion 
of the investigator.  All ECGs will be performed and reviewed locally.
6.2.6.
Laboratory Assessments for Safety Parameters 
Except for pregnancy tests and urinalysis, all safety-related laboratory assessments will be 
performed centrally; however, tests that may result in dose interruption and/or modification 
should also be performed locally to allow for treatment related decisions during subject visits.  
All results from local laboratories used in treatment decisions or adverse event reporting must be 
entered into an unscheduled visit on the eCRF. At Study Day 1 subject must meet eligibility 
criteria based on local or central lab results prior to initiating study therapy.
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
51
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
If screening visit laboratory tests were done ≤7 days prior to enrollment/randomization, these 
laboratory assessments are not required to be repeated at Cycle 1 Day 1, except for those test 
related to protocol exclusion (ANC, platelets, hemoglobin, corrected calcium, SGOT/AST or 
SGPT/ALT, total bilirubin, creatinine clearance) for which screening results were within 10% 
range of the exclusion criteria.
!
Hematology laboratory tests: Hematology includes: white blood cell count with 
differential, ANC, absolute lymphocyte count (ALC), hemoglobin, hematocrit, 
platelet count, and mean corpuscular volume.  Hematology will be performed at 
screening, at every scheduled visit during study treatment, at treatment 
discontinuation, every 21 days during the PFS follow-up phase and at PFS follow-up 
phase discontinuation.  During the PFS follow-up phase and at PFS follow-up phase 
discontinuation only hemoglobin will be assessed.  This assessment must be 
performed by the central laboratory; however, laboratory tests that may result in dose 
interruption and/or modification should also be performed locally to allow for timely 
treatment related decisions during subject visits.
!
Serum chemistry laboratory tests: Serum chemistry includes: total protein, 
albumin, corrected serum calcium, phosphorous, glucose, uric acid, total bilirubin, 
direct bilirubin (only when total bilirubin is increased), alkaline phosphatase, 
AST/SGOT, ALT/SGPT, GGT, sodium, potassium, chloride, carbon dioxide, blood 
urea nitrogen, creatinine, lactate dehydrogenase, magnesium.  Serum chemistry labs 
will be performed at screening, at every scheduled visit during study treatment, at 
treatment discontinuation, every 21 days during the PFS follow-up phase and at PFS 
follow-up phase discontinuation.  During the PFS follow-up phase and at PFS follow-
up phase discontinuation only corrected serum calcium and creatinine will be 
assessed. If a PD is noted based on corrected serum calcium level, a repeat serum 
chemistry test should be performed as soon as possible to confirm the PD.
!
C-reactive protein and creatine kinase assessments will be performed at screening, 
on Day 1 of every cycle starting at Cycle 1 and at treatment discontinuation.
!
Urinalysis: Urinalysis includes: specific gravity, pH, glucose, bilirubin, protein, 
ketones, blood and, if feasible, microscopic analysis [casts, bacteria, RBCs, and 
WBCs].  Urinalysis will be performed at screening, at every cycle Day 1 starting at 
Cycle 1, and at treatment discontinuation.  Urinalysis will be performed by local 
laboratory only and as per local practice.
!
Renal Function:  The creatinine clearance (CrCl) will be calculated based on the 
Cockcroft-Gault formula or the CrCl directly calculated from the 24-hour urine 
collection method at screening, at every cycle Day 1 starting at Cycle 1, and at 
treatment discontinuation.  Cockcroft-Gault formula: CrCl (mL/min) = (140 – age) 
(weight [kg]) / 72 (serum creatinine [mg/dL]); for females, the formula is multiplied 
by 0.85.
6.2.7.
Pregnancy Counseling (males and females)
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted for all subjects at screening, and thereafter for subjects randomized to Treatment Arm 
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
52
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
A (POM+BTZ+LD-DEX) at Cycle 1 Day 1 prior to dosing, every 21 days during treatment, and 
at treatment discontinuation.  
 
6.2.8.
Contraception and Pregnancy Testing Requirements
Acceptable contraception methods need to be aligned to Regulatory guidelines/regulations for 
respective countries and as outlined in the local label (as applicable).  There must be one highly 
effective contraceptive method and one additional effective contraceptive method used for this 
study as specified in the Pregnancy Prevention Plan.  Contraception and pregnancy testing 
timelines for using contraception and pregnancy testing frequencies must be within the 
Regulatory guidelines/regulations for the respective country and Celgene requires additional 
pregnancy precautions as outlined in the Pregnancy Prevention Plan.  
All Females of Child Bearing Potential (FCBP) must have two medically supervised negative 
serum or urine pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting the study.  
The first pregnancy test must be performed within 10-14 days prior to the start of study treatment 
and the second pregnancy test must be performed within 24 hours prior to the start of study 
treatment.  FCBP with regular or no menstrual cycles must agree to have pregnancy tests every 7 
days (weekly) for the first 4 weeks of study treatment (Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 
Day 1, Cycle 2 Day 8) and then every 3 weeks (starting at Cycle 3 Day 1) while on study, at 
treatment discontinuation, and 4 weeks following treatment discontinuation. If menstrual cycles 
are irregular, the pregnancy testing must occur weekly for the first 4 weeks and then every 2 
weeks (starting at Cycle 3 Day 1) while on study, at treatment discontinuation, and at 2 weeks 
and 4 weeks following treatment discontinuation.  Study treatment may not be dispensed for 
FCBP until the investigator has verified that the result of the pregnancy test is negative.
6.3.
Efficacy Assessments
Response (efficacy) assessments must be conducted at the same time points for all subjects 
during their participation in this study in order to accurately compare PFS between the treatment 
arms.  Therefore, every effort must be made to perform these assessments on schedule.  These
efficacy assessments include:  myeloma paraprotein protein electrophoresis and immunofixation, 
serum immunoglobulins, serum free light chain assay, serum hematology (for hemoglobin), 
serum chemistry (for corrected serum calcium and creatinine), and if applicable, clinical and/or 
radiological extramedullary plasmacytoma assessments, skeletal survey, and bone marrow 
aspirate/biopsy.
Efficacy assessments are to be performed at the start of each new cycle.  If the start of a new 
cycle is delayed for more than 7 days from the protocol-defined 21-day dosing cycle, an 
unscheduled visit must be performed for efficacy assessments prior to initiation of the next cycle.
If the treatment delay is greater than 21 days, efficacy assessments must be performed every 21 
days until a new cycle can begin.  For subsequent cycles following a delayed cycle, efficacy 
assessments should be performed at the start of each new cycle.  Treatment response must be 
assessed using results from the central laboratory. 
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
53
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
6.3.1.
Laboratory Assessments for Efficacy Parameters
All efficacy laboratory assessments will be performed centrally. Data generated by central 
laboratories will prevail over locally generated information in the evaluation of the subject’s 
efficacy results.
If screening visit results are ≤ 7 days prior to enrollment/randomization, these laboratory
assessments are not required to be repeated at Cycle 1 Day 1.
!
Myeloma paraprotein (M-Proteins) protein electrophoresis:  Serum protein 
electrophoresis (quantified from the serum protein electrophoresis #sPEP∃test) and 
urine protein electrophoresis (quantified from the urine protein electrophoresis 
#uPEP∃test performed on 24-hour urine collection), will be performed at screening 
and at every cycle on Day 1, at treatment discontinuation, every 21 days during the 
PFS follow-up phase, at PFS follow-up phase discontinuation.  If a response or PD is 
noted based on sPEP and/or uPEP results, sPEP and uPEP tests should be repeated as 
soon as possible to confirm the response or PD.  Investigator evaluation of disease 
response should be based solely on the central laboratory results, not on results from 
local laboratories.  In the event that results from the M-protein samples submitted to 
the central laboratory were not obtained or not analyzable (tube broken, sample 
hemolyzed, etc.), an additional sample should be provided to the central laboratory 
immediately.
!
Myeloma paraprotein (M-Proteins) immunofixation:  Serum and urine 
immunofixation (IFE) tests are performed at screening to identify the 
immunoglobulin subtype of MM and thereafter are triggered to be performed 
whenever M-protein is undetectable / too few to quantify in both sPEP and uPEP
assays.
!
Serum immunoglobulins assessment will be performed at screening and at every 
cycle on Day 1, at treatment discontinuation, every 21 days during the PFS follow-up 
phase, at PFS follow-up phase discontinuation, and at the time of CR confirmation.  
Quantitative immunoglobulin assessment includes IgG, IgA, IgM for all subjects and 
IgE or IgD only for subjects with the respective myeloma sub-type (IgE or IgD).
!
Serum Free Light Chain assay will be performed at screening and at every cycle on 
Day 1, at treatment discontinuation, every 21 days during the PFS follow-up phase, at 
PFS follow-up phase discontinuation, and at the time or CR confirmation.
6.3.2.
Bone Marrow Aspiration and/or Biopsy and Cytogenetics 
At screening, a bone marrow aspirate (and biopsy if necessary) is required and must be obtained 
within 28 days prior to randomization/enrollment to obtain a current estimate of the % plasma 
cells in the marrow.  Analysis for % plasma cells in the marrow will be performed locally.  A
portion of the bone marrow aspirate will be submitted to a central laboratory for cytogenetic 
studies via fluorescent in situ hybridization [FISH] analyses.
After screening, a bone marrow aspirate (or biopsy if necessary) must be performed to confirm a 
CR, and may otherwise be repeated as clinically indicated at the discretion of the treating 
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
54
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
physician.  Celgene may request redacted copies of post-baseline pathology reports from 
subsequent bone marrow biopsies and/or aspirates.
See Section 6.4.6.1 for additional bone marrow aspirate/biopsy sampling details for biomarker 
studies.
6.3.3.
Skeletal Survey 
A skeletal survey by x-ray will be performed at screening and when clinically indicated
thereafter.  All skeletal survey films and analyzed locally by the site investigator/radiologist.  If a 
skeletal survey was performed within 60 days prior to the start of Cycle 1, it may be used as 
screening assessment.  Refer to Appendix D for detailed requirements.
6.3.4.
Extramedullary Plasmacytoma Assessments
If extramedullary plasmacytomas (EMPs) are clinically assessable, clinical assessment will be 
performed at screening, at every Cycle Day 1, at treatment discontinuation, every 21 days during 
the PFS follow-up phase and at PFS follow-up phase discontinuation.
If EMPs are only assessable radiographically (x-ray and/or conventional [spiral] CT/MRI scan), 
scans are required at screening, at Cycle 3 Day 1, every 3 cycles thereafter (Cycle 6 Day 1, Cycle 
9 Day 1, etc.) during treatment, at treatment discontinuation, every 63 days during the PFS 
follow-up phase, at PFS follow-up phase discontinuation, and when clinically indicated to 
confirm a response (≥ PR).  The radiographic modality used at screening (eg, x-ray) must be 
repeated at each assessment time point throughout the study.  All scans will be reviewed locally 
only.
The individual EMPs (both clinically and radiographically assessable) must be consistently 
labeled using the same numerical and descriptive values (eg, EMP#1 left rib, EMP #2 liver) 
throughout the study at the specified time points requested by the protocol.
6.3.5.
Assessment of Response
6.3.5.1.
Investigators’ Assessment for Tumor Response 
Starting from Cycle 2, response will be assessed using results from central laboratories by the 
investigators using the IMWG criteria (Appendix B) at every cycle on Day 1 and at the treatment 
discontinuation visit, every 21 days during the PFS follow-up phase and at PFS follow-up phase 
discontinuation.  All treatment discontinuation decisions due to disease progression will be made 
by treating physicians based on response as assessed using results from central laboratories by 
the IMWG criteria, except for new or increase in bone lesions or soft tissue plasmacytomas.
6.3.5.2.
IRAC Assessment for Tumor Response
An IRAC will be formed by a group of experts in the MM disease area to review efficacy data in 
a blinded manner. For each subject, the IRAC will determine tumor response at scheduled or 
unscheduled visits, and the time of PD (if disease progressed). In addition, the IRAC will 
determine the best overall response of each subject up to time of the data cut-off for interim and 
final analyses.
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
55
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
The IRAC will adjudicate blinded efficacy data incrementally according to IRAC Charter during 
the study.  The IRAC adjudicated response data will be used for efficacy analysis in all interim 
and final analyses.  Primary efficacy analyses will be conducted in tumor response data, 
including progressive disease (PD) that are assessed by the IRAC according to the IMWG 
uniform response criteria (Durie, 2006) (Appendix B); an exploratory analysis using response 
data assessed by the EBMT (Bladé, 1998) (Appendix C) response criteria will also be performed.
6.3.6.
Overall Survival and Subsequent Anti-MM Therapies 
All long-term follow-up phase subjects will be contacted four (4) times a year (every 3 months) 
to obtain survival status for at least 5 years after the last subject is randomized into the study, or
longer if clinically indicated.  Cause of death is to be recorded on the eCRF and the subject’s 
hospital medical record.  All subsequent anti-myeloma therapies must be collected on the eCRF.  
The date of PD and reason for progression based on the IMWG uniform response criteria, if 
available, will also be collected during long-term follow-up for subjects who did not have PD 
during the study treatment or PFS follow-up period, if applicable.
6.4.
Other Assessments
6.4.1.
ECOG Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status will be performed at 
screening, at every cycle Day 1 starting at Cycle 1, at treatment discontinuation, every 21 days 
during the PFS follow-up phase and at PFS follow-up phase discontinuation.  See Appendix E
for the ECOG Performance Status Scale.
6.4.2.
Serum Beta-2 Microglobulin (β2M)
The serum β2M test will be performed centrally at the screening visit only.  The test result 
should be available prior to randomization to allow for appropriate stratification.
6.4.3.
Healthcare Resource Utilization
Information for hospitalizations or emergency department visits that occur during the active 
treatment period will be collected.
6.4.4.
Quality of Life (QoL)
Quality of Life (QoL) instruments ([EORTC QLQ-MY20] and [EORTC QLQ-C30]) and the 
descriptive system of the EQ-5D will be provided to each subject to complete on the first day of 
every cycle (including Cycle 1) at the beginning of the Cycle Day 1 visit prior to any study 
treatment (POM, BTZ, DEX) administration and at treatment discontinuation.  If the collection 
of such information is prohibited per local regulations or is not operationally or logistically 
feasible, such assessments will not be considered as mandatory.  See Appendix I for QoLs.
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6.4.6.
Exploratory Biomarker Sampling
The biomarker sampling will only be performed at sites where such sampling is permitted per 
local regulations, operationally and logistically feasible, and only for subjects who give their 
consent.  For investigative sites where biomarker sampling will be performed, if an assessment is 
not done due insufficient sample or subject non-compliance with the sampling requirement, it 
will not be considered a deviation from the protocol.  All biomarker samples will be destroyed 5 
years after completion of the study or earlier if required by law.
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6.4.6.1.
Minimal Residual Disease (MRD), Genomic, Molecular/Mechanistic Biomarkers
Bone marrow aspirate/biopsy and a whole blood sample for MRD, genomic and 
molecular/mechanistic biomarkers studies will be submitted to a central laboratory at the 
following timepoints:
∀
At screening (if sufficient bone marrow aspirate material is available after 
samples are prepared for the local pathology and central cytogenetic analysis)
∀
At time of CR confirmation (if sufficient bone marrow aspirate material is 
available after samples are prepared for the local pathology analysis)
∀
At time of PD or treatment discontinuation (only if a bone marrow aspirate is 
performed for a subject as part of standard of care and sufficient material is 
available after samples are prepared for the local pathology analysis)
6.4.6.2.
Immune Biomarkers
Blood samples for immune biomarkers studies will be collected and submitted to a central 
laboratory at the following timepoints:  screening, Cycle 1 Day 8, and Cycle 3 Day 8.
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7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
This study will enroll approximately 544 subjects (272 in each arm) at sites globally.
7.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Must be ≥ 18 years at the time of signing the informed consent form.
2. The subject must understand and voluntarily sign an informed consent document prior to 
any study-related assessments/procedures.
3. Must be able to adhere to the study visit schedule and other protocol requirements.
4. Subjects must have documented diagnosis of multiple myeloma and have measurable 
disease by serum or urine protein electrophoresis (sPEP or uPEP): sPEP ≥ 0.5 g/dL or 
uPEP ≥ 200 mg/24 hours.
5. All subjects must have had at least 1 but no greater than 3 prior anti-myeloma regimens. 
(note: induction with or without bone marrow transplant and with or without maintenance 
therapy is considered one regimen.)
6. All subjects must have documented disease progression during or after their last anti-
myeloma therapy.
7. All subjects must have received prior treatment with a lenalidomide-containing regimen 
for at least 2 consecutive cycles.
8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
9. Females of childbearing potential (FCBP†) must agree to utilize two reliable forms of 
contraception simultaneously or practice complete abstinence from heterosexual contact 
for at least 4 weeks before starting study treatment, while participating in the study 
treatment phase (including dose interruptions), and for at least 4 weeks after the last dose 
of POM or 3 months after the last dose of BTZ, whichever is longer, and must agree to 
regular pregnancy testing during this timeframe.
10. Females must agree to abstain from breastfeeding during study treatment and for at least 
4 weeks after study treatment discontinuation.
11. Males must agree to use a latex or synthetic condom during any sexual contact with 
FCBP while participating in the study treatment phase and for at least 4 weeks after the 
last dose of POM or 3 months after the last dose of BTZ, whichever is longer, even if he 
has undergone a successful vasectomy.
                                               
†This protocol defines a female of childbearing potential as a sexually mature woman who: 1) is menstruating, 
amenorrheic from previous medical treatments, under 50 years, and/or perimenopausal.  Adult females not of 
childbearing potential are defined as females who have had a natural menopause (amenorrhea following cancer 
therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, have not had menses at any 
time in the preceding 24 consecutive months), a hysterectomy or bilateral oophorectomy.
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12. Males must also agree to refrain from donating sperm while on pomalidomide and for 4 
weeks after discontinuation from this study treatment.
13. All subjects must agree to refrain from donating blood while on study treatment and for 4 
weeks after discontinuation from this study treatment.
14. All subjects must agree not to share medication.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subjects who had documented progressive disease during therapy or within 60 days of 
the last dose of a bortezomib-containing therapy under the 1.3 mg/m2 dose twice weekly 
dosing schedule
2. Peripheral neuropathy Grade 3, Grade 4 or Grade 2 with pain within 14 days prior to 
randomization
3. Non-secretory multiple myeloma
4. Any of the following laboratory abnormalities:
!
Absolute neutrophil count (ANC) < 1,000/μL
!
Hemoglobin < 8 g/dL (< 4.9 mmol/L)
!
Platelet count < 75,000/μL for subjects in whom < 50% of bone marrow nucleated 
cells are plasma cells; or a platelet count < 30,000/ μL for subjects in whom ≥ 50% of 
bone marrow nucleated cells are plasma cells
!
Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
!
Serum SGOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN)
!
Serum total bilirubin > 1.5 x ULN
5. Subjects with severe renal impairment (Creatinine Clearance [CrCl] <30 mL/min) 
requiring dialysis
6. Subjects with prior history of malignancies, other than MM, unless the subject has been 
free of the disease for ≥ 5 years with the exception of the following non-invasive 
malignancies:
!
Basal cell carcinoma of the skin
!
Squamous cell carcinoma of the skin
!
Carcinoma in situ of the cervix
!
Carcinoma in situ of the breast
!
Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, 
nodes, metastasis] clinical staging system) or prostate cancer that is curative.
7. Previous therapy with pomalidomide
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8. History of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, bortezomib, 
boron, mannitol, or dexamethasone 
9. ≥ Grade 3 rash during prior thalidomide or lenalidomide therapy
10. Incidence of gastrointestinal disease that may significantly alter the absorption of 
pomalidomide
11. Subjects with any one of the following:
!
Clinically significant abnormal ECG finding at screening
!
Congestive heart failure (New York Heart Association Class III or IV)
!
Myocardial infarction within 12 months prior to starting study treatment
!
Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina 
pectoris
12. Subjects who received any of the following within the last 14 days of initiation of study 
treatment:
!
Plasmapheresis
!
Major surgery (kyphoplasty is not considered major surgery)
!
Radiation therapy other than local therapy for myeloma associated bone lesions
!
Use of any systemic anti-myeloma drug therapy
13. Use of any investigational agents within 28 days or 5 half-lives (whichever is longer) of 
treatment
14. Subjects with conditions requiring chronic steroid or immunosuppressive treatment, such 
as rheumatoid arthritis, multiple sclerosis, and lupus, which likely need additional steroid 
or immunosuppressive treatments in addition to the study treatment. Includes subjects 
receiving corticosteroids (> 10 mg/day of prednisone or equivalent) within 3 weeks prior 
to enrollment.
15. Subjects unable or unwilling to undergo protocol required thromboembolism prophylaxis 
or herpes zoster prophylaxis will not be eligible to participate in this study
16. Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study
17. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subjects from signing the informed consent form
18. Pregnant or breastfeeding females
19. Known seropositive for or active viral infection with human immunodeficiency virus 
(HIV)
20. Known active viral infection with hepatitis A virus (HAV).
21. Known seropositive for or active viral infection with hepatitis B virus (HBV):
!
Subjects who are HBsAg negative and viral DNA negative are eligible.
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
!
Subjects who had hepatitis B but have received an antiviral treatment and show non-
detectable viral DNA for 6 months are eligible.
!
Subjects who are seropositive because of hepatitis B virus vaccine are eligible.
22. Known seropositive for or active viral infection with hepatitis C virus (HCV):
!
Subjects who had hepatitis C but have received an antiviral treatment and show no 
detectable viral RNA for 6 months are eligible.
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8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Product(s)
This section contains a summary of prescribing information on pomalidomide, bortezomib, and 
dexamethasone; full prescribing information and labeling should be reviewed and is contained in 
the respective current US Prescribing Information, EU Summary of Product Characteristics 
(SmPC), or equivalent document for the specific region/country.
CC-4047 Pomalidomide
Pomalidomide will be supplied as Investigational Product (IP) by Celgene Corporation for all 
countries as 1 mg, 2 mg, 3 mg, and 4 mg capsules for oral administration. IP will be packaged in 
bottles containing a 21-day supply.  IP should be stored as instructed in the IP packaging label, in 
an area free of environmental extremes and must be accessible only to study personnel.
Bortezomib (Velcade®)
Investigative sites in the United States and Japan will use commercially available bortezomib 
(Velcade®) for this study and will dispense this drug to subjects via prescription. The package 
insert should be consulted for handling, reconstitution, administration, and storage details.
For investigative sites outside of the United States and Japan, bortezomib supplies will be 
provided as commercial material labeled appropriately as Investigational Product (IP) by 
Celgene Corporation.  Bortezomib will be provided in a 3.5 mg vial as Powder for Solution for
Injection.  IP should be stored as instructed in the IP packaging label, in an area free of 
environmental extremes, and must be accessible only to study personnel.  Bortezomib must be 
reconstituted by a healthcare professional. Each 3.5 mg single-use vial of bortezomib must be 
reconstituted with 1.4 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. Dissolution 
of the lyophilised powder is completed in less than 2 minutes. After reconstitution, each ml 
solution contains 2.5 mg bortezomib. The reconstituted solution is clear and colorless, with a 
final pH of 4 to 7. The reconstituted solution must be inspected visually for particulate matter 
and discoloration prior to administration. If any discoloration or particulate matter is observed, 
the reconstituted solution must be discarded. The reconstituted solution should be used 
immediately after preparation. If not used immediately, in-use storage times and conditions prior 
to use are the responsibility of the user. However, the chemical and physical in-use stability of 
the reconstituted solution has been demonstrated for 8 hours at 25°C stored in the original vial 
and/or a syringe. The total storage time for the reconstituted medicinal product should not exceed 
8 hours prior to administration.
As bortezomib 2.5 mg/ml reconstituted solution for injection is to be administered 
subcutaneously, local injection site reactions may occur. In these cases a less concentrated 
bortezomib solution (reconstituted to 1 mg/ml instead of 2.5 mg/ml) may be administered 
subcutaneously.
Dexamethasone
Investigative sites in the United States will use commercially available dexamethasone for this 
study and will dispense this drug to subjects via prescription.  
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For investigative sites outside of the United States, dexamethasone supplies will be provided as
commercial material labeled appropriately as Investigational Product (IP) by Celgene 
Corporation.  Dexamethasone will be provided as 2 mg and 4 mg strength tablets.  The 2 mg 
tablets will be packaged in 50-count bottles and 4 mg tablets will be packaged in 20-count blister 
cards.  IP should be stored as instructed in the IP packaging label, in an area free of 
environmental extremes, and must be accessible only to study personnel.  
Other recommended/required concomitant medications per the protocol such as aspirin (or other 
antithrombotic or anti-coagulants), viral prophylaxis, and growth factors will be provided by the 
investigative site.  Celgene will not provide these medications.
8.2.
Treatment Administration and Schedule
Subjects will be randomized in a 1:1 ratio to Treatment Arm A or B, respectively. 
Subjects taking oral pomalidomide will be instructed to return the study drug bottles (and any 
remaining study drug) at the next visit for drug accountability purposes.  For FCBP, study drug 
will not be dispensed until the investigator has verified that the results of the pregnancy test are 
negative.  Any FCBP other than the subject should not handle study drug unless wearing gloves.
8.2.1.
Treatment Arm A: (POM + BTZ + LD-DEX)
Treatment Arm A: Subjects randomized to Treatment Arm A (POM + BTZ + LD-DEX) will 
receive the following:
!
Oral POM 4 mg/day on Days 1 to 14 of each 21-day treatment cycle 
 
 
  
!
BTZ 
∀
For Cycles 1 – 8: 1.3 mg/m2/dose on Days 1, 4, 8, and 11 of a 21-day cycle
∀
For Cycles 9 onwards: 1.3 mg/m2/dose on Days 1 and 8 of a 21-day cycle
Bortezomib doses must be at least 72 hours apart.
Bortezomib will be administered SQ for all subjects consented after Protocol Amendment 1
activation.  Subjects consented prior to Protocol Amendment 1 activation may continue to 
receive IV bortezomib or may be switched to SQ bortezomib at the treating physician’s 
discretion.
!
Oral DEX
∀
For Cycles 1 to 8, 20 mg/day (≤ 75 years old) or 10 mg/day (> 75 years old) on 
Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle.
∀
For Cycles 9 and onward, 20 mg/day (≤ 75 years old) or 10 mg/day (> 75 years 
old) on Days 1, 2, 8, and 9 of a 21-day cycle.
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Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
8.2.2.
Treatment Arm B: (BTZ + LD-DEX)
Treatment Arm B: Subjects randomized to Treatment Arm B (BTZ + LD-DEX) will receive 
the following:
!
BTZ 
∀
For Cycles 1 – 8: 1.3 mg/m2/dose on Days 1, 4, 8, and 11 of a 21-day cycle
∀
For Cycles 9 onwards: 1.3 mg/m2/dose on Days 1 and 8 of a 21-day cycle
Bortezomib doses must be at least 72 hours apart.
Bortezomib will be administered SQ for all subjects consented after Protocol Amendment 1
activation.  Subjects consented prior to Protocol Amendment 1 activation may continue to 
receive IV bortezomib or may be switched to SQ bortezomib at the treating physician’s 
discretion.
!
Oral DEX
∀
For Cycles 1 to 8, 20 mg/day (≤ 75 years old) or 10 mg/day (> 75 years old) on 
Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle.
∀
For Cycles 9 and onward, 20 mg/day (≤ 75 years old) or 10 mg/day (> 75 years 
old) on Days 1, 2, 8, and 9 of a 21-day cycle.
8.3.
Overdose
Overdose, as defined for this protocol, refers to pomalidomide, bortezomib and dexamethasone
dosing only.
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of pomalidomide, bortezomib, or dexamethasone assigned to a given patient, regardless of 
any associated adverse events or sequelae.  
!
PO any amount over the protocol-specified dose
!
IV 10% over the protocol-specified dose
!
SC 10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified 
rate.
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form.  See Section
11.1 for the reporting of adverse events associated with overdose.
8.4.
Dose Modification and Interruption
Dosing interruptions and reductions are permitted throughout the study. Subjects will be 
evaluated for adverse events at each visit with the NCI CTCAE (version 4.0 or higher) used as a 
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guide for the grading of severity. Dosing is to be modified in subjects who experience a dose-
limiting toxicity (DLT) as described in the following appropriate sections.
In the event of any pomalidomide dose reduction for a subject randomized to Treatment Arm A
in the United States, site staff must contact IVRS/IWRS to record the new dose level and obtain 
the new study treatment assignment.  For sites in Japan, in the event of a dose reduction for POM 
and/or DEX for subjects randomized to Treatment Arm A or B, site staff must contact 
IVRS/IWRS to record the new dose level and obtain the new study treatment assignment.  In the 
event of any dose reductions for subjects randomized to either Treatment Arm A or B outside of 
the United States and Japan, site staff must contact IVRS/IWRS to record the new dose level and 
obtain the new study treatment assignment.
If the treatment has been interrupted and the next cycle is delayed beyond 21 days after Day 1 of 
the prior cycle, then Day 1 of the next cycle will be defined as the first day that treatment is 
resumed.
For Treatment Arm A (POM+BTZ+LD-DEX):
!
If POM dosing is withheld, then BTZ and LD-DEX dosing may be continued at the 
discretion of the treating physician. 
!
If POM is permanently discontinued, then the subject must be permanently 
discontinued from all study treatments. 
!
If BTZ dosing is withheld or permanently discontinued, then POM and LD-DEX may 
be continued at the discretion of the treating physician. 
!
If BTZ and LD-DEX dosing is withheld or permanently discontinued, then POM may 
be continued at the discretion of the treating physician. 
!
If both POM and BTZ dosing is withheld, then LD-DEX must also be withheld.
!
If LD-DEX dosing is withheld or permanently discontinued, then POM and BTZ may 
be continued. 
For Treatment Arm B (BTZ+LD-DEX):
!
If BTZ dosing is withheld, then LD-DEX dosing must also be withheld. 
!
If BTZ is permanently discontinued, then the subject must be permanently 
discontinued from all study treatments.
!
If LD-DEX is withheld or permanently discontinued, then BTZ may be continued. 
8.4.1.
Dose Modification Instructions for Pomalidomide
Detailed instructions for pomalidomide dose interruptions and reductions are provided in Table 2
and Table 3 outlines the dose reduction steps for pomalidomide.
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Table 2:
Dose Modification Instructions for Pomalidomide (Treatment Arm A only)
Toxicity
Dose Modification
Neutropenia
Grade 4 neutropenia (ANC < 500/μL) 
or
Febrile neutropenia (fever ≥38.5°C 
and ANC < 1,000/μL)
Withhold the dose for remainder of cycle.  If the subject was not 
receiving Granulocyte colony-stimulating factor (G-CSF) 
therapy, G-CSF therapy may be started at the discretion of the 
treating physician.  On Day 1 of the next cycle, the dose of 
pomalidomide may be maintained if neutropenia was the only 
pomalidomide-related toxicity requiring a dose modification and 
G-CSF treatments are continued.  Otherwise, decrease by one 
dose level at start of next cycle.
Note, ANC must be ≥ 1000/ μL to resume dosing.
Thrombocytopenia
Grade 4 Thrombocytopenia (Platelets 
<25,000/μL)
Withhold the dose for remainder of cycle.  Dosing may resume 
at one dose level lower once the platelet count has recovered to ≥ 
50,000/μL.
Rash = Grade 3
Withhold dose for remainder of cycle.  Decrease by one dose 
level when dosing is resumed at next cycle (rash must be 
resolved or improved to ≤ Grade 1 before dose resumption).
Rash = Grade 4 or Blistering
Permanently discontinue study treatment.
Constipation ≥ Grade 3
Withhold dose for remainder of cycle.  Initiate bowel regimen.  
Decrease by one dose level when dosing is resumed at next cycle 
(constipation must be resolved or improved to ≤ Grade 2 before 
dose resumption).
Venous Thromboembolic Event 
(VTE) ≥ Grade 3
Withhold dose for remainder of cycle.  Initiate anticoagulation 
treatment.  Maintain dose level when dosing resumed at next 
cycle at discretion of treating physician.
Other ≥ Grade 3 pomalidomide-
relatedadverse events
a
Withhold dose for remainder of cycle.  Decrease by one dose 
level when dosing resumed at next cycle (adverse event must be 
resolved or improved to ≤ Grade 2 before restarting dosing).
a For Grade 3 or 4 AEs that are not considered to be related to pomalidomide, the treating physician should consult 
with the Celgene Medical Monitor for dose interruptions and reductions.
To initiate a new cycle of pomalidomide following a dose interruption, the neutrophil count must 
be ≥ 1000/μL with or without G-CSF, the platelet count must be ≥ 50,000/μL, and non-
hematologic AEs must be resolved or improved as outlined in Table 2.
If recovery from toxicities is prolonged and POM dose withholding is beyond 14 days, then the 
dose of pomalidomide should be decreased by one dose level when dosing is resumed in the new 
cycle.
Table 3 outlines the dose reduction steps for pomalidomide.
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Table 3:
Pomalidomide Dose Reduction Steps 
Dose Level
Oral Pomalidomide
Dose (Days 1-14 of 21-day cycle)
Starting Dose
4 mg
Dose Level -1
3 mg
Dose Level -2
2 mg
Dose Level -3
1 mg
The minimum permitted dose level for pomalidomide is 1 mg.  No dose re-escalation is 
permitted for pomalidomide.
8.4.2.
Dose Modification Instructions for Bortezomib
Table 4 details instructions for bortezomib dose interruptions and reductions and Table 5 outlines 
the dose reduction levels for bortezomib; however, dose modification decisions for bortezomib 
will be at the treating physician’s discretion per the full prescribing information and labeling in 
the respective current US Prescribing Information, EU Summary of Product Characteristics 
(SmPC), or equivalent document for the specific region/country.
Table 4:
Bortezomib Dose Modification 
Toxicity
Bortezomib Dose Modification
≥ Grade 3 non-hematological toxicity (excluding 
neuropathy)
Withhold bortezomib until the symptoms of the toxicity 
have resolved, bortezomib therapy may be reinitiated at 
reduced bortezomib dosing by 1 dose level
Grade 4 hematological toxicity
Withhold bortezomib until the symptoms of the toxicity 
have resolved, bortezomib therapy may be reinitiated at 
reduced bortezomib dosing by 1 dose level
Grade 1 neuropathy without pain or loss of function
No action
Grade 1 neuropathy with pain or Grade 2 neuropathy
Reduce bortezomib dosing by one level
Grade 2 neuropathy with pain or Grade 3 neuropathy
Withhold bortezomib until toxicity resolves, bortezomib 
therapy may be reinitiated at a reduced dose level of 0.7 
mg/m2 and change treatment schedule to once per week
(Days 1 and 8 of a 21-day cycle)
Grade 4 neuropathy
Permanently discontinue study treatment
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Table 5:
Bortezomib Dose Reduction Levels
Dose Level
Bortezomib
Dose Level
(Cycle 1-8:  Days 1, 4, 8, 11 of a 21-day cycle
Cycle ≥ 9:  Days 1, 8 of a 21-day cycle)
Starting Dose
1.3 mg/m2
Dose Level -1
(25% reduction from starting dose)
1 mg/m2
Dose Level -2 
(25% reduction from dose level -1)
0.7 mg/m2
The minimum permitted dose level for bortezomib is 0.7 mg/m2.  No dose re-escalation is 
permitted for bortezomib.
8.4.3.
Dose Modification Instructions for Low-Dose Dexamethasone
Table 6 details instructions for low-dose dexamethasone dose interruptions and reductions and 
Table 7 outlines the dose reduction steps for low-dose dexamethasone, however; dose 
withholding / resumption decision is at the treating physician’s discretion per the full prescribing 
information and labeling in the respective current US Prescribing Information, EU Summary of 
Product Characteristics (SmPC), or equivalent document for the specific region/country.
Table 6:
Dose Reductions for Low-Dose Dexamethasone Related Toxicities
Toxicity
Low-Dose Dexamethasone Dose Modification
Dyspepsia = Grade 1-2
Maintain dose and treat with histamine (H2) blockers or equivalent.  
Decrease by one dose level if symptoms persist.
Dyspepsia ≥ Grade 3
Withhold dose until symptoms are controlled.  Add H2 blocker or 
equivalent and decrease one dose level when dosing is resumed.
Edema ≥ Grade 3
Use diuretics as needed and decrease dose by one dose level.
Confusion or mood alteration ≥ 
Grade 2
Withhold dose until symptoms resolve.  When dosing is resumed
decrease dose by one dose level.
Muscle weakness (steroid 
myopathy) ≥ Grade 2
Withhold dose until muscle weakness ≤ Grade 1.  When dosing is 
resumed decrease dose by one dose level.
Hyperglycemia ≥ Grade 3
Decrease dose by one dose level.  Treat with insulin or oral 
hypoglycemic agents as needed.
Acute pancreatitis
Discontinue dexamethasone from treatment regimen.
Other ≥ Grade 3 dexamethasone-
related adverse events
Stop dexamethasone dosing until the adverse event resolves to ≤ 
Grade 2. Decrease by one dose level when dosing is resumed.
If recovery from toxicities is prolonged and LD-DEX dose withholding is beyond 14 days, then 
the dose of dexamethasone will be decreased by one dose level when dosing is resumed in the 
new cycle.
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Table 7:
Low-Dose Dexamethasone Dose Reduction Steps 
Dose Level
≤ 75 years old
Dose (Cycle 1-8:  Days 1, 2, 4, 5, 8, 9, 
11, 12 of a 21-day cycle
Cycle ≥ 9:  Days 1, 2, 8, 9 of a 21-day 
cycle)
> 75 years old
Dose (Cycle 1-8:  Days 1, 2, 4, 5, 8, 9, 
11, 12 of a 21-day cycle
Cycle ≥ 9:  Days 1, 2, 8, 9 of a 21-day 
cycle)
Starting Dose
20 mg
10 mg
Dose Level -1
12 mg
6 mg
Dose Level -2 
8 mg
4 mg
Dexamethasone should be discontinued if subject is unable to tolerate 8 mg if ≤ 75 years old or 4 
mg if > 75 years old.
8.5.
Method of Treatment Assignment
This study will utilize the IVRS/IWRS for randomization.  Designated research personnel at each 
investigational sites will be assigned password protected, coded identification numbers which 
gives them the authorization to call into IVRS/IWRS to randomize eligible subjects. 
Celgene trial staff will review specific eligibility criteria for all screened subjects prior to 
randomization of subjects via the IVRS/IWRS.  Celgene trial staff will be required to activate a 
subjects in the IVRS/IWRS before site staff may randomize and obtain the treatment assignment 
via IVRS/IWRS.
For sites in the US, in the event of any dose reduction for POM, site staff must contact 
IVRS/IWRS to record the new dose level and obtain the new study treatment assignment.  For 
sites in Japan, in the event of a dose reduction for POM and/or DEX, site staff must contact 
IVRS/IWRS to record the new dose level and obtain the new study treatment assignment.  For 
sites outside the US and Japan, in the event of any dose reductions for POM, BTZ and DEX, site 
staff must contact IVRS/IWRS to record the new dose level and new study treatment assignment.
8.6.
Packaging and Labeling
The label(s) for IP will include sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
8.7.
Investigational Product Accountability and Disposal
US Sites:
Pomalidomide will be provided to all US sites by Celgene and labeled as Investigational Product 
(IP), as such, the investigator(s) or designee(s) is responsible for taking an inventory of each 
shipment of IP received, and comparing it with the accompanying study drug shipping order 
form.  The investigator(s) or designee(s) will verify the accuracy of the information on the form 
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and call the IVRS to register the study medication received at the site.  At the study site, IP will 
be stored according to the storage conditions described on the IP packaging label in a locked, 
safe area to prevent unauthorized access.  The IP must be stored as directed on IP packaging
label at controlled temperature and a temperature log must be maintained in the source 
documents.
Pomalidomide IP accountability prior to dispensation will be assessed by the investigator or 
designee.  Applicable information such as lot number, capsule count and expiration date should 
be collected, as well as information provided by the subject or the caregiver (eg, subject dosing 
diary).  Investigational Product accountability should be assessed before drug dispensing for 
each subsequent treatment cycle in the treatment phase, starting on Day 1 of Cycle 2, and at the 
Treatment Discontinuation visit.  The investigator(s) or designee(s) is responsible for accounting 
for all IP that is issued to and returned by the subject during the course of the study according to 
applicable regulatory requirements. Any unused IP must be returned by a study subject and 
retained by the investigative site for accountability to be conducted by a Celgene representative 
(or designee). If any IP is lost or damaged, its disposition should be documented. At the periodic 
monitoring visits, a Celgene representative (or designee) will conduct IP accountability and 
address any discrepancies. Upon satisfactory reconciliation of all IP, returned IP may be 
destroyed. At the conclusion of the study, all remaining study drug will be counted, reconciled 
with dispensing records, documented, and destroyed at the clinic site or allocated drug 
destruction location after completion of drug accountability by a Celgene representative (or 
designee). The Celgene representative (or designee) will ensure that a final report of drug 
accountability to the unit dose level (ie, tablet) is prepared and placed in both the investigator 
study file and the central clinical study file.
Celgene Corporation will instruct the investigator(s) on the return, disposal and destruction of 
Pomalidomide.  A copy of the site’s Standard Operating Procedure (SOP) for drug destruction 
may be collected by the sponsor (or designee). Any revisions to a site’s destruction process 
must be provided and approved by the sponsor (or designee) prior to implementation on this 
protocol. Any site without a sponsor (or designee) approved destruction SOP and process will be 
required to return IP to Celgene.
Ex-US Sites:
At sites outside of the United States and Japan, Celgene will provide Pomalidomide, 
Dexamethasone and Bortezomib (Velcade) labeled as Investigational Product (IP). At Japanese 
sites, Celgene will provide pomalidomide and dexamethasone labeled as Investigational Product 
(IP). Each investigative site participating in this study will be responsible for accountability of 
all Celgene-provided drug products.  The investigator(s) or designee(s) is responsible for taking 
an inventory of each shipment of each product received, and comparing it with the 
accompanying study drug shipping order form. The investigator(s) or designee(s) will verify the 
accuracy of the information on the form and call the IVRS to register the study medication 
received at the site.  At the study site, all IP will be stored according to the storage conditions 
described on the IP packaging label in a locked, safe area to prevent unauthorized access. The IP 
must be stored as directed on IP packaging label at controlled temperature and a temperature log 
must be maintained in the source documents.
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Confidential and Proprietary
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Pomalidomide, Dexamethasone and Bortezomib accountability prior to dispensation/
administration will be assessed by the investigator or designee.  Applicable information such as 
lot number, capsule/tablet count, vial administered and expiration date should be collected, as 
well as information provided by the subject or the caregiver (eg, subject dosing diary).  
Investigational Product accountability should be assessed before drug dispensing for each 
subsequent treatment cycle in the treatment phase, starting on Day 1 of Cycle 2, and at the 
Treatment Discontinuation visit.  The investigator(s) or designee(s) is responsible for accounting 
for all IP that is issued to and returned by the subject during the course of the study according to 
applicable regulatory requirements. Any unused IP must be returned by a study subject and 
retained by the investigative site for accountability to be conducted by a Celgene representative 
(or designee). If any IP is lost or damaged, its disposition should be documented. At the periodic 
monitoring visits, a Celgene representative (or designee) will conduct IP accountability and 
address any discrepancies. Upon satisfactory reconciliation of all IP, returned IP may be 
destroyed. At the conclusion of the study, all remaining study drug will be counted, reconciled 
with dispensing records, documented, and destroyed at the clinic site or allocated drug 
destruction location after completion of drug accountability by a Celgene representative (or 
designee). The Celgene representative (or designee) will ensure that a final report of drug 
accountability to the unit dose level (ie, tablet) is prepared and placed in both the investigator 
study file and the central clinical study file.
Celgene Corporation will instruct the investigator(s) on the return, disposal and destruction of 
each IP.  A copy of the site’s Standard Operating Procedure (SOP) for drug destruction may be 
collected by the sponsor (or designee). Any revisions to a site’s destruction process must be 
provided and approved by the sponsor (or designee) prior to implementation on this protocol. 
Any site without a sponsor (or designee) approved destruction SOP and process will be required 
to return IP to Celgene.
8.8.
Investigational Product Compliance
US & Ex-US sites
The Investigator and/or designee will document the number of capsules of pomalidomide issued 
to and returned by each subject at each study visit.  The Investigator and/or designee will also be 
responsible for documenting subject compliance for bortezomib and dexamethasone for the
study.  Study site personnel will review the dosing information with the subject (or legally 
authorized representative) on scheduled clinic visit days.  Study site personnel will perform an IP 
administration compliance check and record this information in the subject’s source 
documentation and on the appropriate CRF.  Administration of all IP will be recorded including 
dispensing, dosing, and any changes in dosage administration such as interruption or reduction in 
dosing due to an AE.
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9.
CONCOMITANT MEDICATIONS AND PROCEDURES
9.1.
Permitted Concomitant Medications and Procedures
Other therapies considered necessary for the subject’s well being may be administered at the 
discretion of the investigator.  These therapies may include antibiotics, analgesics, 
antihistamines, or other medications and transfusions of red blood cells, platelets, or fresh frozen 
plasma given to assist in the management of complications associated with MM or its therapy.
Subjects with myeloma-associated bone lesion may receive bisphosphonate therapy throughout 
the study, unless such therapy is contraindicated. The use of hematopoietic growth factors is 
permitted (the use of myeloid growth factors is encouraged when the absolute neutrophil count is 
less than 1,000/μL) at the discretion of the treating physician.
Subjects who fail absolute neutrophil count (ANC), hemoglobin or platelet eligibility criteria at 
screening CANNOT be re-tested for the study after being treated with growth factors or 
platelet/blood transfusion. However, subjects who meet the ANC, hemoglobin and platelet 
eligibility criteria due to growth factor treatment or platelet/blood transfusion received prior to 
screening are acceptable and are not considered as screening failures.
Radiation therapy to a pathological fracture site or to treat bone pain is permitted. Such subjects 
are allowed to remain on the treatment phase of the study.
The use of steroids is limited to the dexamethasone dose described in the study.  Please see 
Section 9.2 for further details.
All therapies administered during the study will be recorded on the Concomitant Medication 
eCRF page.
In the event of any treatment emergent adverse events, the treating physician may order any 
medically necessary unscheduled local laboratory procedures or exams to be performed.
9.2.
Prohibited Concomitant Medications and Procedures
Concomitant use of other approved or investigational anti-myeloma therapy while the subject is 
taking study treatment is prohibited. Subsequent anti-myeloma treatment should not be initiated 
prior to PD.
Chronic use of steroids or any other immunosuppressive therapies is prohibited in this study.  
Use of inhaled, topical, intranasal corticosteroids or local steroid injections (eg, intra-articular 
injection) is permitted.
Drugs known to prolong QT corrected (QTc) interval should be avoided unless deemed 
medically necessary. See Appendix G for link to a comprehensive list of drugs known to prolong 
QTc. A thorough QT study (CC-4047-CP-010) was conducted in healthy subjects according to 
the E14 Guidance to assess the potential of Pomalidomide (POM) to delay cardiac re-
polarization, especially as prolongation of the QT interval.  The result of the QT prolongation 
assessment was observed to be negative, indicating a low risk of POM-associated QT 
prolongation.
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9.3.
Required Concomitant Medications and Procedures
Recent or active cancer is a recognized prothrombotic risk factor for increasing the risk of VTE.  
Increased plasma viscosity related to monoclonal paraproteinemia has been implicated as a risk 
factor for VTE in MM subjects.  Clinical studies have shown that thalidomide and lenalidomide 
in combination with dexamethasone or other chemotherapeutic agents increase the risk of VTE 
(Baz, 2005; Weber, 2007).  Aspirin has been reported to be effective in reducing the incidence of 
deep vein thrombosis (DVT) in MM subjects treated with thalidomide or lenalidomide (Baz, 
2005).  For the current study, low-dose aspirin, low molecular weight heparin, or other 
equivalent antithrombotic or anti-coagulant will be given during the study to all subjects 
assigned to Treatment Arm A, as well as to Treatment Arm B subjects who have a prior history 
of deep vein thrombosis (DVT) or pulmonary embolism (PE). Antithrombotic prophylaxis will 
be recorded on the eCRF at each visit. At the discretion of the treating physician, other 
Treatment Arm B subjects may receive the same antithrombotic prophylaxis as those in 
Treatment Arm A.  Subjects who develop symptomatic DVT will be assessed and diagnosed 
objectively by Doppler ultrasonography or a comparable method. The IDMC will review safety 
data on a regular basis to ensure subjects are adequately protected from any potential risk. 
Diagnostic algorithms are provided in Appendix A.
As per the Velcade® Prescribing Information (October 2014), antiviral prophylaxis should be 
considered in subjects being treated with bortezomib. In the randomized studies in previously 
untreated and relapsed MM, herpes zoster reactivation was more common in subjects treated 
with bortezomib (13%) than in the control groups (4-5%). Herpes simplex was seen in 2-8% in 
subjects treated with bortezomib and 1-5% in the control groups. In the previously untreated MM
study, herpes zoster virus reactivation in the bortezomib, melphalan, and prednisone arm was 
less common in subjects receiving prophylactic antiviral therapy (3%) than in subjects who did 
not receive prophylactic antiviral therapy (17%). In the post-marketing experience, rare cases of 
herpes meningoencephalitis and ophthalmic herpes have been reported.
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Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
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10.
STATISTICAL ANALYSES
10.1.
Overview
This is a multicenter, randomized, open-label study to compare the efficacy and safety of POM + 
BTZ + LD-DEX versus BTZ + LD-DEX.  For the POM + BTZ + LD-DEX treatment arm, the 
dose is based on the MTD study CC-4047-MM-005 using the same treatment combination POM 
+ BTZ + LD-DEX.
10.2.
Study Population Definitions
Three study populations will be used for analysis: 
!
The intent-to-treat (ITT) population:  All randomized subjects. The primary efficacy 
analysis will be based on this population
!
Safety population:  All randomized subjects who take at least one dose of study 
medication. All safety analyses will be based on this population
!
Efficacy Evaluable (EE) population:  All ITT subjects who take at least one dose of study 
medication and who have a baseline and at least one post-baseline efficacy assessment
10.3.
Sample Size and Power Considerations
Based on the primary endpoint PFS, at 2-sided significance level of 5%, with one interim 
analysis for futility only, an estimated total of 381 disease progression/death events are required 
to detect a 33% increase in median PFS in the POM treatment arm (Treatment Arm A; median = 
12 months) compared to that in the comparator arm (Treatment Arm B; median = 9 months) with 
80% power. In order to obtain PFS events from approximately 70% of the study ITT population 
for the final PFS analysis, a total of 544 randomized subjects are required to test the hypothesis.  
The interim analysis on PFS will take place when approximately 50% PFS information (191 
events) has occurred. The interim analysis results will be examined for futility only with the pre-
specified type II error spending functions described in Section 10.9.
Celgene amended the protocol in Amendment 5 to perform the final PFS analysis earlier than 
originally planned (381 PFS events).  Recently published data from a number of Phase 3 studies 
revealed that the progression-free survival (PFS) of the bortezomib with low-dose 
dexamethasone (BTZ+LD-DEX) arm on this study CC-4047-MM-007 (OPTIMISMM), that 
requires prior treatment with lenalidomide as per Protocol Inclusion Criteria #7 (Section 7.2), is 
expected to be shorter than the original OPTIMISMM protocol statistical assumption of 9 
months (relevant median PFS data from Phase 3 ENDEAVOR, PANORAMA-1 and CASTOR
studies ranging from 7 to 8 months) (Moreau, 2017; Palumbo, 2016; San-Miguel, 2014). 
Subsequently, if the assumption for the pomalidomide, bortezomib and low-dose dexamethasone 
(POM+BTZ+LD-DEX) arm and other study assumptions remain unchanged, the number of PFS 
events required for the final analysis would be less than originally planned. The data cutoff date 
for the revised final PFS analysis will be October 2017, by which time approximately 320 PFS 
events are projected to be reached, representing an approximate 57% event rate (out of 559 
randomized patients). This would allow for 80% power to test a median PFS of 12 months in 
Arm A versus 8.8 months in Arm B, corresponding to an estimated hazard ratio of 0.73.
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
75
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
Overall survival (OS) will be tested if PFS and ORR results are significant (see Section 10.10). 
With one planned interim analysis OS at the time of the final PFS analysis (estimated to be at 
approximately 50% OS information), at a 2-sided overall significance level of 5%, a total of 379
deaths are required to detect a 33% increase in median OS in the POM treatment arm (Treatment 
Arm A; median = 40 months) compared with that of the comparator arm (Treatment Arm B; 
median= 30 months) with 75% power. 
Sample size calculation is conducted using EAST® Version 6.
10.4.
Background and Demographic Characteristics
All baseline demographic and disease characteristics will be presented by treatment. Continuous 
variables such as subjects’ age, height, weight, and some baseline disease characteristics will be 
summarized using descriptive statistics, while categorical and ordinal variables such as gender, 
race and some baseline disease characteristics will be summarized using frequency tabulations.  
Medical history data will be summarized using frequency tabulations by system organ class and 
preferred term.
10.5.
Subject Disposition
Subject disposition (analysis population allocation, randomized, dosed, discontinued, along with 
primary reason for discontinuation) will be summarized by treatment using frequency and 
percent for both study treatment and follow-up phases.  A summary of subjects enrolled by site 
will be provided. Protocol deviations will be summarized using frequency tabulations.
10.6.
Efficacy Analysis
10.6.1.
Primary Endpoint: Progression Free Survival (PFS) 
Progression free survival (PFS) will be calculated as the time between the randomization and 
PD, as determined by the IRAC based on the International Myeloma Working Group Uniform 
Response criteria (IMWG), or death in the study treatment or PFS follow-up phase, whichever 
occurs earlier.  PFS using the EBMT response criteria will also be performed as an exploratory 
analysis.
Subjects who withdrew study treatment for any reason or received other anti-myeloma therapy 
without documented PD (as determined by the IRAC) will be censored on the date of their last 
response assessment in the study treatment phase prior to the study treatment discontinuation or 
initiation of other anti-myeloma therapy, respectively.  Subjects who are in the study treatment 
phase at the time of the data cut-off date without PD will be censored on the date of their last 
adequate response assessment. These rules are based on the FDA guidance for cancer trial 
endpoints (FDA Guidance, 2007), and the following table (Table 8) specifies the application of 
the guidance for various common situations for the calculation of PFS.
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Protocol CC-4047-MM-007
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Table 8:
Censoring Rules for PFS
Situation
Date of Progression or Censoring
Situation 
Outcome
No baseline assessments and alive 
after 2 scheduled assessments
Randomization
Censored
Death within the first two scheduled 
assessments without any adequate 
response assessment
Date of death
Event
Progression documented between 
scheduled assessments
Earliest of: 
1.
Date of M-protein assessment showing 
increase in serum monoclonal paraprotein 
and/or urine paraprotein
2.
Date of bone marrow assessment showing 
increase in bone marrow plasmacytosis 
and plasma cells
3.
Date of plasmacytoma assessment showing 
appearance of new soft tissue 
plasmacytomas or increase in size of 
existing plasmacytoma(s)
4.
Date of skeletal survey showing appearance of 
new lytic bone lesions or increase in the 
size of the existing bone lesions
5.
Date of lab test showing development of 
hypercalcemia serum calcium >11.5 mg/dl 
Event
Death between adequate 
assessments 
Date of death
Event
No progression
Date of last adequate assessment with evidence of 
no progression
Censored
Study discontinuation for reasons 
other than disease progression or 
death
Date of last adequate assessment with evidence of 
no progression
Censored
New anti-myeloma /non-protocol 
treatment started prior to 
progression
Date of last adequate assessment with evidence of 
no progression prior to the start of new anti-
myeloma treatment
Censored
Death or progression after an 
extended lost-to-follow-up time 
(two or more missed scheduled 
assessments) 
Date of last adequate assessment with evidence of 
no progression
Censored
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PFS will be compared between treatment arms using a log-rank test stratified by the three 
baseline factors used in the randomization. In terms of the survival functions for treatment arm 
comparison, the null and alternative hypotheses are as follows:
H0: Sa(t) = Sc(t) for all t
versus
H1: Sc(t) ≠ Sa(t) for all t
where Sc is the survivor function for the control arm and Sa is the survival function for the 
treatment arm.
The Kaplan-Meier method will be used to estimate the survival distribution functions for each 
treatment arm.  The median PFS along with the two-sided 95% confidence interval for the 
median will be estimated.  In addition, the probabilities of progression –free survival at specific 
time-points (eg, 26, 52, 78, and 104 weeks) will be computed, with corresponding standard 
errors (Greenwood’s formula, Klein and Moeschberger 2003).  The plots of survival curves 
using the Kaplan-Meier method will be presented.  A Cox proportional hazards model will be 
used to estimate hazard rate (risk) ratio along with 95% CIs. 
An unstratified log-rank test will be performed as a secondary analysis for PFS, in addition to the 
stratified analysis described above.
10.6.2.
Secondary Endpoints
10.6.2.1.
Overall Survival
Overall survival (OS) is calculated as the time from randomization to death from any cause.  
Subjects who died will be considered as having OS events on the date of death. All subjects who 
are lost to follow-up prior to the date of data cut-off or who withdrew consent from the trial will 
be censored at the last date known to be alive.  Subjects who are still in the study treatment phase 
at the date of data cut-off will be censored at the last available date that the subject is known to 
be alive, or data cut-off date, whichever is earlier.
OS will be compared between treatment arms (ie, POM + BTZ + LD-DEX vs. BTZ + LD-DEX).  
The same statistical methods used for the PFS analysis will be used for the OS analysis. The 
analysis of OS will be based on all data available, including the survival data from the study 
treatment phase, PFS follow-up phase and the long-term follow-up phase.
10.6.2.2.
Response Assessment by the IMWG Criteria
Tumor response, including PD, will be assessed by the investigators and the IRAC, using the 
IMWG criteria (Appendix B).  The primary analysis for response will be based on the IRAC’s 
assessments. The response assessments by investigators will be presented separately. 
The overall response rate [ORR; as defined as at least a PR] will be calculated as the number of 
confirmed responders divided by the number of subjects by treatment in the ITT population. The 
ORR together with the relative proportions in each response category (ie, stringent CR [sCR], 
CR, very good PR [VGPR], PR, SD, and PD) by treatment using the IMWG criteria will be 
examined. Confirmed responses that are documented after the initiation of other anti-myeloma 
treatment will not be counted as responses. However, these subjects will be included in the 
denominator for ORR calculation.
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Comparisons of ORR between treatment arms will be performed using a stratified Cochran-
Mantel-Haenszel test by adjusting for the stratification factors. The distribution of subjects in the 
6 response categories (excluding the ‘Response not Evaluable (NE)’ category) will be compared 
between treatment arms using the Wilcoxon rank sum test (1=sCR, 2 = CR, 3 = VGPR, 4 = PR, 
5 = SD, 6 = PD).
10.6.2.3.
Duration of Response
Duration of myeloma response is defined as the duration from the time when the IMWG 
response criteria are first met for sCR or CR or VGPR or PR until the first date the response 
criteria are met for PD or until the subject died from any cause, whichever occurs first.  Duration 
of response for subjects last known to be alive with no progression after a sCR or CR or VGPR 
or PR will be censored at the date of last adequate response assessment.  Subjects with confirmed 
responses that occurred after receiving any other anti-myeloma therapy will be censored at the 
last adequate assessment prior to the initiation of such treatment.  Subjects who are non-
responders will be excluded from this analysis.  Duration of response will be analyzed using the 
same statistical method as that for PFS.
10.7.
Safety Analysis
All safety analyses will be conducted in the safety population by treatment arms. 
Adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) version 14 or higher.  The intensity of AEs will be graded according to the 
NCI CTCAE version 4.0 or higher.
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on 
or after the first dose date of the study treatment and within 28 days after the last dose date.  
TEAEs, AEs leading to study medication discontinuation, AEs leading to dose 
reduction/interruption, AEs related to study medication, serious AEs and AE leading to death 
will be summarized by system organ class, and preferred term for each treatment arm.  A 
summary of AEs with NCI CTCAE grade 3 or higher, as well as the most frequent AEs 
(preferred terms), AEs by relationship to study treatment, will be provided.  A summary of AEs 
by dosing cycle based on onset date will also be provided.
If a subject experiences the same preferred term multiple times then the event will be counted 
only once and by greatest severity.
All deaths and reasons for death will be summarized. Death within 28 days of the first dose of 
study medication and within 28 days of the last dose of study medication will be summarized 
separately. 
Clinical laboratory values will be graded according to NCI CTC version 4.0 or higher for 
applicable tests.  Baseline grade and worst grade during treatment for selected laboratory results 
will be summarized. Shift from baseline to the worst grade observed during the treatment for 
selected laboratory results will also be provided. 
For vital signs, shift from baseline to worst during the treatment in below, within, and above the 
normal ranges will be displayed in cross–tabulations.  Summary statistics (N, Mean, Standard 
Deviation, Median, Minimum, and Maximum) of observed and change from baseline values will 
be presented.
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The overall ECG interpretation will be summarized by presenting the number and percentage of 
subjects with ‘Normal’, ‘Abnormal, not clinically significant’ and ‘Abnormal, clinically 
significant’.  Shift from baseline to worst during the treatment in the overall ECG interpretation 
will be displayed in cross–tabulations.
Graphical displays will be provided where useful to assist in the interpretation of results.
10.8.
Exploratory Endpoints
10.8.2.
Exploratory Efficacy Analysis
10.8.2.1.
Response using the EBMT Criteria
Tumor response, including PD, using the EBMT criteria (Appendix C) will be assessed by the 
IRAC only.  The ORR together with the relative proportions in each response category will be 
examined. Responses after subjects receive other anti-myeloma treatments will be counted as the 
response for the new treatments received instead of the original study assigned treatments and 
will not be included in the response rate analysis.
Comparisons of ORR between treatment arms (2x2 table) will be performed using Fisher’s exact 
test and odds ratio will be presented together with its 95% confidence intervals.  The distribution 
of subjects in the 5 response categories (excluding the ‘Response not Evaluable (NE)’ category) 
will be compared between treatment arms using the Wilcoxon rank sum test (1= CR, 2 = PR, 3 = 
minimal response [MR], 4 = SD, 5 = PD). 
10.8.2.2.
Time to Progression and Time to Response
Time to progression (TTP) is defined as the time from randomization to the first documented 
disease progression based on the IMWG response criteria by the IRAC. Censoring for TTP is the 
same as for PFS except that death is not counted as an event. The same statistical methods used 
for PFS analysis will be used for the TTP analysis.
Time to response is calculated as the time from randomization to the initial documented response 
(PR or better) based on IMWG criteria. Time to response (responders only) will be compared 
between treatment arms using the Wilcoxon rank sum test, with subjects with the longest time to 
response having the highest rank.
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10.8.2.3.
Time to Treatment Failure
As a sensitivity analysis for PFS, time to treatment failure (TTF) will be calculated as the time 
from randomization to discontinuation of study treatment for any reason, including disease 
progression as determined by IRAC or investigator using either IMWG or EBMT response 
criteria, treatment discontinuation due to toxicity, initiation of other anti-myeloma treatment, and 
death.  Subjects who have not discontinued the study treatment phase or the PFS follow-up phase 
at the time of analysis will be censored on the date of last assessment.
The same statistical methods used for the PFS analysis will be used for the TTF analysis.
10.8.2.4.
Progression-free Survival 2 (PFS2)
PFS2 is defined as the time from randomization to second objective disease progression, or death 
from any cause, whichever occurs first, based on the ITT population. Patients who are alive and 
for whom a second objective disease progression has not been observed should be censored at 
the last time known to be alive and without second objective disease progression.
The Kaplan-Meier method will be used to estimate the survival distribution functions for each 
treatment arm.  A Cox proportional hazards model will be used to estimate hazard rate (risk) 
ratio along with 95% CIs. 
10.8.2.5.
Sub-group Analysis
The effect of treatment on the key efficacy variables PFS, ORR and OS will be investigated 
within subgroups including following variables by their baseline values:
!
Region (US vs. ex-US)
!
Age group (% 75 years vs. > 75 years);
!
Gender (Male vs. Female);
!
ECOG Performance Status (0, 1 vs. 2)
!
Baseline cytogenetic categories
!
Number prior anti-myeloma regimen (1 vs. >1);
!
β2M at screening (< 3.5 mg/L vs. ≥ 3.5 m/L – ≤ 5.5 mg/L vs. ≥ 3.5 mg/L)
!
Prior bone marrow or peripheral stem transplantation (Yes vs. No)
The methods described in previous sections will be used for each subgroup separately.
Additional multivariate analyses on PFS and OS will be conducted to evaluate the treatment
effect while adjusting for the above-mentioned factors.
10.8.3.
Clinical Benefits 
Clinical benefits include the following:
!
Improvement in hemoglobin value (defined as at least one category improvement 
from baseline in CTCAE grade for hemoglobin level)
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!
Improvement in renal function (defined as at least one category improvement from 
baseline in CTCAE grade for serum creatinine), 
!
Improvement of ECOG performance status (defined as at least one category 
improvement from baseline in ECOG)
!
Improvement in hypercalcaemia (defined as at least one category improvement from 
baseline in CTCAE grade for calcium level)
!
Improvement in non-myeloma immunoglobulins (restoration to normal level)
Clinical benefits defined above will be compared between treatment arms using the Wilcoxon 
rank sum test, with subjects with the longest time to clinical benefit having the highest rank.
10.8.4.
Quality of Life (QoL)
The European Organization for Research and Treatment of Cancer QoL Questionnaire for 
Patients with Multiple Myeloma (EORTC QLQ-MY20) Module and the European Organization 
for Research and Treatment of Cancer QoL Questionnaire for Patients with Cancer (EORTC 
QLQ-C30) Module will be used in this study. 
The EORTC QLQ-C30 and EORTC-QLQ-MY20 will be analyzed using change from baseline 
and percentage of change from baseline according to the functional scores and the 
recommendations in the EORTC scoring manual.
EQ-5D scores will be derived for each subject using country-specific weights (primary analysis 
will be done using UK weights). Using EQ-5D scoring instructions, overall scores will be 
analyzed using change from the screening assessment at each post-screening time point. The 
worst change from screening among all available post-screening measurements for each subject 
will also be analyzed.
The expectation is that treatment with POM + BTZ + LD-DEX will not impact subjects QoL as 
compared with BTZ + LD-DEX.
Change scores from baselines will be analyzed using MIXED model using baseline covariates 
where appropriate.
Details will be given in the statistical analysis plan.
10.8.5.
Healthcare Resource Utilization
Healthcare resource utilization measurements, including hospitalizations or emergency 
department visits that occur during the active treatment period, will be summarized by treatment 
arm using appropriate descriptive statistics.
10.8.6.
Exploratory Biomarker Analysis
Exploratory analyses will be performed to investigate MRD, genomic, molecular/mechanistic 
and immune biomarkers which may predict the response or resistance to POM and overall 
survival, event free survival and response rates.  Since the number of samples collected may be 
small, descriptive statistics will be performed for the quantitative analyses if warranted. 
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10.9.
Interim Analysis
One interim PFS analysis is planned when approximately 50% of the PFS information is 
reached, ie, 191 out of the total of 381 PFS events required for the final PFS analysis. The results 
of the interim PFS analysis will be used for futility assessment only, for which a non-binding 
stopping boundary will be applied based on gamma function with gamma = -6. 
Since the interim analysis has been planned and implemented prior to Protocol Amendment 5, it 
is not impacted by Amendment 5.
Overall Survival will be evaluated twice in this study: the first OS analysis will be conducted at 
the final PFS analysis, at approximately 320 events. The projected number of deaths will be
approximately 50%  of the total number of deaths (379) required for the final OS analysis. The 
second or final OS analysis will be conducted when the study reaches 379 deaths. The 
superiority stopping rule is for the interim analysis of OS only (at the time of final PFS), using a 
step-down approach. If the final PFS analysis shows significant difference between treatment 
arms (p < 0.05, 2-sided), and the ORR analysis also shows significant difference (p < 0.05, 2-
sided), then the interim analysis for superiority and stopping will be carried out for OS. The 
superiority boundary for OS is based on Lan-Demets implementation of the Pocock boundaries, 
which spends more alpha at earlier look of the data.
10.10.
Statistical Approaches for Control of Alpha and Other 
Considerations
The secondary endpoints for which claims may be made in the label include overall survival and
overall response rate. There will be two PFS analyses (including one futility analysis), one ORR 
analysis and two OS analyses.
The family-wise type I error rate will be controlled by a step-down approach from PFS to ORR 
and then to OS comparison. Specifically, ORR will only be tested if null hypothesis for PFS is 
rejected at 2-sided 5% significance level; OS interim analysis will only be carried out if null 
hypothesis for ORR is rejected at 2-sided 5% significance level.
Specifically, when the number of PFS events is reached for the final PFS analysis, PFS will be 
tested first. If the value of the log-rank statistic for PFS is significant at the final analysis (p <
0.05, 2-sided), then overall response rate (ORR) will be tested next, at the same significance 
level of 5%, 2-sided. If the test of ORR is significant, then OS will be tested at the overall 5% 
significance level, 2-sided.
The significance level of the OS analysis will be based on the number of death events at the time 
of the analysis (eg, total number of 379 deaths in 2 arms required for the final analysis), using the 
Pocock superiority boundary for each of the two OS comparisons (interim OS at the time of the 
final PFS analysis, and the final OS analysis).  The step-down approach is taken at the time of 
the final PFS analysis. ORR will be tested at the same significance level of 2-sided 0.05 level if 
PFS is tested significant, and the OS interim analysis will be performed only if the tests for PFS 
and ORR are both significant at the 2-sided 5% significance level – and then the OS comparison 
between treatment arms will be conducted in which a group sequential test with an overall Type I 
error probability of 5% (2-sided) is run for the hypothesis.
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11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a subject during the course of a study.  It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, 
including laboratory test values (as specified by the criteria below), regardless of etiology.  Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome.
An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to a study treatment (pomalidomide, bortezomib, or 
dexamethasone) should be reported as an AE.  If an overdose is associated with an AE, the 
overdose and adverse event should be reported as separate terms.  All subjects will be monitored 
for AEs during the study.  Assessments may include monitoring of any or all of the following 
parameters:  the subject’s clinical symptoms, laboratory, pathological, radiological or surgical 
findings, physical examination findings, or findings from other tests and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent to 
at least 28 days after the last dose of study treatment (ie, pomalidomide, bortezomib, or 
dexamethasone) for subjects not continuing in the PFS follow-up Phase. Only study/protocol 
related AEs will be recorded by the Investigator for subjects who continue in the PFS follow-up 
phase of the study.  AEs that lead to study discontinuation should be followed until resolution or 
stabilization. 
Serious Adverse Events (SAEs), regardless of relationship to study treatment (pomalidomide, 
bortezomib, and/or dexamethasone), that occur from the time the subject signs informed consent 
to at least 28 days after the last dose of study drug (pomalidomide, bortezomib, or 
dexamethasone), and those made known to the Investigator at any time thereafter that are 
suspected of being related to study treatment (pomalidomide, bortezomib and/or dexamethasone) 
must be reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the 
event.
Note that second primary malignancies will be monitored as events of interest and must be 
reported as serious adverse events regardless of the treatment arm (Section 11.5).
11.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
11.2.1.
Seriousness 
A serious adverse event (SAE) is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
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!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect;
!
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events regardless of the treatment arm the subject is in (see Section 11.5).  This 
includes any SPM, regardless of causal relationship to study treatment (pomalidomide, 
bortezomib, or dexamethasone), occurring at any time from the time of signing the informed 
consent up to and including the long-term follow-up period. Events of SPM are to be reported 
using the SAE report form and must be considered an “Important Medical Event” even if no 
other serious criteria apply; these events must also be documented in the appropriate page(s) of 
the CRF and subject’s source documents.  Documentation on the diagnosis of the SPM must be 
provided at the time of reporting as a serious adverse event (eg, any confirmatory histology or 
cytology results, X-rays, CT scans, etc.).
Events not considered to be SAEs are hospitalizations for:
!
A standard procedure for protocol therapy administration.  However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE.
!
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
The administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
A procedure for protocol/disease-related investigations (eg, surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE.
!
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
A procedure that is planned (ie, planned prior to starting of treatment on study); must 
be documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
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!
An elective treatment of or an elective procedure for a pre-existing condition 
unrelated to the studied indication.
!
Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to study treatment (POM, BTZ, DEX), action taken regarding study treatment 
(POM, BTZ, DEX), and outcome.
11.2.2.
Severity / Intensity
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event.
The severity of AEs will be graded based upon the subject’s symptoms according to the current 
active minor version of National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE, Version 4.0 or higher.); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40.
AEs that are not defined in the NCI CTCAE should be evaluated for severity according to the 
following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
!
Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
!
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.
Seriousness, not severity, serves as a guide for defining regulatory obligations.
11.2.3.
Causality 
The Investigator must determine the relationship between the administration of study treatment
and the occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
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Not suspected:
Means a causal relationship of the adverse event to study 
treatment administration is unlikely or remote, or other 
medications, therapeutic interventions, or underlying conditions 
provide a sufficient explanation for the observed event.
Suspected:
Means there is a reasonable possibility that the administration 
of study treatment caused the adverse event.  ‘Reasonable 
possibility’ means there is evidence to suggest a causal 
relationship between the study treatment and the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional study 
treatment that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
11.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
11.2.5.
Action Taken
The Investigator will report the action taken with study treatment (pomalidomide, bortezomib, 
dexamethasone) as a result of an AE or SAE, as applicable (eg, discontinuation, interruption, or 
reduction of study treatment, as appropriate) and report if concomitant and/or additional 
treatments were given for the event. 
11.2.6.
Outcome
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered or death (due to the 
SAE). 
11.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
!
results in discontinuation from the study;
!
requires treatment, modification/ interruption of study treatment dose, or any other 
therapeutic intervention; or
!
is judged to be of significant clinical importance.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF.  If the abnormality was not a 
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part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE.
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
11.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.
11.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated βhCG or positive pregnancy test in a 
female of childbearing potential regardless of disease state) occurring while the subject is on
study treatment, or within 3 months after last dose of bortezomib or 28 days after last dose of 
pomalidomide whichever occurs later, are considered immediately reportable events. Study 
treatment is to be discontinued immediately and the subject instructed to return any unused 
portion of the IP to the Investigator.  The pregnancy, suspected pregnancy, or positive pregnancy 
test must be reported to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, using the Pregnancy Initial Report Form, or approved equivalent form.  
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.  The Investigator will 
follow the female subject until completion of the pregnancy, and must notify Celgene Drug 
Safety immediately about the outcome of the pregnancy (either normal or abnormal outcome) 
using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
11.4.2.
Male Subjects
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking investigational product should notify the Investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately.
11.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
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or other appropriate method, using the SAE Report Form, or approved equivalent form.  This 
instruction pertains to initial SAE reports as well as any follow-up reports.
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events regardless of the treatment arm the subject is in.  This includes any SPM, 
regardless of causal relationship to study treatment (pomalidomide, bortezomib and/or 
dexamethasone), occurring at any time from the time of signing the informed consent up to and 
including the long-term follow-up period.  Events of SPM are to be reported using the SAE 
report form or approved equivalent and must be considered an “Important Medical Event” even 
if no other serious criteria apply; these events must also be documented in the appropriate 
page(s) of the CRF and subject’s source documents.  Documentation on the diagnosis of the 
SPM must be provided at the time of reporting as a serious adverse event (eg, any confirmatory 
histology or cytology results, X-rays, CT scans, etc.).
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to study treatment
[pomalidomide, bortezomib and/or dexamethasone]) that occur from the time the subject signs 
informed consent to at least 28 days after the last dose of study treatment (pomalidomide, 
bortezomib or dexamethasone) and those made known to the Investigator at any time thereafter 
that are suspected of being related to study treatment (pomalidomide, bortezomib and/or 
dexamethasone).  SAEs occurring prior to treatment (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.
Where required by local legislation, the Investigator is responsible for informing the IRB/EC of 
the SAE and providing them with all relevant initial and follow-up information about the event.  
The Investigator must keep copies of all SAE information on file including correspondence with 
Celgene and the IRB/EC.
11.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
11.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to Pomalidomide based on the Investigator Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) in accordance 
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and
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presentation of adverse reaction reports arising from clinical trials on investigational products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.
For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the
expectedness of events suspected of being related to the other IP [bortezomib and/or
dexamethasone], based on the EU SmPCs.
Events of e.g. disease progression for the disease under study (including deaths due to disease 
progression for indications that are considered to be fatal) will be assessed as expected adverse 
events and will not be reported as expedited safety reports to regulatory authorities.
Celgene or its authorized representative shall notify the Investigator of the following information
(in Japan, Celgene KK shall notify the Heads of the Institutes in addition to the Investigator(s)):
!
Any AE suspected of being related to the use of study treatment (pomalidomide, 
bortezomib, dexamethasone) in this study or in other studies that is both serious and 
unexpected (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
!
In Japan, measures taken in foreign countries to ensure patient safety, study reports 
that indicates potential risk of cancer, etc., or biannual SAE report according to the 
local regulations.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 15.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information contact information, please refer to the Serious 
Adverse Event Report Form / Completion Guidelines or to the Pregnancy Report Form / 
Completion Guidelines.
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12.
DISCONTINUATIONS
The following events are considered sufficient reasons for discontinuing a subject from the study 
treatment phase:
!
Adverse Event(s) 
!
Pregnancy
!
Progressive Disease (PD)
!
Protocol violation
!
Withdrawal of consent 
!
Death
!
Lost to follow-up
!
Study Terminated by Sponsor
The following events are considered sufficient reasons for discontinuing a subject from the PFS 
follow-up phase:
!
Progressive Disease (PD)
!
Protocol violation
!
Withdrawal of consent 
!
Death
!
Lost to follow-up
!
Study Terminated by Sponsor
The following events are considered sufficient reasons for discontinuing a subject from the 
Long-term follow-up phase:
!
Withdrawal of consent 
!
Death
!
Lost to follow-up
!
Completion of follow-up (5 years after the last subject is randomized)
!
Study Terminated by Sponsor
The reason for discontinuation from each phase of the study will be captured in the eCRFs and
source document as applicable.
The decision to discontinue a subject remains the responsibility of the treating physician, which 
will not be delayed or refused by the sponsor.  However, prior to discontinuing a subject, the 
investigator may contact the Medical Monitor and forward appropriate supporting documents for 
review and discussion.
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13.
EMERGENCY PROCEDURES
13.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or Back-up Medical Monitor by telephone at the number(s) listed on 
the Emergency Contact Information page of the protocol (after title page).
In the unlikely event that both Clinical Research Physician/Medical Monitor and Back-up 
Medical Monitor cannot be reached, please contact the Celgene Global Emergency Call Center 
by telephone at the number listed on the Emergency Contact Information page of the protocol 
(after title page).This Celgene Global Emergency Call Center is available 24 hours a day and 7 
days a week. The representatives are responsible for obtaining your call-back information and 
contacting the on call Celgene Medical Monitor, who will then contact you promptly.
Note: The back-up 24 hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician/Medical Monitor or Back-up Medical Monitor 
for emergency calls. 
13.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the IP package labeling.
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14.
REGULATORY CONSIDERATIONS
14.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International 
Conference on Harmonization (ICH) Guideline E6 and in accordance with the general ethical 
principles outlined in the Declaration of Helsinki. The study will receive approval from an 
IRB/EC prior to commencement. The Investigator will conduct all aspects of this study in 
accordance with applicable national, state, and local laws of the pertinent regulatory authorities.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions.
The Investigator should maintain a list of Sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
document and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of CRFs and queries.
14.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original informed consent document signed and dated by the study 
subject and by the person consenting the study subject prior to the study subject’s entry into the 
study, must be maintained in the Investigator’s study files and a copy given to the study subject.  
In addition, if a protocol is amended and it impacts on the content of the informed consent, the 
informed consent document must be revised.  Study subjects participating in the study when the 
amended protocol is implemented must be re-consented with the revised version of the informed 
consent document.  The revised informed consent document signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
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14.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed informed consent document, it is the responsibility of the Investigator to obtain 
such permission in writing from the appropriate individual.
14.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, informed consent document, and any other 
appropriate documents will be submitted to the IRB/EC with a cover letter or a form listing the 
documents submitted, their dates of issue, and the site (or region or area of jurisdiction, as 
applicable) for which approval is sought. If applicable, the documents will also be submitted to 
the authorities in accordance with local legal requirements.
IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the informed consent document 
should also be revised.
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The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.
14.7.
Ongoing Information for Institutional Review Board / Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible; 
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
14.8.
Closure of the Study
Celgene reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc.).
In addition, the Investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:
!
Unsatisfactory enrollment;
!
GCP noncompliance;
!
Inaccurate or incomplete data collection;
!
Falsification of records;
!
Failure to adhere to the study protocol.
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15.
DATA HANDLING AND RECORDKEEPING 
15.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
15.2.
Data Management
Data will be collected via electronic CRF (eCRFs).  This data will be electronically verified 
through use of programmed edit checks specified by the clinical team.  Discrepancies in the data 
will be brought to the attention of the clinical team, and investigational site personnel, if 
necessary.  Resolutions to these issues will be reflected in the database.  An audit trail within the 
system will track all changes made to the data.
15.3.
Record Retention
Essential documents must be retained by the Investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. The investigator must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer.  Essential documents include, but are not limited to, the following:
!
Signed informed consent documents for all subjects;
!
Subject identification code list, screening log (if applicable), and enrollment log;
!
Record of all communications between the Investigator and the IRB/EC;
!
Composition of the IRB/EC;
!
Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);
!
List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;
!
Copies of CRFs (if paper) and of documentation of corrections for all subjects;
!
IP accountability records;
!
Record of any body fluids or tissue samples retained;
!
All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator/Institution should take measures to prevent accidental or premature destruction of 
these documents.
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16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
16.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  Before the study is initiated at a site visit or at an investigator meeting, all aspects of 
the study are reviewed with the Investigator and the staff.  Prior to enrolling subjects into the 
study, a Celgene representative will review the protocol, CRFs, procedures for obtaining 
informed consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring 
will include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  At each monitoring visit, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative for accuracy, adherence 
to the protocol and Good Clinical Practice.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (eg, FDA, EMA, Health Canada) and 
company authorized representatives.  The Investigator should make every effort to be available 
for the audits and/or inspections.  If the Investigator is contacted by any regulatory authority 
regarding an inspection, he/she should contact Celgene immediately.
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17.
PUBLICATIONS
The results of this study may be published in a medical publication, journal, or may be used for 
teaching purposes.  Additionally, this study and its results may be submitted for inclusion in all 
appropriate health authority study registries, as well as publication on health authority study 
registry websites, as required by local health authority regulations.  Selection of first authorship 
will follow Celgene’s publication policy (MA-SOP-105) which typically is based on several 
considerations, including, but not limited to study participation, contribution to the protocol 
development, and analysis and input into the manuscript, related abstracts, and presentations in a 
study.
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18.
REFERENCES 
All references available upon request.
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Baz R, Li L, Marchant-Kottke K, et al.  The role of aspirin in the prevention of thrombotic 
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Corral LG, Haslett PA, Muller GW, et al.  Differential cytokine modulation and T cell activation 
by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha.  J 
Immunol 1999;163:380-6.
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mation/PIs/Roxane/Dexamethasone/Dexamethasone+Tablets+Solution+and+Intensol.pdf.
Dimopoulos, Spencer A, Attal M, et al.  Lenalidomide plus dexamethasone for relapsed or 
refractory multiple myeloma. N Engl J Med 2007;357:2123-32.
Durie BGM, Harousseau J-L, Miguel JS, et al.  International Uniform Response Criteria for 
Multiple Myeloma.  Leukemia 2006;20:1467-1473.
Fermand JP, Katsahian S, Divine M, et al.  High-dose therapy and autologous blood stem-cell 
transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: 
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Hayashi T, Hideshima T, Akiyama M, Podar K, et al. Molecular mechanisms whereby 
immunomodulatory drugs activate natural killer cells: clinical application. Brit J Haematol
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Hernandez-Ilizaturri FJ, Reddy N, Holkova B, et al.  Immunomodulatory Drug CC-5013 or 
POMALIDOMIDE and rituximab enhance antitumor activity in a severe combined 
immunodeficient mouse lymphoma model.  Clin Cancer Res 2005;11:5984-5992.
Hideshima T, Chauhan D, Shima Y, et al.  Thalidomide and its analogues overcome drug 
resistance of human multiple myeloma cells to conventional therapy.  Blood 2000;96:2943-2950.
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Ionita I, Cheveresan M, Calamar D, Ionita C, Oros D, Ionita H. Clinical efficacy of velcade 
(Bortezomib) and dexamethasone therapy in patients with refractory or relapsed multiple 
myeloma. Haematologica 2009;94(Suppl~ 2):2-628.
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Science 2010;327:1345-49.
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originally published online Jul 7, 2010.
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myeloma.  Tar Oncol 2009;4(1):23-36.
Kumar SK, et al.  Improved survival in multiple myeloma and the impact of novel therapies.  
Blood 2008;111(5):2516-2520.
Kyprolis [Prescribing Information]. Onyx Pharmaceuticals, Inc., South San Francisco, CA; July 
2012 http://www.kyprolis.com/Content/pdf/PrescribingInformation.pdf 
Lacy M, Hayman S, Gertz M, Dispenzieri A, et al.  Pomalidomide (CC4047) plus low-dose 
dexamethasone as therapy for relapsed multiple myeloma.  J Clin Oncol 2009; 27:5008-5014.
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(Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). 
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myeloma refractory to both bortezomib and lenalidomide: Comparison of two dosing strategies 
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Society of Hematology (ASH) 2010c; December 4-7; Orlando, FL; USA: Abstract #863.
Leleu X, Attal M, Arnulf B, et al. Phase 2 Multicenter, Randomized, Open Label study of 2 
Modalities of Pomalidomide plus low dose-dexamethasone in Patients with Multiple Myeloma, 
Refractory to both Lenalidomide and Bortezomib. IFM 2009-02. 2011a ASH Annual Meeting 
Abstract # 0812.
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immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide.  
Leukemia 2012;1–10
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myeloma cells: therapeutic implications.  Blood 2002 Jun 15; 99(12):4525-30.
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dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study.  Leukemia 
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inhibitors of TNF-α production. Bioorg Med Chem Lett 1999; 9:1625-1630.
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National Comprehensive Cancer Network.  NCCN Clinical Practice Guidelines in Oncology.  
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Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, et al.  Randomized phase III 
study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in 
relapsed or refractory multiple myeloma: combination therapy improves time to progression.  J 
Clin Oncol 2007;25:3892-3901.
Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, 
bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 375(8): 754-66.
Pomalyst® [Prescribing Information]. Celgene Corporation, Summit, NJ; February 2013 
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Revlimid® [Prescribing Information]. Celgene Corporation, Summit, NJ; November 2013 
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Richardson PG, Barlogie B, Berenson J, et al. A Phase 2 Study of Bortezomib in Relapsed, 
Refractory Myeloma. N Engl J Med 2003;348(26): 2609-17.
Richardson PG, Sonneveld P, Schuster MW, et al.  Bortezomib or high-dose dexamethasone for 
relapsed multiple myeloma.  N Engl J Med 2005; 352 (24): 2487-98.
Richardson PG, Barlogie B, Berenson J, et al.  Extended follow-up of a phase II trial in relapsed, 
refractory multiple myeloma: final time-to-event results from the SUMMIT trial.  Cancer 
2006a;106:1316-9.
Richardson PG, Sonneveld P, Schuster MW, et al.  Extended follow-up of a phase 3 trial in 
relapsed multiple myeloma: final time-to event results of the APEX Trial.  Blood 2007c; 110: 
3557-3560.
Richardson PG, Mitsiades C, Schlossman R, Munshi N, Anderson K.  New drugs for myeloma.  
The oncologist 2007a Jun; 12(6):664-89.
Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase 1 dose-escalation trial of 
lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma.  JCO 
2009a;27(34):5713-5719.
Richardson PG, Weller E, Lonial S, et al.  Lenalidomide, bortezomib, and dexamethasone 
combination therapy in patients with newly diagnosed multiple myeloma.  Blood 2010c;116: 
679-686.
Richardson PG, Jagannath S, Jakubowiak A, et al. Phase II Trial of Lenalidomide, Bortezomib, 
and Dexamethasone in Patients (pts) with Relapsed and Relapsed/Refractory Multiple Myeloma 
(MM):  Updated Efficacy and Safety Data After > 2 Years of Follow-up.  2010 ASH Annual 
Meeting Abstract #3049.
Richardson PG, Siegel D, Baz R, et al.  A Phase 1/2 multicenter, randomized, open label dose 
escalation study to determine the maximum tolerated dose (MTD), safety, and efficacy of 
pomalidomide alone or in combination with low-dose dexamethasone in patients with relapsed 
and refractory multiple myeloma who have received prior treatment that includes lenalidomide 
and bortezomib. 2011a ASH Annual Meeting Abstract # 0634. 
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Richardson PG, Hofmeister C, Siegal D, et al. MM-005: A phase 1 trial of pomalidomide, 
bortezomib, and low-dose dexamethasone (PVD) in relapsed and/or refractory multiple myeloma
(RRMM).  Abstract presented at ASH Annual Meeting; 2013a Dec 7; New Orleans, LA, 
Abstract # 1969. 
Richardson PG, Siegel D, Baz R, et al. Phase 1 study of pomalidomide MTD, safety, and 
efficacy in patients with refractory multiple myeloma who have received lenalidomide and 
bortezomib. Blood 2013;121(11):1961-1967.
Rychak E, Mendy D, Adams M, Miller K, et al. Overcoming resistance; the use of pomalidomide 
and dexamethasone (DEX) in re-sensitizing lenalidomide-resistant multiple myeloma (MM) 
cells. 2011 the 13th International Myeloma Workshop (IMW). Poster # 328.
San-Miguel J, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, et al. 
Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and 
dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a 
multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014;15(11):1195-206. 
doi:10.1016/S1470-2045(14)70440-1.
Schey SA, Fields P, Bartlett JB, et al.  Phase I study of an immunomodulatory thalidomide 
analog, POMALIDOMIDE, in relapsed or refractory multiple myeloma.  J Clin Oncol 2004 22: 
3269-3276.
Streetly MJ, Gyertson K, Daniel Y, Zeldis JB, Kazmi M, Schey SA.  Alternate day 
pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo 
immunomodulation.  Br J Haematol 2008; 141(1): 41-51.
Teo ST, et al.  Thalidomide as a novel therapeutic agent: new uses for an old product.  Drug 
Discovery Today 2005;10:107-14.
Velcade® [Prescribing Information]. Millennium Pharmaceuticals, Cambridge, MA; October
2014 http://www.velcade.com/Files/PDFs/VELCADE_PRESCRIBING_INFORMATION.pdf.
Verhelle D, Corral LG, Wong K, Mueller JH, Moutouh-de Parseval L, Jensen-Pergakes K, et al.  
Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding 
normal CD34+ progenitor cells.  Cancer Res 2007 Jan 15; 67(2):746-55.
Weber DM, Chen C, Niesvizky R, et al.  Lenalidomide plus dexamethasone for relapsed multiple 
myeloma in North America.  N Engl J Med 2007; 357: 21: 2133-2142.
Wells PS, Anderson D, et al.  Evaluation of d-dimer in the diagnosis of suspected deep vein 
thrombosis N Engl J Med Sept 25, 2003 349(13): 1227-35.
Wells PS, Anderson D, et al.  Derivation of a simple clinical model to categorize patients 
probability of pulmonary embolism: increasing the models utility with simpliRED D-dimer.  
Thromb Haemost 2000;83:416-20.
Zhu YX, Braggio E, Shi CX et al. Cereblon expression is required for the antimyeloma activity 
of lenalidomide and pomalidomide. Blood 2011;118(18):4771-9.
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19.
APPENDICES
Appendix A:
VTE Algorithms
VTE Diagnostic Procedure
1. Refer to the DVT Pre-Test Probability Score Table. Add up the score and determine the 
patient’s pre-test probability for DVT.
2. Refer to the DVT Diagnostic Algorithm. According to the pre-test probability follow the 
relevant diagnostic algorithm.
Wells1 DVT Pre-Test Probability (PTP) Score
Clinical Characteristic
Score
Active cancer (treatment ongoing or within previous 6 months or palliative)
1
Paralysis, paresis, or recent plaster immobilization of the lower extremities
1
Recently bedridden for 3 days or more or major surgery within the previous 12 weeks 
requiring general or regional anesthesia
1
Localized tenderness along the distribution of the deep venous system
1
Entire leg swollen
1
Calf swelling 3cm > asymptomatic side (measured 10 cm below tibial tuberosity)
1
Pitting edema confined to the symptomatic leg
1
Collateral superficial veins (nonvaricose)
1
Previously documented deep-vein thrombosis
1
Alternative diagnosis as likely or greater than that of DVT
-2
1 Wells PS, Anderson D et al. Evaluation of D-dimer in the Diagnosis of Suspected Deep Vein Thrombosis. N Engl 
J Med Sept 25, 2003 349(13): 1227-35.
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Clinical Probability Assessment
DVT Unlikely (Score <2)
DVT Likely (Score ≥2)
D-dimer
D-dimer
Discharge –
No DVT
US
US
US
Treat
Discharge –
No DVT
Treat
No DVT –
Follow Up
Serial US
No DVT –
Follow Up
Adapted from 6B6 D-Dimertm The Essential Element Wall Chart
Legend:
US - Bi-lateral leg vein ultrasonography
                            PTP Score
DVT Unlikely        <2
DVT Likely           ≥2 
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PE Diagnostic Procedure
1. Refer to the PE Pre-Test Probability Score Table. Add up the score and determine the 
patient’s pre-test probability for PE.
2. Refer to the PE Diagnostic Algorithm. According to the pre-test probability follow the 
relevant diagnostic algorithm.
Wellsa PE Pre-Test Probability (PTP) Score
Clinical Characteristic
Score
Clinical signs and symptoms of DVT (minimum of leg swelling and pain with 
palpation of the deep veins)
3.0
An alternative diagnosis is less likely than PE
3.0
Heart rate greater than 100 beats/min
1.5
Immobilization or surgery in the previous 4 weeks
1.5
Previous DVT/PE
1.5
Hemoptysis
1.0
Malignancy (at treatment, treated in the last 6 months or palliative)
1.0
a Wells PS, Anderson D, et al. Derivation of a simple Clinical Model to Categorize Patients Probability of Pulmonary Embolism: 
Increasing the Models Utility with SimpliRED D-dimer. Thromb Haemost 2000;83:416-20.
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Clinical Probability 
Low
High
D-dimer
PE Excluded
VQ/CT Scan
Normal
Non-High
Moderate
High
PE 
Excluded
US
US
Treat
PE 
Excluded
PA or 
Other 
Tests
D-dimer
VQ/CT Scan
Normal
Non-High
High
PE 
Excluded
US
Treat
Manage according to 
initial D-dimer result
US in 1 
week
PE 
Excluded
Treat
Treat
D-dimer
VQ/CT Scan
Normal
Non-High
High
PE 
Excluded
US
Treat
Manage according to 
initial D-dimer result
PA or US 
in 1 week
PE 
Excluded
Treat
Treat
Adapted from 6B6 D-Dimertm The Essential Element Wall Chart
Legend:
US - Bi-lateral leg vein ultrasonography
PA - Pulmonary Angiography
VQ - Ventilation/Perfusion Scan
CT – Computed Tomography
                                    PTP Score
Low Probability            <2.0
Moderate Probability    2.0 – 6.0
High Probability           >6.0
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Appendix B:
International Myeloma Working Group Response Criteria
Response 
Category
Response Criteria
a
SCR
CR as defined below plus
Normal FLC ratio and
Absence of clonal cells in bone marrow
b
by immunohistochemistry or 
immunofluorescence
c
CR
Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and ≤ 5% plasma cells in bone marrowb
VGPR
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or 90% or greater reduction in serum M-protein plus urine M-
protein level < 100 mg per 24 hours
PR
≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein 
by ≥ 90% or to < 200 mg per 24 hours
If the serum and urine M-protein are unmeasurable
d a ≥ 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of 
the M-protein criteria
If serum and urine M-protein are unmeasurable, and the serum free light assay is 
also unmeasurable, ≥ 50% reduction in plasma cells is required in place of M-
protein provided baseline bone marrow plasma cell percentage was ≥ 30%
In addition to the above, if present at baseline a ≥ 50% reduction in the size of 
soft tissue plasmacytomas is also required
SD
e
Not meeting criteria for CR, VGPR, PR, or progressive disease
Relapse Category
f
Relapse Criteria
Progressive 
disease
Requires only one of the following:
Increase of ≥ 25% from nadir in:
Serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL)
g
Urine M-component and/or (the absolute increase must be ≥ 200 mg/24 hours)
In patients without measurable serum and urine M-protein levels the difference 
between involved and uninvolved FLC levels, the absolute increase must be > 
100 mg/dL.
Bone marrow plasma cell percentage, the absolute % must be ≥ 10%
h
Definite development of new bone lesions or soft tissue plasmacytomas increase 
in the size of existing bone lesions or soft tissue plasmacytomas.
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 
mmol/L) that can be attributed solely to the plasma cell proliferative disorder.
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Appendix B: International Myeloma Working Group Response Criteria (Continued)
Relapse Categoryf
Relapse Criteria
Clinical relapse
Clinical relapse requires one or more of:
(Not used for TTP 
or PFS)
Development of new soft tissue plasmacytoma or bone lesions
Definite increase in the size of existing plasmacytomas or bone lesions.  A 
definite increase is defined as a 50% (and at least 1 cm) increase as measured 
serially by the sum of the products of the cross-diameters of the measurable 
lesion
Hypercalcemia (> 11.5 mg/dL [2.65 mmol/L])
Decrease in hemoglobin of ≥ 2 g/dl (1.25 mmol/L)
Rise in serum creatinine by 2 mg/dL or more (177 μmol/L or more)
Relapse from CR
i
Any one or more of the following:
Reappearance of serum or urine M-protein by immunofixation or electrophoresis
Development of ≥ 5% plasma cells in the bone marrowh
Appearance of any other sign or progression
a All response categories require two consecutive assessments made at any time before the institution of any new 
therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies 
were performed.  Radiographic studies are not required to satisfy these response criteria.
b Confirmation with repeat biopsy not necessary.
c Presence/absence of clonal cells is based upon the κ/λ ratio by immunohistochemistry and/or immunofluorescence 
requires a minimum of 100 plasma cells for analysis.  An abnormal ration reflecting presence of an abnormal clone 
is κ/λ of > 4:1 or < 1:2.
d Applicable only to patients who have ‘measurable’ disease defined by at least one of the following three 
measurements: Serum M-protein ≥ 1 g/dl, Urine M-protein ≥ 200 mg/24 hour, Serum FLC assay involved FLC 
level ≥ 10 mg/dl provided serum FLC ration is abnormal.
e Not recommended for use as an indicator of response; stability of disease is best described by providing the time 
too progression estimates).
f All relapse categories require two consecutive assessments made at any time before classification as relapse or 
disease progression and/or the institution of any new therapy.
g For progressive disease, serum M-component increases of ≥ 1 gm/dL are sufficient to define relapse if starting M-
component is ≥ 5 g/dL.
h Relapse from CR has the 5% cutoff versus 10% for other categories or relapse.
i To only be used if the end point studied is disease-free survival. For purposes of calculating time to progression 
and progression-free survival, CR patients should also be evaluated using criteria listed above for progressive 
disease.
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Appendix C: European Group for Blood and Marrow Transplantation 
Criteria
Response
Criteria for Response
Complete 
response (CR)
a
Complete response (CR) requires all of the following:
1. Absence of the original monoclonal paraprotein in serum and urine 
by immunofixation, maintained for a minimum of 42 days (6 weeks).  
The presence of oligoclonal bands consistent with oligoclonal 
immune reconstitution does not exclude CR
2. < 5% plasma cell in a bone marrow aspirate and also on bone marrow 
biopsy, if biopsy is performed.  However, if absence of monoclonal 
protein is sustained for at least 42 days (6 weeks), it is not necessary 
to repeat the bone marrow, except in patients with non-secretory 
myeloma where the marrow examination must be repeated after an 
interval of at least 42 days (6 weeks) to confirm CR.
1. No increase in size or number of lytic bone lesions (development of a 
compression fracture does not exclude response).  If absence of 
monoclonal protein is sustained for at least 42 days (6 weeks), it is 
not necessary to repeat the skeletal survey.
2. Disappearance of soft tissue plasmacytomas.
Partial Response 
(PR)
Partial response (PR) requires all of the following
1. ≥50% reduction in the level of serum monoclonal paraprotein, 
maintained for a minimum of 42 days (6 weeks).
2. Reduction in 24-hour urinary light chain extraction by & 90% or to 
∋200 mg, maintained for a minimum of 42 days (6 weeks).
3. For patients with non-secretory myeloma, & 50% reduction in plasma 
cells in bone marrow aspirate and on bone marrow biopsy, if a biopsy 
is performed, maintained for a minimum of 42 days (6 weeks).
4. & 50% reduction in the size of the soft tissue plasmacytomas (by 
radiography or clinical examination)
5. No increase in size or number of lytic bone lesions (development of a 
compression fracture does not exclude response).  If the reduction of 
the monoclonal protein required for PR is sustained for at least 42 
days (6 weeks), it is not necessary to repeat the skeletal survey.
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Appendix C:  European Group for Blood and Marrow Transplantation Criteria 
(Continued)
Response
Criteria for Response
Minimal 
Response (MR)
Minimal response (MR) requires all of the following:
1. 25-49% reduction in the level of serum monoclonal paraprotein, 
maintained for a minimum of 42 days (6 weeks).
2. Reduction in 24-hour urinary light chain extraction by 50-89%, which 
still exceeds 200 mg per 24 hours, maintained for a minimum of 42 
days (6 weeks).
3. For patients with non-secretory myeloma, 25-49% reduction in 
plasma cells in bone marrow aspirate and on bone marrow biopsy, if 
a biopsy is performed, maintained for a minimum of 42 days (6 
weeks).
4. 25-49% reduction in the size of the soft tissue plasmacytomas (by 
radiography or clinical examination).
5. No increase in size or number of lytic bone lesions (development of a 
compression fracture does not exclude response).  If the reduction of 
the monoclonal protein required for MR is sustained for at least 
42 days (6 weeks), it is not necessary to repeat the skeletal survey.
Stable Disease 
Not meeting the criteria for either MR or PD
Progressive 
disease (for 
patients not in CR)
One or more of the following:
> 25% increase in the level of the serum monoclonal paraprotein, which must also 
be an absolute increase of at least 5 g/L and confirmed by at least one repeated 
investigation
> 25% increase in the 24 h urinary light chain excretion, which must also be an 
absolute increase of at least 200 mg/24 h and confirmed by at least one repeated 
investigation
> 25% increase in plasma cells in a bone marrow aspirate or biopsy, which must 
also be an absolute increase of at least 10%
Definite increase in the size of existing bone lesions or soft tissue plasmacytomas.
Development of new lytic bone lesions or soft tissue plasmacytomas (development 
of a compression fracture does not exclude continued response and may not indicate 
PD).
Development of hypercalcaemia (corrected serum calcium >11.5 mg/dL [2.8 
mmol/L]) not attributable to any other cause.
a If some, but not all, the criteria for CR are fulfilled; the response is classified as a partial response (PR) provided 
that all other requirements for PR are satisfied.  This includes patients in whom routine electrophoresis is negative 
but in whom immunofixation has not been performed.
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Appendix D:
Skeletal (Bone) Survey Films
The following are the minimum plain radiological films required for the skeletal (bone) survey: 
!
Lateral skull 
!
AP and lateral cervical spine 
!
AP and lateral thoracic spine 
!
AP and lateral lumbar spine 
!
PA chest 
!
AP pelvis 
!
AP upper extremities, shoulder to elbow 
!
AP lower extremities, hip to knee 
Other radiological films may be necessary to view symptomatic areas or known pre-existing 
lesions in skeletal regions not included in the films above.
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Appendix E:
ECOG Performance Status Scale
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
our work of a light or sedentary nature, eg, light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair
5
Dead
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Appendix F:
Cockcroft-Gault Estimation Of Creatinine Clearance (CrCl)
Cockcroft-Gault estimation of creatinine clearance (CRcl): CRcl (mL/min) = (140 – age) (weight 
[kg]) / 72 (serum creatinine [mg/dl]); for females, the formula is multiplied by 0.85 (Cockcroft, 
1976; Luke, 1990).
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Appendix G:QT Drugs by Risk Group
To access a current list of QT-prolonging drugs grouped by risk of torsades, possible risk of 
torsades, and conditional risk of torsades visit http://www.qtdrugs.org/.
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Appendix H:
Staging Systems for Multiple Myeloma
Table 9:
Staging Systems for Multiple Myeloma
Stage
Durie-Salmon Criteria
a
ISS Criteria
b
I
All of the following:
Hemoglobin value > 10 g/dL
Serum calcium value normal or < 12 mg/dL
Bone x-ray, normal bone structure (scale 0), or 
solitary bone plasmacytoma only
Low M-component production rates
IgG value < 5 g/dL; 
IgA value < 3 g/dL
Urine light chain M-component on
electrophoresis < 4 g/24h
Serum beta-2 microglobulin < 3.5 
mg/L
Serum albumin ≥ 3.5 g/dL
II
Neither Stage I nor Stage II
Neither Stage I nor Stage II
III
One or more of the following:
Hemoglobin value < 8.5 g/dL
Serum calcium value normal or > 12 mg/dL
Advanced lytic bone lesions (scale 3)
High M-component production rates
IgG value > 7 g/dL; 
IgA value > 5 g/dL
Urine light chain M-component on
electrophoresis > 12 g/24h
Serum beta-2 microglobulin ≥ 5.5 
mg/L
Subclassification Criteria
A Normal renal function (serum creatinine value < 2.0 
mg/dL)
B  Abnormal renal function (serum creatinine value ≥ 2.0 
mg/dL)
Not applicable
a Durie BGM, Salmon SE.  A clinical staging system for multiple myeloma.  Cancer 1975; 36:842-854.
b Greipp P, San Miquel J, Durie B, et al.  International staging system for multiple myeloma.  Journal of Clinical 
Oncology 2005;23:3412-3420.
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Appendix I:Quality of Life Questionnaires
The following Quality-of-Life Questionnaires will be used for this study:
!
The European Organization for Research and Treatment of Cancer QoL 
Questionnaire for Patients with Multiple Myeloma (EORTC QLQ-MY20) Module, 
and
!
The European Organization for Research and Treatment of Cancer QoL 
Questionnaire for Patients with Cancer (EORTC QLQ-C30) Module, and
!
The descriptive system of the EQ-5D, which will be used for converting the 
information into utilities for economic analysis.
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Appendix J:
List of Abbreviations
Table 10:
List of Abbreviations
Abbreviation
Definition
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE
Adverse event
ALC
Absolute lymphocyte count
ALL
Acute Lymphocytic Leukemia
ALT
Alanine aminotransferase
AML
Acute Myeloid Leukemia 
ANC
Absolute neutrophil count
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AP
Anteroposterior
ASCT
Autologous Stem Cell Transplant
AST
Aspartate aminotransferase
Β2M
Beta-2 microglobulin
βHCG
Beta-human chorionic gonadotropin
BSA
Body Surface Area
BTZ
Bortezomib
CLL
Chronic Lymphocytic Leukemia
CR
Complete response
CrCl
Creatinine clearance
CRBN
Cereblon
CRF
Case Report Form
CRP
Clinical Research Physician
CT
computed tomography
DDB1
DNA damage-binding protein 1
DEX
Dexamethasone
DLT
Dose limiting toxicity
DVT
Deep vein thrombosis
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
122
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
Abbreviation
Definition
eCRF
Electronic case report form
EE
Efficacy evaluable
EMBT
European Group for Blood and Marrow Transplant
EMP
Extramedullary plasmacytoma
EORTC QLQ
European Organization for Research and Treatment of Cancer Quality of Live 
Questionnaire
EU
European Union
FCBP
Female of Childbearing Potential
FDA
Food and Drug Administration
FISH
fluorescent in situ hybridization
GCP
Good clinical practice
G-CSF
Granulocyte colony-stimulating factor
GGT
Gamma glutamyl transpeptidase
HAV
hepatitis A virus
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IC50
half maximal inhibitory concentration
ICH
International Committee on Harmonization
IDMC
Independent data monitoring committee
IFE
Immunofixation
IgA
Immunoglobulin A
IgD
Immunoglobulin D
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IgM
Immunoglobulin M
iMiD
Immunomodulating drug
IMWG
International Myeloma Working Group
IP
Investigational product
IRAC
Independent Response Adjudication Committee
IRB/EC
Institutional Review Board / Ethics Committee
ITT
Intent to treat
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
123
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
Abbreviation
Definition
IUD
Intrauterine device
IV
Intravenous
IVRS/IWRS
Interactive voice/web response system
Kd
Carfilzomib with dexamethasone
LD-DEX
Low-dose dexamethasone
LPS
Lipopolysaccharide
MDS
Myelodysplastic Syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MM
Multiple myeloma
MR
Minimal Response
MRI
Magnetic Resonance Imaging
MPD
Maximum planned dose
MRD
Minimal Residual Disease
MTD
Maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NE
Not evaluable
NK
Natural killer
ORR
Overall Response Rate
OS
Overall survival 
PA
posteroanterior
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PE
Pulmonary embolism
PFS
Progression-free survival
PK
Pharmacokinetics
PLD
Pegylated liposomal doxorubicin
POM
Pomalidomide
PR
Partial response
QoL
Quality of Life
RBC
Red blood cell
RRMM
Relapsed or Refractory Multiple Myeloma
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EDMS Doc. Number: 22009596 - 17358576
Pomalidomide (CC-4047)
Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
124
Protocol CC-4047-MM-007 Amendment 5 Final: 14 June 2017
Abbreviation
Definition
SAE
Serious adverse event
sCR
Stringent complete response
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
sPEP
Serum protein electrophoresis
SPM
Second Primary Malignancy
SQ
Subcutaneous
SUSAR
Suspected Unexpected Serious Adverse Reaction
TNF
Tumor necrosis factor
TNM
tumor, nodes, metastasis
TTF
Time to treatment failure
TTP
Time-to-progression
Tx d/c
Treatment discontinuation
ULN
Upper limit of normal
uPEP
Urine protein electrophoresis
Vd
Bortezomib with dexamethasone
VGPR
Very Good Partial Response
VTE
Venous thromboembolism
WBC
White blood cell
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EDMS Doc. Number: 22009596 - 17358576
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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EDMS Doc. Number: 22009596 - 19348407
Pomalidomide (CC-4047)
Summary of Changes CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
3
CC-4047-MM-007 Amendment 5 Final:  14 Jun 2017
1.
JUSTIFICATION FOR AMENDMENT
Recently published data from a number of Phase 3 studies has revealed that the progression-free 
survival (PFS) of the bortezomib with low-dose dexamethasone (BTZ+LD-DEX) arm on study 
CC-4047-MM-007 (OPTIMISMM), that requires prior treatment with lenalidomide as per 
protocol Inclusion Criteria #7 (Section 7.2), is expected to be shorter than the current 
OPTIMISMM protocol statistical assumption of 9 months (relevant median PFS data from Phase 
3 ENDEAVOR, PANORAMA-1 and CASTOR studies ranging from 7 to 8 months) (Moreau, 
2017; Palumbo, 2016; San-Miguel, 2014).
Subsequently, if the assumption for the pomalidomide, bortezomib, and low-dose 
dexamethasone (POM+BTZ+LD-DEX) arm and other study assumptions remain unchanged, the 
number of PFS events required for the final analysis would be less than originally planned in the 
study protocol and has been reached.
Therefore, Celgene proposes to amend the protocol to perform the final PFS analysis before the 
originally planned PFS events (381) are reached. The estimated time for applicable approvals of 
this protocol amendment is approximately October 2017, which will be used as the cutoff date 
for the revised final PFS analysis. By that time, with a 5-month follow-up time for the last 
subject enrolled, approximately 320 PFS events are projected to be reached, representing an 
approximate 57% event rate (out of 559 randomized subjects). This would allow for 80% power 
to test a hazard ration of 0.73. Celgene considers the study data to be mature for the primary 
endpoint (PFS), and the expected treatment difference to be achievable as well as clinically 
meaningful. The median follow-up time is expected to be approximately 16 months, considered 
appropriate as supported by recently reported relapsed or refractory multiple myeloma (RRMM)
registration trials in similar patient settings (Dimopoulos, 2016; Moreau, 2016; Moreau, 2017; 
Palumbo, 2016; San-Miguel, 2014). Therefore, the number of PFS events required for the final 
PFS analysis is amended to approximately 320.
Updated statistical considerations for the study will be specified in the protocol amendment and 
revised statistical analysis plan (SAP).
Main changes included in this amendment have been made to the Protocol Summary, Section 
1.2, Section 10.3, Section 10.9, and Section 18 References.
Referenced publications: 
Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, 
lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-31.
Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. Oral ixazomib, 
lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17):1621-34. 
doi:10.1056/NEJMoa1516282.
Moreau P, Joshua D, Chng WJ, Palumbo A, Goldschmidt H, Hájek R, et al. Impact of prior 
treatment on patients with relapsed multiple myeloma treated with carfilzomib and 
dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. 
Leukemia. 2017;31(1):115-22.
Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, 
bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-66.
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EDMS Doc. Number: 22009596 - 19348407
Pomalidomide (CC-4047)
Summary of Changes CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
4
CC-4047-MM-007 Amendment 5 Final:  14 Jun 2017
San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, et al. 
Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and 
dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a 
multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195-206. 
doi:10.1016/S1470-2045(14)70440-1.
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EDMS Doc. Number: 20715971 - 19348407
Pomalidomide (CC-4047)
Summary of Changes CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
3
Protocol CC-4047-MM-007 Amendment 4 SOC final:  9 Dec 2015
1.
JUSTIFICATION FOR AMENDMENT
The efficacy data reported by Lacy1 were updated with longer follow-up and 12 additional events
which resulted in accurate progression-free survival (PFS). Based on that, the assumption of 
median PFS has been adjusted in Study CC-4047-MM-007 which resulted in the revision of the 
study sample size.
Significant changes included in this amendment are summarized below:
!
Revision in overall sample size
∀
The assumption of the median PFS duration of the experimental arm (Arm A) has 
been adjusted from 12.6 months to 12 months and the study power has been 
reduced from 85% to 80%.
∀
The revised sample size will assume a median PFS of 9 months in the control arm
(Arm B) versus 12 months in the experimental arm (Arm A), with 80% power at 
2-sided significance level of 5%. This will require 381 PFS events and a total of 
544 subjects to be enrolled for an approximately 70% event rate.
∀
The interim analysis on PFS will take place when approximately 50% PFS 
information (191 events) has occurred.
∀
The OS interim analysis will take place when approximately 50% OS information 
(190 deaths) has occurred.
Updated Sections: Protocol Summary, Section 4.1, Section 7.1, Section 10.3, Section 10.9, 
Section 10.10
The amendment also includes minor updates to the following sections:
!
Clarification on the timing between randomization and study treatment start (Cycle 1 
Day 1)
!
Addition for requests of redacted pathology reports from unscheduled bone marrow 
biopsies or aspirates performed to confirm a Complete Response (CR)
Updated Sections: Protocol Summary, Table 1 Table of Events, footnote f and w, Section 4.3, 
Section 6.1.3, Section 6.3.2, Section 10.8.2.4
1. Lacy, Martha Q., MD, et al. " 304 Pomalidomide, Bortezomib and Dexamethasone 
(PVD) for patients with relapsed Lenalidomide Refractory Multiple Myeloma (MM)." 
ASH 2014. Oral presentation-December 8, 2014
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EDMS Doc. Number: 20582617 - 19348407
Pomalidomide (CC-4047)
Summary of Changes CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
3
Protocol CC-4047-MM-007 Amendment 3 Final:  16 Oct 2015
1.
JUSTIFICATION FOR AMENDMENT
The Celgene sponsored study of pomalidomide in combination with dexamethasone in 
relapsed/refractory multiple myeloma showed a median progression-free survival (PFS) and 
overall survival (OS) of 4.0 and 12.7 months respectively1.  More recent published data revealed 
that the triplet combination of cyclophosphamide, pomalidomide and dexamethasone (CPD) 
achieved an overall response rate (ORR) of 65%, a median PFS of 9.2 months and a median OS 
of 16.4 months2 and the triplet combination of pomalidomide, bortezomib and dexamethasone 
(PVD) reported high clinical activity with an 81% ORR (complete response [CR]+very good 
partial response [VGPR]+partial response [PR]) and a median PFS of 17.7 months3.  These 
efficacy results suggest that the addition of a third agent to pomalidomide with dexamethasone 
significantly increases the efficacy in relapsed/refractory multiple myeloma.
Due to the enrollment challenges experienced in the CC-4047-MM-007 study, with 117 subjects
enrolled over the course of 32 months, Celgene convened a European Advisory Board meeting.  
The recommendation was for Celgene to evaluate the likely treatment effect based upon recent 
published data, to re-evaluate the protocol required statistical power, and to consider expanding 
the study to include sites globally.
Considering the Advisory Board recommendations and the encouraging efficacy results reported 
with triplet combinations, specifically PVD3; Celgene has revised the study’s statistical 
assumptions by increasing the estimated PFS of the experimental arm (PVD) from 12 months to 
12.6 months (treatment difference increased from 33% to 40% over the control arm), and by 
reducing the study power from 90% to 85%; resulting in a sample size reduction.  Further, 
Celgene has expanded the study globally in order to ensure enrollment targets are met within
appropriate timeframes.
Significant changes included in this amendment are summarized below:
!
Approval status of Pomalyst in the United States has been updated following full 
approval notification on 23 April 2015
!
Reduction in overall sample size
o
The primary purpose of this protocol amendment is to take into account recent 
published evidence and thereby re-evaluate the statistical assumptions for the 
study.  The estimated PFS duration of the experimental arm (PVD) has been 
adjusted from 12 months to 12.6 months (increased from 33% to 40% over the 
control arm) and the study power has been reduced from 90% to 85%, resulting in 
a sample size reduction from approximately 782 subjects to 450 subjects.

Based on the primary endpoint PFS, at one-sided significance level of 
0.025 with an interim analysis for futility, a total of 318 disease 
progression/death events are required to detect a 40% increase in median 
PFS in the pomalidomide (POM) treatment arm (Treatment Arm A; 
median = 12.6 months) compared to that in the comparator arm 
(Treatment Arm B; median = 9 months) with 85% power.  Considering 
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EDMS Doc. Number: 20582617 - 19348407
Pomalidomide (CC-4047)
Summary of Changes CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
4
Protocol CC-4047-MM-007 Amendment 3 Final:  16 Oct 2015
subjects could be lost to follow-up, approximately 450 subjects will be 
enrolled in this study.

At one-sided significance level of 0.025 and with one planned interim 
analysis on overall survival (OS) at the time of the final PFS analysis 
(estimated to be at 50% OS information [147 deaths]), a total of 293 
deaths are required to detect a 40% increase in median OS in the POM 
treatment arm (Treatment Arm A; median = 42 months) compared with 
that of the comparator arm (Treatment Arm B; median = 30 months) with 
80% power.
!
Updates to time points for contraceptive requirements and pregnancy testing
o
The time points for contraceptive requirements and pregnancy testing for females 
of child-bearing potential (FCBP) following last dose of study treatment have 
been updated to be consistent with both pomalidomide and bortezomib
prescribing information
The amendment also includes several other minor clarifications and corrections:
!
Clarification on the timing of pomalidomide dosing in subjects enrolled into 
Treatment Arm A
!
Clarification on the timing of bortezomib dosing in subjects enrolled into both 
Treatment Arm A and B
!
Incorporation of study drug dispensation strategy for sites participating in Japan
!
Clarification of how Celgene Drug Safety will determine the expectedness of events 
with suspected relationship to the Investigational Product, for the purposes of 
regulatory reporting in the EEA
!
Addition of the QTc study conclusion has been updated
!
Additional editorial changes and corrections
References:
1. San Miguel et al, Pomalidomide plus low-dose dexamethasone versus high-dose 
dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-
003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013a;14(11):1055-66.
2. Baz R et al, Pomalidomide, cyclophosphamide, and dexamethasone is superior to 
pomalidomide and dexamethasone in relapsed and refractory myeloma: results of a 
multicenter randomized phase II study. Blood. 2014;124(21): Abstract 303.
3. Lacy MQ et al, Pomalidomide, bortezomib and dexamethasone (PVD) for patients with 
relapsed lenalidomide refractory multiple myeloma (MM). Blood. 2014;124 
(21).Abstract 304.
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EDMS Doc. Number: 19945962 - 19348407
Pomalidomide (CC-4047)
Summary of Changes Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
3
Protocol CC-4047-MM-007 Amendment #2 final:14 Nov 2014
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
The main purpose of this protocol amendment is to allow for the expansion of trial enrollment to 
countries and sites outside of the US in order to aid in completing enrollment.  The changes 
outlined throughout this document are required in order to expand globally; including updates to 
the Investigational Product sections and the collection of both Exploratory Biomarker samples 
and Quality of Life information.
Additional editorial changes are made to comply with Celgene Corporation required language 
and can be found in sections pertaining to Overdose, End of Trial and Pregnancy.  Typographical 
errors have also been corrected.
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Pomalidomide (CC-4047)
Summary of Changes Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
3
Protocol CC-4047-MM-007 Amendment #1 final: 27 Mar 2014
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Updated route of administration for the bortezomib in both treatment arms to 
subcutaneous from intravenous
∀
For Treatment Arm A (POM + BTZ + DEX), the dose was based on the results 
from the CC-4047-MM-005 (MM-005) Phase 1 dose escalation MTD study in 
which bortezomib was administered via IV infusion.  In the MM-005 study, the 
maximum planned dose (MPD), POM (4 mg) + IV BTZ (1.3 mg /m2) and DEX 
(20 mg subjects ≤ 75 years old/10 mg (subjects > 75 years old) was reached 
without any DLTs. Considering an early POM single agent MTD study 
(Richardson, 2013) as well as the findings in MM-005, the MPD was determined 
to be the optimal dose for the triple combination therapy.  With the optimal dose 
determined, MM-007 was initiated using the MPD dose for the combination of 
POM + BTZ + LD-DEX (with IV BTZ).  During the conduct of the MM-005 
study, subcutaneous (SQ) BTZ was approved as an alternative administration 
method for BTZ (23 Jan 2013).  The SQ BTZ was reported to have a decreased 
incidence of neurotoxicity versus the IV BTZ (Velcade® Prescribing Information, 
2012).  To explore the SQ route of BTZ administration in combination with POM 
and DEX, the MM-005 protocol was amended to add an additional cohort of 6 
subjects at the MPD/optimal dose for the combination of POM + BTZ + LD-DEX
with BTZ administered via SQ injection.  Based on the safety, efficacy and PK 
data for this SQ BTZ cohort and general adoption in medical practice of SQ BTZ 
as standard of care due to decreased neurotoxicity, BTZ administration is now 
changed to SQ for both arms in the MM-007 study (Treatment Arm A and B).
!
Added quality of life assessment to allow for an exploratory evaluation of the 
differences in health-related quality of life of POM + BTZ + LD-DEX versus BTZ + 
LD-DEX in subjects with relapsed or refractory MM
!
Added biomarker sampling  to allow for an exploratory evaluation of Minimal 
Residue Disease (MRD), genomic, molecular/mechanistic and immune biomarkers 
and their correlation to clinical outcome measures
!
Added an endpoint to allow for an exploratory evaluation of the Progression-free 
survival after next-line therapy (PFS2) 
!
Corrected to specify that all subjects will be followed in the long-term follow-up 
phase until death or for at least 5 years after the last subject is randomized into the 
study, or longer if clinically indicated (unless the follow-up is shorter due to 
withdrawal of consent, loss to follow-up, or death).  Initially it was written that all 
subjects would be followed in the long-term follow-up phase until death or for at least 
5 years after the subject’s randomization date.
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Pomalidomide (CC-4047)
Summary of Changes Protocol CC-4047-MM-007
Celgene Corporation
Confidential and Proprietary
4
Protocol CC-4047-MM-007 Amendment #1 final: 27 Mar 2014
!
Clarified references to investigational product (pomalidomide) versus study treatment 
(pomalidomide, bortezomib, dexamethasone) since pomalidomide is being provided 
as IP by Celgene Corporation, while investigative sites will use commercially 
available bortezomib and dexamethasone and will dispense these drugs to subjects via 
prescription.  
!
Clarified that samples for possible additional genetic studies for analysis of SPM risk 
factors will only be prepared and stored if acceptable per the local institutional 
policies for such sampling/storage of samples and only if sufficient sample is 
available after local pathology and central cytogenetic analysis is completed.    
!
Clarified that for subjects who are diagnosed with a SPM, bone marrow aspirate, 
bone marrow biopsy and peripheral blood smears will be sent for central pathology 
review only if acceptable per the local institutional policies.
!
Corrected that the reporting period for AEs will be from time of consent to 28 days 
after last dose of study treatment (pomalidomide, bortezomib, dexamethasone) versus 
28 days after the treatment discontinuation visit.
!
Added antiviral prophylaxis to the list of other recommended/required concomitant 
medications per the protocol since per protocol (and bortezomib label) oral acyclovir 
or equivalent antiviral therapy per institutional guidelines is required for herpes zoster 
prophylaxis. 
!
Clarified how VTE monitoring is to be performed for the study.
!
Updated Adverse Event section of the protocol per updates to the Celgene template 
language
!
Updated for change in Medical Monitor.
!
The amendment also includes several other minor clarification and corrections.
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