Conditions: Multiple Myeloma
Keywords: Phase 2 Open-Label Durvalumab Daratumumab Multiple Myeloma Relapsed and Refractory (RRMM) FUSION MM-003 PD-L1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 37
Healthy volunteers: no

Brief summary:
This is an open-label, multicenter study to confirm the safety and efficacy of durvalumab + daratumumab (D2) in subjects with relapsed and refractory multiple myeloma. This study will also explore the safety and efficacy of the addition of pomalidomide + dexamethasone to durvalumab + daratumumab (PD3).

On 05 Sep 2017, a Partial Clinical Hold was placed on this study by the United States (US) Food and Drug Administration (FDA). The decision by the FDA was based on data related to risks of anti-programmed cell death-1 (PD-1) antibody, pembrolizumab, in combination with IMiDs® immunomodulatory drugs in patients with multiple myeloma. As a result, enrollment into this study has been discontinued. Subjects who are receiving clinical benefit, based on the discretion of the investigator, may remain on study treatment after being reconsented.

Detailed description:

Arms:
arm 1: * Intravenous (IV) durvalumab at 1500mg on Day 1 or 2 of a 28-day cycle
* IV daratumumab at 16mg/kg on days 1, 8, 15 and 22 at cycles 1-2; on days 1 and 15 at cycles 3-6; and on day 1 from cycle 7 onward arm 2: * Intravenous (IV) durvalumab at 1500mg on Day 1 or 2 of a 28-day cycle
* IV daratumumab at 16mg/kg on days 1, 8, 15 and 22 at cycles 1-2; on days 1 and 15 at cycles 3-6; and on day 1 from cycle 7 onward
* oral POM at 4mg/day on days 1 to 21
* oral/IV dex at 40mg/day (\>75 years old) or 20mg/day (\>75 years old) on days 1, 8, 15 and 22

Interventions: intervention 1: Daratumumab intervention 2: Durvalumab intervention 3: Pomalidomide intervention 4: Dexamethasone
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Phase 2, Multicenter, Open-label, Study to Determine the Safety and Efficacy for the 
Combination of Durvalumab (DURVA) and Daratumumab (DARA) (D2) in Subjects With Relapsed 
and Refractory Multiple Myeloma (RRMM) (FUSION MM-003) 
 
PROTOCOL MEDI4736-MM-003 
 
NCT Number: NCT02807454 
  
Document Date (Date in which document was last revised): January 7, 2021 


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TITLE PAGE
A PHASE 2, MULTICENTER, OPEN-LABEL, STUDY TO 
DETERMINE THE SAFETY AND EFFICACY FOR THE
COMBINATION OF DURVALUMAB (DURVA) AND 
DARATUMUMAB (DARA) (D2) IN SUBJECTS WITH 
RELAPSED AND REFRACTORY MULTIPLE 
MYELOMA (RRMM) (FUSION MM-003)
PROTOCOL NUMBER:
MEDI4736-MM-003
DATE FINAL:
01 Apr 2016 
DATE AMENDMENT No. 1.0 FINAL:
21 Dec 2016
DATE AMENDMENT No. 2.0 FINAL:
15 Dec 2017
DATE AMENDMENT No. 3.0 FINAL:
19 Dec 2019
DATE AMENDMENT No. 4.0 FINAL:
07 Jan 2021
EudraCT NUMBER:
2016-001209-17
IND NUMBER:
127058
SPONSOR NAME/ ADDRESS:
Celgene International II, Sàrl
Rue des Moulins 4 
2108 Couvet
Switzerland
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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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information: US/Canada
Name: 
Title: 
Address: 3401 Princeton Pike, Lawrence, NJ 08648 USA
Phone: 
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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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{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.  
{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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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, International Council for Harmonisation (ICH) 
Good Clinical Practices Guidelines, and local regulations governing the conduct of clinical 
studies.
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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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PROTOCOL SUMMARY
On 05 Sep 2017, a Partial Clinical Hold was placed on this study by the United States (US) Food 
and Drug Administration (FDA). The decision by the FDA was based on data related to risks of 
anti-programmed cell death-1 (PD-1) antibody, pembrolizumab, in combination with 
immunomodulatory drugs (IMiDs®) in patients with multiple myeloma. As a result, enrollment 
into this study has been discontinued. Subjects who are receiving clinical benefit, based on the 
discretion of the investigator, may remain on study treatment after being reconsented. 
Study Title
A Phase 2, Multicenter, Open-label, Study to Determine the Safety and Efficacy for the 
Combination of Durvalumab (DURVA) and Daratumumab (DARA) (D2) in Subjects with 
Relapsed and Refractory Multiple Myeloma (RRMM)
Indication
Multiple myeloma with at least 3 prior therapies including a proteasome inhibitor (PI) and an 
immunomodulatory agent or double-refractory to a PI and an immunomodulatory agent. 
Objectives
Primary: To determine the safety and efficacy of D2 in subjects with RRMM
Secondary:

Evaluate additional measures of efficacy (time-to-response, duration of response, 
progressive-free survival) of D2 in subjects with RRMM

Evaluate the pharmacokinetics (PK) of DURVA and DARA in subjects with RRMM
Study Design
This is an open-label, multicenter, Phase 2 study preceded by a run-in phase to evaluate the 
safety of the proposed dose. The safety run-in cohort will use a 3+3 design to confirm the 
tolerability for D2. The Phase 2 portion of the study will use a Simon 2-stage design to determine 
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the efficacy and safety of D2.
 
Safety Run-in Phase
A 3+3 design will be used to confirm the tolerability of the proposed doses for D2. The 
recommended phase 2 doses (RP2D) of each agent will be tested in the first cohort. Only if this 
dose level is not tolerable will dose reductions be evaluated. The dose by cohort is as follows:
Cohort
IV DURVA
Cycle 1: Day 2 / 28-day cycle
Cycles ≥ 2: Day 1 or 2 / 28-day cycle
IV DARA
Cycles 1-2: Day 1, 8, 15, 22 /28-day cycle
Cycle3-6: Day 1, 15 /28-day cycle
Cycle ≥ 7: Day 1 /28-day cycle
1
a
1500 mg
16 mg/kg
b
-1
750 mg
16 mg/kgb, c
DARA = daratumumab; DURVA = durvalumab; IV = intravenous; MPD = maximum planned dose.
a The Cohort 1 dose level is the Maximum Planned Dose (MPD).
b DARA infusion rate reduction, per the Darzalex™Prescribing Information, will be implemented to mitigate 
toxicities as required. 
c If DARA infusion rate reduction does not mitigate the toxicities, additional subjects may be enrolled using a 
reduced infusion rate starting with the first dose of DARA.
Subsequent enrollment beyond 3 to 6 subjects will not occur until the Dose Review Team (DRT) 
has reviewed the safety data through Cycle 1 of each cohort. The DRT consists of the Celgene 
medical monitor, Celgene lead safety physician, Celgene biostatistician, other Celgene functional 
area representatives, as appropriate, study-specific consultant(s) (MD/PhD), as required, and site 
investigator and/or designees who have enrolled subjects to the study.
Phase 2 Portion
The Phase 2 portion of the study will use a Simon 2-stage design to determine the efficacy and 
safety of D2 (Simon, 1989).
Stage 1
Once the RP2D is confirmed, a cohort of 32 subjects (including subjects enrolled in the safety 
run-in portion) will be enrolled at the RP2D to determine the safety and preliminary efficacy of 
D2. 
Stage 2
If the threshold for minimum overall response rate are met in Stage 1, an additional 68 subjects 
will be enrolled to further confirm the safety and efficacy of D2 at the RP2D. 
For all subjects enrolled in the study, upon confirmed progressive disease (PD), for subjects who 
have had at least 2 cycles of D2, pomalidomide (POM) + dexamethasone (dex) may be added to 
the D2 regimen at the investigator’s discretion. 
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Study Population
The study population will consist of subjects with multiple myeloma who have received at least 
3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or 
who are double-refractory to a PI and an immunomodulatory agent. 
Length of Study
The study will consist of the following consecutive phases: Screening, Treatment, and 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. 
For subjects who have had at least 2 cycles of D2, upon PD, at the investigator’s discretion, POM 
+ dex may be added to the D2 regimen. All subjects will have an End of Treatment (EOT) Visit 
within 7 days after discontinuation of all study treatment. Subjects are to return to the study site 
28 (+3) days after the EOT visit and 90 (+3) days after the last dose of DURVA or DARA for 
safety follow-up visits, and then, all subjects who received POM as part of study treatment, will 
be followed for second primary malignancies (SPMs) every 6 months until the end of the trial 
(once last subject completes the 90 day posttreatment follow-up visit). 
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary 
 analysis, as prespecified in the protocol, 
whichever is the later date.
Study Treatments
For subjects receiving D2 regimen:

Intravenous DARA at the assigned dose level (16 mg/kg) for Cycles 1 to 2 Day 1, 8, 
15, 22/28-day cycle, Cycle 3 to 6 Day 1, 15 /28-day cycle, Cycle ≥ 7 Day 1/28-day 
cycle

Intravenous DURVA at the assigned dose level (1500 or 750 mg) on Cycle 1 Day 
2/28-day cycle then Cycle ≥ 2 on Day 1 or 2/28-day cycle
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Overview of Key Efficacy Assessments

Myeloma paraprotein

Serum immunoglobulins

Serum free light chains

Corrected serum calcium

Percent plasma cells in the bone marrow 

Radiographic assessments of lytic bone lesions

Extramedullary plasmacytoma (EMP) assessments

Response per International Myeloma Working Group (IMWG) criteria
Overview of Key Safety Assessments

Complete physical examination including vital signs

Clinical laboratory evaluations

Pregnancy testing/counseling

Electrocardiogram (ECG)

Concomitant medications and procedures

Adverse events (AEs) 

Second primary malignancies
Pharmacokinetic

Serum/plasma samples will be collected to assay plasma concentrations of DURVA 
and DARA
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Other

Eastern Cooperative Oncology Group (ECOG) Performance Status
Statistical Methods
Simon's 2-stage design (Simon, 1989) will be used. The null hypothesis that the true overall 
response rate (ORR) is < 30% will be tested against a one-sided alternative. In the first stage, 
32 subjects will be accrued. If there are 11 or fewer responses in these 32 subjects 
(11/32 = 34.4%), the study will be stopped. Otherwise, 68 additional subjects will be accrued to a
total of 100. The null hypothesis will be rejected if 39 or more responses are observed in 
100 subjects (39/100 = 39%). This design yields a Type I error rate of 0.05 and power of 80% 
when the true overall response rate is 45%. All analyses will use descriptive statistics. No formal 
statistical comparison/testing will be performed.
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................18
1.1.
Disease Background ...............................................................................................18
1.2.
Compound Background ..........................................................................................18
1.2.1.
Durvalumab (MEDI4736).......................................................................................18
1.2.2.
Daratumumab.........................................................................................................19
1.2.3.
Pomalidomide.........................................................................................................19
1.3.
Rationale ................................................................................................................19
1.3.1.
Study Rationale and Purpose ..................................................................................19
1.3.2.
Rationale for the Study Design ...............................................................................20
1.3.4.
Rationale for Choice of Combination Compounds ..................................................22
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................24
3.
OVERALL STUDY DESIGN ................................................................................26
3.1.
Study Design ..........................................................................................................26
3.1.1.
D2 Arm...................................................................................................................26
3.1.1.1.
D2 Safety Run-In Phase...........................................................................................26
3.1.1.2.
D2 Phase 2 Portion ..................................................................................................27
3.1.1.3.
Addition of Pomalidomide Plus Dexamethasone to Daratumumab Plus 
Durvalumab Upon Progressive Disease ..................................................................27
3.1.3.
Dose Review Team.................................................................................................27
3.1.4.
Dose-limiting Toxicity............................................................................................28
3.2.
Study Duration for Subjects....................................................................................32
3.3.
End of Trial ............................................................................................................32
4.
STUDY POPULATION.........................................................................................33
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4.1.
Number of Subjects ................................................................................................33
4.2.
Inclusion Criteria....................................................................................................33
4.3.
Exclusion Criteria...................................................................................................34
5.
TABLE OF EVENTS.............................................................................................38
6.
PROCEDURES......................................................................................................45
6.1.
Screening Period.....................................................................................................45
6.2.
Treatment Period ....................................................................................................47
6.2.1.
End of Treatment....................................................................................................48
6.3.
Follow-up Period....................................................................................................49
6.3.1.
Safety Follow-up ....................................................................................................49
6.3.2.
Second Primary Malignancy Follow-up..................................................................50
6.4.
Efficacy Assessments .............................................................................................50
6.4.1.
Laboratory Assessments for Efficacy Parameters....................................................50
6.4.2.
Bone Marrow Aspiration and/or Biopsy..................................................................51
6.4.3.
Bone Lesion Assessment ........................................................................................51
6.4.4.
Extramedullary Plasmacytoma Assessments...........................................................52
6.4.5.
Assessment of Response.........................................................................................52
6.5.
Pharmacokinetics....................................................................................................52
6.5.1.
Pharmacokinetics of Durvalumab ...........................................................................52
6.5.2.
Pharmacokinetics of Daratumumab.........................................................................53
6.8.
Blood Type, Rh and Indirect Antiglobulin Test (IAT).............................................54
7.
DESCRIPTION OF STUDY TREATMENTS........................................................56
7.1.
Description of Investigational Products...................................................................56
7.1.1.
Durvalumab (MEDI4736).......................................................................................56
7.1.2.
Daratumumab (Darzalex)........................................................................................57
7.1.3.
Pomalidomide (POM).............................................................................................57
7.1.4.
Dexamethasone (Dex).............................................................................................57
7.2.
Treatment Administration and Schedule .................................................................57
7.2.1.
Treatment Administration.......................................................................................57
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7.2.1.1.
Durvalumab (MEDI4736).......................................................................................57
7.2.1.2.
Daratumumab (Darzalex)........................................................................................58
7.2.1.3.
Pomalidomide.........................................................................................................59
7.2.1.4.
Dexamethasone ......................................................................................................59
7.2.2.
Treatment Schedule ................................................................................................60
7.2.2.1.
Daratumumab Plus Durvalumab Treatment Schedule .............................................60
7.2.3.
Overdose ................................................................................................................61
7.2.4.
Dose Modifications and Interruptions .....................................................................61
7.2.4.1.
Dose Modification Instructions for Durvalumab .....................................................61
7.2.4.2.
Dose Modification Instructions for Daratumumab...................................................62
7.2.4.3.
Dose Modification Instructions for Pomalidomide ..................................................62
7.2.4.4.
Dose Modification Instructions for Low-dose Dexamethasone................................63
7.3.
Method of Treatment Assignment...........................................................................63
7.4.
Packaging and Labeling..........................................................................................64
7.5.
Investigational Product Accountability and Disposal ..............................................64
7.6.
Investigational Product Compliance........................................................................64
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................65
8.1.
Permitted Concomitant Medications and Procedures...............................................65
8.2.
Prohibited Concomitant Medications and Procedures..............................................65
8.3.
Required Concomitant Medications and Procedures................................................66
9.
STATISTICAL CONSIDERATIONS ....................................................................67
9.1.
Overview................................................................................................................67
9.2.
Study Population Definitions ..................................................................................67
9.3.
Sample Size and Power Considerations...................................................................67
9.4.
Background and Demographic Characteristics........................................................68
9.5.
Medical History......................................................................................................68
9.6.
Concomitant Medications and Procedures...............................................................68
9.7.
Subject Disposition.................................................................................................68
9.8.
Efficacy Analysis....................................................................................................69
9.8.1.
Response (International Myeloma Working Group Criteria) ...................................69
9.8.2.
Time-to-Response...................................................................................................69
9.8.3.
Duration of Response .............................................................................................69
9.8.4.
Progression-free survival (PFS) ..............................................................................69
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9.9.
Safety Analysis.......................................................................................................69
9.10.
Interim Analysis .....................................................................................................70
9.11.
Other Topics...........................................................................................................70
9.11.1.
Pharmacokinetic Analysis.......................................................................................70
10.
ADVERSE EVENTS..............................................................................................72
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................72
10.2.
Evaluation of Adverse Events.................................................................................72
10.2.1.
Seriousness.............................................................................................................72
10.2.2.
Severity/Intensity....................................................................................................74
10.2.3.
Causality ................................................................................................................74
10.2.4.
Duration .................................................................................................................75
10.2.5.
Action Taken..........................................................................................................75
10.2.6.
Outcome.................................................................................................................75
10.3.
Abnormal Laboratory Values..................................................................................75
10.4.
Pregnancy...............................................................................................................76
10.4.1.
Females of Childbearing Potential: .........................................................................76
10.4.2.
Male Subjects.........................................................................................................76
10.5.
Reporting of Serious Adverse Events......................................................................76
10.5.1.
Safety Queries ........................................................................................................77
10.6.
Expedited Reporting of Adverse Events..................................................................77
10.7.
Adverse Events of Special Interest..........................................................................78
10.7.1.
Second Primary Malignancies.................................................................................78
11.
DISCONTINUATIONS .........................................................................................80
11.1.
Treatment Discontinuation......................................................................................80
11.2.
Study Discontinuation ............................................................................................80
12.
EMERGENCY PROCEDURES.............................................................................81
12.1.
Emergency Contact.................................................................................................81
12.2.
Emergency Identification of Investigational Products .............................................81
13.
REGULATORY CONSIDERATIONS...................................................................82
13.1.
Good Clinical Practice............................................................................................82
13.2.
Investigator Responsibilities ...................................................................................82
13.3.
Subject Information and Informed Consent.............................................................83
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13.4.
Confidentiality........................................................................................................83
13.5.
Protocol Amendments.............................................................................................83
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................83
13.7.
Ongoing Information for Institutional Review Board/Ethics Committee .................84
13.8.
Termination of the Study ........................................................................................84
14.
DATA HANDLING AND RECORDKEEPING.....................................................85
14.1.
Data/Documents .....................................................................................................85
14.2.
Data Management...................................................................................................85
14.3.
Record Retention....................................................................................................85
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................87
15.1.
Study Monitoring and Source Data Verification......................................................87
15.2.
Audits and Inspections............................................................................................87
16.
PUBLICATIONS ...................................................................................................88
17.
REFERENCES.......................................................................................................89
18.
APPENDICES........................................................................................................92
Appendix A: Table of Abbreviations.........................................................................................92
Appendix B: International Myeloma Working Group Uniform Response Criteria .....................96
Appendix C: ECOG Performance Status ...................................................................................98
Appendix D: Staging Systems for Multiple Myeloma................................................................99
Appendix E: Durvalumab Treatment Modification and Toxicity Management Guidelines.......100
Appendix E-1: Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Immune-mediated Adverse Events.................................................100
Appendix E-2: Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Infusion-related Reactions .............................................................130
Appendix E-3: Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Non-immune-mediated Reactions..................................................131
Appendix E-4: Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Other–Immune-mediated Reactions...............................................133
Appendix F: Guideline for Asthma Eligibility Criteria ............................................................135
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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................24
Table 2:
Study Endpoints .....................................................................................................24
Table 3:
Dose Levels by Cohort ...........................................................................................26
Table 4:
Table of Events.......................................................................................................38
Table 6:
Daratumumab Preinfusion and Postinfusion Medications........................................59
Table 7:
Dose Modification Instructions for Pomalidomide ..................................................62
Table 8:
Pomalidomide Dose Reduction Steps......................................................................62
Table 9:
Dose Modifications for Low-dose Dexamethasone Related Toxicities ....................63
Table 10:
Low-Dose Dexamethasone Dose Reduction Steps ..................................................63
Table 11:
Staging Systems for Multiple Myeloma ..................................................................99
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................30
Figure 2:
Study Schematic .....................................................................................................31
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1.
INTRODUCTION
On 05 Sep 2017, a Partial Clinical Hold was placed on this study by the United States (US) Food 
and Drug Administration (FDA). The decision by the FDA was based on data related to risks of 
anti-programmed cell death-1 (PD-1) antibody, pembrolizumab, in combination with 
immunomodulatory drugs (IMiDs®) in patients with multiple myeloma. As a result, enrollment 
into this study has been discontinued. Subjects who are receiving clinical benefit, based on the 
discretion of the investigator, may remain on study treatment after being reconsented.
1.1.
Disease Background
Multiple myeloma (MM) is a rare and incurable progressive neoplastic disease that accounts for 
10% of all hematological malignancies. It has been estimated that 62,469 new cases and 
43,091 deaths from MM occurred globally in 2012 (Ferlay, 2013).
Significant progress has been made in the treatment of MM with various combinations of 
melphalan, prednisone, dexamethasone, doxorubicin, cyclophosphamide, etoposide, cisplatin, 
immunomodulatory agents (thalidomide, lenalidomide and pomalidomide), and proteasome 
inhibitors (eg, bortezomib, carfilzomib, and ixazomab) or with autologous stem cell transplant 
following high-dose chemotherapy and more recently monoclonal antibodies (eg, daratumumab, 
elotuzumab) (National Comprehensive Cancer Network [NCCN]-MM Guidelines, 2016). The
main considerations for choosing an appropriate treatment for relapsed and refractory multiple 
myeloma (RRMM) are: risk level, prior therapy, duration of response to prior therapy, residual 
toxicity, age, physical condition, and whether the patient is a candidate for stem cell 
transplantation (NCCN-MM Guidelines, 2016). Despite the progress in treatment options for 
MM, the disease follows a relapsing course in the majority of patients, regardless of treatment 
regimen or initial response to treatment. Multiple myeloma remains incurable using conventional 
treatments, with an overall 5-year relative survival rate of 45% (Howlader, 2014). New therapies 
are needed to treat RRMM patients.
1.2.
Compound Background
1.2.1.
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) (DURVA) is a human immunoglobulin G (IgG)1 kappa monoclonal 
antibody (mAb) directed against human programmed cell death ligand 1 (PD-L1) protein. 
Refer to the durvalumab Investigator’s Brochure (IB) for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) 
profile of the investigational product (IP).
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1.2.2.
Daratumumab
Daratumumab (DARA) is a human IgG1ĸ monoclonal antibody (mAb) that binds with high 
affinity to a unique epitope on CD38.
 
 
 DARA was approved under the accelerated approval regulations in 
the United States (US) on 16 Nov 2015 for the treatment of patients with multiple myeloma who 
have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an 
immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.
In the European Union (EU) DARA received conditional approval on 20 May 2016 as 
monotherapy for the treatment of adult patients with RRMM, whose prior therapy included a PI
and an immunomodulatory agent and who have demonstrated disease progression on the last 
therapy.
Refer to the DARA IB for detailed information concerning the available pharmacology, 
toxicology, drug metabolism, clinical studies, and AE profile; as well as the current US label
(Darzalex™Prescribing Information [PI]) and Summary of Product Characteristics [SmPC] for
the EU.
1.2.3.
Pomalidomide
Pomalidomide (POM) is a novel drug in the class of immunomodulatory drugs known as IMiDs® 
compounds, and is structurally similar to thalidomide.
 
 
 
 
Refer to the POM IB for detailed information concerning the available pharmacology, 
toxicology, drug metabolism, clinical studies, and AE profile of the IP; as well as the current 
label (Pomalyst® PI; Imnovid™Summary of Product Characteristics [SmPC]).
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
The importance of the immune system in cancer development and progression has been 
recognized during the past decade (Hanahan, 2000). Failure of immune surveillance of pre-
neoplastic lesions and micro-metastases is a key step in cancer development. Chronically 
immunosuppressed individuals show higher rates of cancer. This observation led to the 
hypothesis that sporadic cancers among immune-competent individuals are likely to be 
minimally immunogenic, allowing for passive escape from immune surveillance. Recent data 
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suggest that this may be an oversimplification. Some sporadic tumors are highly immunogenic, 
but actively suppress the local immune environment through production of immunosuppressive 
cytokines (Shields, 2010). As such, the local tumor environment is likely a highly dynamic 
environment where most tumors grow and metastasize through adaptive responses that modulate 
antitumor immunity. The complexity and redundancy of the immune system offers multiple 
targets that may be manipulated to maximize the body’s inherent immune response to a tumor. 
Immune response may be augmented by directly stimulating effector cells, indirectly stimulating 
effectors by augmenting antigen presentation activity or costimulation, or by suppressing 
immunosuppressive factors, cells, or messages (Monti, 2005).
Targeted immunotherapy based on monoclonal antibodies against relevant tumor antigens has 
not only shown to be feasible, but also an effective approach in treating hematological 
malignancies. In 2015, DARA was approved under the accelerated approval regulations in the 
US for the treatment of patients with MM who have received at least three prior lines of therapy 
including a PI and an immunomodulatory agent or who are double-refractory to a PI and an 
immunomodulatory agent. In the EU DARA received conditional approval in 2016 as 
monotherapy for the treatment of adult patients with RRMM, whose prior therapy included a PI
and an immunomodulatory agent and who have demonstrated disease progression on the last 
therapy. However, treatment options for heavily treated patients are limited, especially for those 
with disease that is double refractory to a PI and an immunomodulatory drug (Laubach, 2016). 
To date, targeting MM cells by a combination-therapy approach has demonstrated superior 
clinical response as compared with that of single agents (Cavo, 2011). In theory, combination 
treatment of anti-PD-L1 mAb, like durvalumab, with other anti-MM therapies that modulate 
MM-host immune responses, like DARA, may enhance both host anti-MM immunity and 
clinical response and warrant further exploration in a relapsed/refractory population being 
considered in this study.
Furthermore, the combination of immunostimulatory antibodies with backbone therapy has 
shown promising activity in RRMM. Elotuzumab (in combination with LEN and dexamethasone 
[dex]) is approved for the treatment of for the treatment of patients with MM who have received 
1 to 3 prior therapies (Empliciti™Prescribing Information [PI]). In addition, promising 
therapeutic activity has been seen with pembrolizumab (anti PD-1 antibody) in combination with 
POM + dex and LEN + dex and also DARA in combination with LEN+ dex in heavily treated 
RRMM patients (San Miguel, 2015; Badros, 2015; Plesner, 2015). The future of successful MM 
treatment lies in both the development of novel agents targeting the MM cells or the bone 
marrow microenvironment, and the development of rationally-based combination therapies. 
1.3.2.
Rationale for the Study Design
The study will consist of a safety run-in phase to determine the tolerability of the proposed doses 
of the DARA + DURVA (D2) regimen using a 3+3 design. If the doses are tolerable, the Phase 2 
portion of the study will be initiated using a Simon 2-Stage design, where a limited number of 
subjects will be enrolled in Stage 1 to ensure a sufficient efficacy signal is seen prior to enrolling 
additional subjects in Stage 2.
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1.3.4.
Rationale for Choice of Combination Compounds
Daratumumab is a novel human IgG k monoclonal antibody that targets CD38, a protein that is 
highly expressed on MM cells. Daratumumab is approved under the accelerated approval 
regulations in the US for the treatment of patients with multiple myeloma who have received at 
least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory 
agent or who are double-refractory to a PI and an immunomodulatory agent. In the EU 
Daratumumab received conditional approval on 20 May 2016 as monotherapy for the treatment 
of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a 
proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease 
progression on the last therapy. Daratumumab acts through multiple immune effector-mediated 
mechanisms, including complement-dependent cytotoxicity, antibody-dependent cell-mediated 
cytotoxicity, and antibody-dependent cellular phagocytosis. In addition to direct targeting of 
CD38+ myeloma cells, recently published data suggests an immune stimulating/modulatory role 
for DARA. Increases in CD8+: CD4+ T cell ratios, antiviral responses, and T-cell clonality were 
all observed after DARA treatment in a heavily pretreated, relapsed, and refractory patient 
population not expected to have strong immune responses (Krejcik, 2015). Improved clinical 
responses were associated with changes in these parameters. In addition, DARA was shown to 
deplete regulatory T cells (Tregs) that express high levels of CD38. Reduction of these immune 
suppressive Tregs may promote expansion of cytotoxic CD8+ T cells which could have 
additional anti-tumor effects. These data suggest an immune modulatory role of DARA that may 
contribute to its efficacy (Krejcik, 2015).
Durvalumab (MEDI4736) is a human immunoglobulin G (IgG)1 kappa monoclonal antibody 
(mAb) directed against the human PD-L1 protein. Durvalumab selectively binds human PD-L1 
with high affinity and blocks its ability to bind to the PD-1 protein and cluster of differentiation 
(CD)80. Programmed cell death protein 1 is highly expressed on MM patient T cells and Natural 
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Killer (NK) cells; and both plasmacytoid dendritic cells (pDCs) and MM cells express PD-1 
ligand PD-L1. It has been shown that pDCs allow T-cell and NK-cell immune suppression in the 
MM bone marrow (BM) milieu by engaging immune checkpoints via PD-L1/PD-1 signaling axis 
(Ray, 2015). Blockade of PD-L1/PD-1 using anti-PD-L1 antibody generates MM-specific CD8+ 
cytotoxic T lymphocytes activity, as well as enhances NK-cell-mediated MM cell cytolytic 
activity.
As PD-L1-expressing pDCs are increased in MM BM and localize with PD-L1-positive MM 
cells (Chauhan, 2009), PD-L1 expression may correlate with progression of disease, with highest 
levels in RRMM. Indeed, a recent study showed that PD-L1 expression positively correlates with 
increased proliferative potential of tumor cells and resistance to therapies in MM 
(Tamura, 2013). Combination treatment of anti-PD-L1 mAb, like DURVA, with other anti-MM 
therapies that modulate MM-host immune responses, like DARA, may enhance both host 
anti-MM immunity and clinical response and warrant further exploration in a relapsed/refractory 
population being considered in this study.
In addition, based on recent data from the combinations of immunomodulatory agents (POM and 
LEN) with monoclonal antibodies (elotuzumab, daratumumab, pembrolizumab), exploration of 
the addition of POM + dex to DARA and DURVA should be considered in this heavily 
pretreated population with poor overall survival (see Section 1.3.1).  
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2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to determine the safety and efficacy of D2 in subjects 
with RRMM.
Secondary Objectives
The secondary objectives are:

Evaluate additional measures of efficacy of D2 in subjects with RRMM

Evaluate the pharmacokinetics (PK) of DURVA and DARA in subjects with 
RRMM
Table 2:
Study Endpoints
Endpoint
Name
Description
Primary 
Overall response rate 
(ORR)
Tumor response, including progressive disease (PD) 
according to the International Myeloma Working Group 
(IMWG) Uniform Response Criteria (Rajkumar, 2011).
Primary 
Safety 
Type, frequency, seriousness and severity of adverse 
events (AEs), and relationship of AEs to study treatment 
Secondary 
Time-to-response 
(TTR)
Time from enrollment to the first documentation of 
response (Partial Response [PR] or greater)
Secondary 
Duration of response 
(DOR)
Time from the first documentation of response (PR or 
greater) to the first documentation of PD
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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Secondary
Progression-free 
survival (PFS)
Time from enrollment to the first documentation of PD 
or death from any cause during study, whichever occurs 
earlier
Secondary
PK parameters
Typical serum/plasma PK parameters for DURVA and 
DARA, such as maximum observed concentration (Cmax), 
area under the concentration-time curve (AUC), time to 
maximum concentration (Tmax), terminal elimination 
half-life (t1/2), clearance (CL/F), and volume of
distribution (Vz/F)
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3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is an open-label, multicenter Phase 2 study preceded by a run-in phase to evaluate the safety 
of the proposed dose. The safety run-in cohort will use a 3+3 design to confirm the tolerability 
for D2. Phase 2 portion of the study will use a Simon 2-stage design to determine the efficacy 
and safety of D2.  See Figure 1 and Figure 2.  
 
3.1.1.
D2 Arm
3.1.1.1.
D2 Safety Run-In Phase
A 3+3 design will be used to confirm the tolerability of the proposed doses for D2. The 
recommended phase 2 doses (RP2D) of each agent will be tested in the first cohort. Only if this 
dose level is not tolerable will dose reductions be evaluated. The dose by cohort will be per 
Table 3.
Table 3:
Dose Levels by Cohort
Cohort
IV DURVA
Cycle 1: Day 2 / 28-day cycle
Cycle ≥ 2: Day 1 or 2/ 28-day cycle
IV DARA
Cycles 1-2: Day 1, 8, 15, 22 /28-day cycle
Cycle3-6: Day 1, 15 /28-day cycle
Cycle ≥ 7: Day 1 /28-day cycle
1
a
1500 mg
16 mg/kg
b
-1
750 mg
16 mg/kgb, c
DARA = daratumumab; DURVA = durvalumab; IV = intravenous; MPD = maximum planned dose.
a The Cohort 1 dose level is the Maximum Planned Dose (MPD).
b DARA infusion rate reduction, per the Darzalex PI and SmPC, will be implemented to mitigate toxicities as 
required. 
c If DARA infusion rate reduction does not mitigate the toxicities, additional subjects may be enrolled using a 
reduced infusion rate starting with the first dose of DARA.
The following dose escalation rules will be applied in determining if the proposed doses are 
tolerable:

Initially, 3 subjects will be enrolled into Cohort 1. The dose-limiting toxicity (DLT) 
evaluation period will be the first treatment cycle.

If ≤ 1 of the 3 initial subjects experiences a DLT within the first cycle, then 3 
additional subjects will be enrolled at the Cohort 1 dose level.

If 2 or more of the 6 subjects experience a DLT within the first cycle, then 
de-escalation to the Cohort -1 dose level may be initiated following review of 
safety of the initial 6 subjects by the Dose Review Team (DRT)

If ≤ 1 of the 6 subjects experiences a DLT within the first cycle, then Phase 2 
Simon Stage 1 at the Cohort 1 dose level may be initiated following review of 
safety of the initial 6 subjects by the DRT.
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
If 2 or 3 of the 3 initial subjects in Cohort 1 experience a DLT within the first cycle, 
then de-escalation to the Cohort -1 dose level may be initiated following review of 
safety of the initial 3 subjects by the DRT. If de-escalation is agreed upon by DRT, 
the same rules as above will apply to Cohort -1.
3.1.1.2.
D2 Phase 2 Portion
The Phase 2 will use a Simon 2-stage design to determine the efficacy and safety of D2 
(Simon, 1989).
D2 Simon Stage 1
Once the RP2D is confirmed, a cohort of 32 subjects (including subject enrolled in the safety 
run-in portion) will be enrolled at the RP2D to determine the safety and preliminary efficacy of 
D2. 
D2 Simon Stage 2
If the threshold for minimum overall response rate (ORR) is met in Stage 1, an additional 68 
subjects will be enrolled to further confirm the safety and efficacy of D2 at the RP2D. 
3.1.1.3.
Addition of Pomalidomide Plus Dexamethasone to Daratumumab Plus 
Durvalumab Upon Progressive Disease 
For all subjects enrolled into D2Arm, upon confirmed PD, for subjects who have had at least 
2 cycles of D2, POM + dex may be added to the D2 regimen at the investigator’s discretion. 
3.1.3.
Dose Review Team 
The DRT consists of the Celgene medical monitor, Celgene lead safety physician, Celgene 
biostatistician, other Celgene functional area representatives, as appropriate, study-specific 
consultant(s) (MD/PhD), as required, and site investigator and/or designees who have enrolled 
subjects to the study.
The DRT members are responsible for all dosing decisions for the study. Dosing decisions may 
include de-escalation to a lower dose; continuation, delay, or termination of dosing, and 
repetition of or expansion of a cohort. All available safety and, if applicable,
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Pharmacokinetic
(PK
), 
 and preliminary efficacy data will be 
reviewed and can be considered in the DRT’s decisions.
Dose Review Team meetings will be held to review all data, monitor safety, and make dosing 
and expansion decisions.
3.1.4.
Dose-limiting Toxicity
Dose-limiting toxicities will be evaluated during the DLT evaluation period for subjects in the D2
safety run-in phase
 
 The DLT 
evaluation period for the D2
Arms will be defined as the first treatment cycle. Subjects 
are considered evaluable for assessment of DLT if they:

Receive at least 1 dose of study treatments within an assigned treatment arm and 
experience a DLT 

Receive at least 1 dose of study treatments and experience a DLT after POM + dex 
added
OR

Receive 1 dose of DURVA and all DARA doses as per relevant treatment cycle, ≥ 16 
doses of POM and ≥ 3 doses of dex and complete the safety follow-up through the 
end of the DLT evaluation period. 
Nonevaluable subjects will be replaced. 
Grading of DLTs will be according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) Version 4.03.
A DLT will be defined as below:
Hematologic DLT
a.
Grade 4 neutropenia observed for greater than 5 days duration
b. Grade 3 neutropenia associated with fever (≥ 38.5°C) of any duration.
c.
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, or any 
requirement for platelets transfusion.
d. Any other Grade 4 hematologic toxicity that does not resolve to subject’s 
pretreatment baseline level within 72 hours
e.
Grade 4 anemia, unexplained by underlying disease.
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Nonhematologic DLT
a.
Any nonhematological toxicity ≥ Grade 3 except for alopecia and nausea controlled 
by medical management
b. Any treatment interruption greater than 2 weeks due to an AE.
While the rules for adjudicating DLTs in the context of dose escalation are specified above, an 
AE not listed above may be defined as a DLT after consultation with the sponsor and 
investigators, based on the emerging safety profile.
The study will be conducted in compliance with the International Council for Harmonisation
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
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Figure 1:
Overall Study Design
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Figure 2:
Study Schematic
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3.2.
Study Duration for Subjects 
The study will consist of the following consecutive phases: Screening, Treatment, and 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. 
For subjects who have had at least 2 cycles of D2, upon PD, at the investigator’s discretion, POM 
+ dex may be added to the D2 regimen. All subjects will have an End of Treatment (EOT) Visit 
within 7 days after discontinuation of all study treatment. Subjects are to return to the study site 
28 (+3) days after the EOT visit and 90 (+3) days after the last dose of DURVA or DARA for
safety follow-up visits, and then, all subjects who received POM as part of study treatment, will 
be followed for second primary malignancies (SPMs) every 6 months until the end of the trial 
(once last subject completes the 90-day post-treatment follow-up visit). 
On 05 Sep 2017, a Partial Clinical Hold was placed on this study by the US FDA. The decision 
by the FDA was based on data related to risks of anti-PD-1antibody, pembrolizumab, in 
combination with IMiDs in patients with multiple myeloma. As a result, enrollment into this 
study has been discontinued. Subjects who are receiving clinical benefit, based on the discretion 
of the investigator, may remain on study treatment after being reconsented. 
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary 
 analysis, as pre-specified in the protocol, 
whichever is the later date.
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4.
STUDY POPULATION
4.1.
Number of Subjects
Up to approximately 144 subjects with RRMM will be enrolled worldwide. 

D2 Cohort:  Run-in cohort up to 18; Simon Stage 1 up to 26; Simon Stage 2 up to 68
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject received at least 3 prior anti-myeloma regimens including a PI and an 
immunomodulatory agent or is double-refractory to a PI and an immunomodulatory 
agent. 

Induction, bone marrow transplant with or without maintenance therapy is 
considered one regimen

Refractory is defined as disease that is nonresponsive on therapy, or progresses 
within 60 days of last therapy. Nonresponsive disease is defined as either failure to 
achieve minimal response or development of progressive disease while on therapy.

For subjects who received more than 1 regimen containing a PI their disease must be 
refractory to the most recent PI containing regimen.

For subjects who received more than 1 regimen containing an immunomodulatory 
agent their disease must be refractory to the most recent immunomodulatory agent 
containing regimen.
2. Subject has measurable disease defined as:
a.
M-protein (serum protein electrophoresis (sPEP) or urine protein electrophoresis 
(uPEP): sPEP ≥0.5 g/dL or uPEP ≥ 200 mg/24 hours) and/or 
b. Light chain MM without measurable disease in the serum or the urine: serum 
immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin 
kappa lambda free light chain ratio
3. Subject achieved a response (MR or better) to at least 1 prior treatment regimen
4. Subject has evidence of PD on or within 60 days of the most recent prior treatment 
regimen
5. Subject received an alkylating agent alone or in combination with other myeloma 
treatment
6. Subject has an Eastern Cooperative Oncology Group performance-status score of 2 or 
less
7. Subject’s toxicities resulting from previous therapy (including peripheral neuropathy) 
have resolved or stabilized to ≤Grade 1.
8. Subject is at least 18 years of age at the time of signing the informed consent form (ICF). 
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9. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
10. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
11. Females of childbearing potential (FCBP1) must:
a.
Have 2 negative pregnancy tests as verified by the investigator prior to starting study 
treatment. She must agree to ongoing pregnancy testing during the course of the 
study, and after end of study treatment. This applies even if the subject practices true 
abstinence from heterosexual contact.
b. Either practice true abstinence2 from heterosexual contact (which must be reviewed 
on a monthly basis and source documented) or agree to use, and be able to comply 
with, effective contraception without interruption, 28 days prior to starting study 
treatment, during the study therapy (including dose interruptions), and for at least 
90 days after discontinuation of study treatment. 
c.
Refrain from egg cell donation for at least 90 days after the final dose of DURVA or 
DARA, whichever is later.
12. Male subjects must:
a.
Either practice true abstinence2 (which must be reviewed on a monthly basis) or agree 
to use a condom during sexual contact with a pregnant female or a female of 
childbearing potential while participating in the study, during dose interruptions and 
for at least 90 days following study treatment discontinuation, even if he has 
undergone a successful vasectomy. 
b. Refrain from sperm donation for at least 90 days after the final dose of DURVA or 
DARA, whichever is later.
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has had prior exposure to anti-CTLA-4, anti-PD-1, anti-PD-L1 mAbs, cell-based 
therapies (eg, CAR-T cells), or cancer vaccines
2. Subject received DARA or other CD38 antibodies therapies previously
3. Subject received any of the following within the last 14 days of initiating study treatment:
a.
Plasmapheresis
b. Major surgery (as defined by the investigator)
c.
Radiation therapy other than local therapy for myeloma associated bone lesions
d. Use of any systemic anti-myeloma drug therapy
                                               
1 A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not 
undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea 
following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had 
menses at any time in the preceding 24 consecutive months)].
2 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
35
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
4. Subject received prior treatment with a monoclonal antibody within 5 half-lives of 
initiating study treatment
5. Subject used any investigational agents within 28 days or 5 half-lives (whichever is 
longer) of initiating study treatment
6. Subject is receiving concurrent chemotherapy or biologic or hormonal therapy for cancer 
treatment. Note: Concurrent use of hormones for noncancer-related conditions (eg, 
insulin for diabetes and hormone replacement therapy) is acceptable.
7. History of organ or allogeneic stem cell transplantation
8. Subject has received autologous stem cell transplantation (ASCT) within 12 weeks before 
the date of randomization.
9. Subject has any of the following laboratory abnormalities:
a.
Absolute neutrophil count (ANC) < 1,000/µL
b. Platelet count: < 75,000/µL (it is not permissible to transfuse a subject to reach this 
level)
c.
Hemoglobin < 8 g/dL (< 4.9 mmol/L)(it is not permissible to transfuse a subject to 
reach this level)
d. Creatinine Clearance (CrCl) < 45 mL/min
e.
Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
f.
Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × 
upper limit of normal (ULN)
g. Serum total bilirubin > 1.5 × upper limit of normal (ULN) or > 3.0 mg/dL for subjects 
with documented Gilbert’s syndrome 
10. Subject has clinical evidence of central nervous system (CNS) or pulmonary leukostasis, 
disseminated intravascular coagulation, or CNS MM
11. Subject has known chronic obstructive pulmonary disease (COPD) with a forced 
expiratory volume in 1 second (FEV1) 50% of predicted normal. Note that FEV1 testing 
is required for subjects suspected of having COPD and subjects must be excluded if 
FEV1 is < 50% of predicted normal. 
12. Subject has known moderate or severe persistent asthma within the past 2 years (see 
Appendix F) or uncontrolled asthma of any classification. Note that subjects who 
currently have controlled intermittent asthma or controlled mild persistent asthma are 
allowed to participate in the study.
13. Subject has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome 
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), 
or amyloidosis
14. Subject has nonsecretory MM
15. Subject has known allergy or hypersensitivity to study drug formulations
16. Subject has active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis, celiac disease, 
irritable bowel disease, or other serious gastrointestinal chronic conditions associated 
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
36
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
with diarrhea; systemic lupus erythematosus; Wegener syndrome; myasthenia gravis; 
Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc) within the past 3 years 
prior to the start of treatment. The following are exceptions to this criterion: 
a.
Subjects with vitiligo or alopecia.
b. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement.
c.
Psoriasis not requiring systemic treatment.
17. Subject has history of primary immunodeficiency
18. Subject is positive for human immunodeficiency virus (HIV), chronic or active hepatitis 
B or active hepatitis A or C.
19. Subject has received live, attenuated vaccine within 30 days prior to the first dose of 
DURVA (NOTE: Subjects, if enrolled, should not receive live vaccine during the study 
and 30 days after the last dose of DURVA)
20. Subject is currently using or has used immunosuppressive medication within 14 days 
prior to the first study dose of study treatment. The following are exceptions to this 
criterion:
a.
Intranasal, inhaled, or local steroid injections (eg, intra-articular injection).
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or equivalent.
c.
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
21. Subject has any one of the following:
a.
Clinically significant abnormal electrocardiogram (ECG) finding at screening
b. Congestive heart failure (New York Heart Association Class III or IV)
c.
Myocardial infarction within 12 months prior to starting study treatment
d. Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina 
pectoris
22. Subject has 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 noninvasive 
malignancies:
a.
Basal cell carcinoma of the skin
b. Squamous cell carcinoma of the skin
c.
Carcinoma in situ of the cervix
d. Carcinoma in situ of the breast
e.
Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, 
nodes, metastasis] clinical staging system) or prostate cancer that is curative
23. Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to become 
pregnant during the participation in the study. 
24. Subject has significant medical condition, laboratory abnormality, or psychiatric illness 
that would prevent the subject from participating in the study
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
37
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
25. Subject has a condition including the presence of laboratory abnormalities, which places 
the subject at unacceptable risk if he/she were to participate in the study
26. Subject has a condition that confounds the ability to interpret data from the study
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
38
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
5.
TABLE OF EVENTS
Table 4:
Table of Events
Screening 
Period
Treatment Period
Follow-up Period
Events
-28 to -1 
C 1-2
(±3 days)
C 3-6
(±3 days)
≥ C7 
(±3
days) 
EOT (≤7 
days from 
trt discon 
decision)
28 days 
(+3) 
after 
EOT
90 days 
(+3) 
after last 
DURVA/
DARA 
dose
SPM follow-
up every 6
months (±2 
weeks) after 
90 day 
follow-up 
visit
a
D1
b
D 
2g
D
8
D 
15
D 
22
D 1
D 15
D 1
STUDY ENTRY AND GENERAL ASSESSMENTS 
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
IRT registration
X
X
-
-
-
-
-
-
-
X
-
-
-
Complete medical history
X
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease history
X
-
-
-
-
-
-
-
-
-
-
-
-
Prior disease therapies
X
-
-
-
-
-
-
-
-
-
-
-
-
Forced expiratory volume 
test (subjects with COPD)
X
-
-
-
-
-
-
-
-
-
-
-
-
Prior/concomitant 
medication evaluation
X (-28 
days from 
screening)
Continuous, until 90 days after last dose of DURVA or DARA, whichever is later
-
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
39
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
Table 4:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-up Period
Events
-28 to -1 
C 1-2
(±3 days)
C 3-6
(±3 days)
≥ C7 
(±3
days) 
EOT (≤7 
days from 
trt discon 
decision)
28 
days 
(+3) 
after 
EOT
90 days 
(+3) after 
last 
DURVA/
DARA 
dose
SPM follow-
up every 6 
months (±2 
weeks) after 
90 day 
follow-up 
visita
D 
1b
D 
2g
D
8
D 
15
D 
22
D 1
D 15
D 1
Blood Type, Rh, and IAT
-
X
-
-
-
-
-
-
-
-
-
-
-
SAFETY ASSESSMENTS
Prior/concomitant 
procedures evaluation
X (-28 
days from 
screening)
Continuous, until 90 days after last dose of DURVA or DARA, whichever is later
-
AE evaluation
Continuous starting after informed consent signature, until 90 days after last dose of DURVA or DARA, 
whichever is later
-
Monitoring for SPMs
only for subjects receiving 
POM as part of study 
treatment
-
Continuous from first dose of POM to the end of trial (once last subject completes the 90-day follow-up visit)
Physical examination 
X
X
-
-
-
-
X
-
X
X
-
-
-
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
-
Height
X
-
-
-
-
-
-
-
-
-
-
-
-
Weight
X
X
X
X
X
X
X
X
X
X
X
X
-
12-lead ECG
X
C1
-
-
-
-
C6
-
-
X
-
-
-
Hepatitis and HIV testing
X
-
-
-
-
-
-
-
-
-
-
-
-
Hematologyh
X
X
X
X
X
X
X
X
X
X
X
X
-
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
40
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
Table 4:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-up Period
Events
-28 to -1 
C 1-2
(±3 days)
C 3-6
(±3 days)
≥ C7 
(±3
days) 
EOT (≤7 
days from 
trt discon 
decision)
28 days 
(+3) 
after 
EOT
90 days 
(+3) 
after 
last 
DURVA
/DARA 
dose
SPM follow-
up every 6 
months (±2 
weeks) after 
90 day 
follow-up 
visita
D 
1b
D 
2g
D
8
D 
15
D 
22
D 1
D 15
D 1
Coagulation parameters
X
X
-
-
X
-
X
-
X
X
-
-
-
Chemistry 
X
X
X
X
X
X
X
X
X
X
X
X
-
Thyroid Function Tests
X
X
-
-
-
-
X
-
X
X
-
X
-
Renal Function (CrCl) 
X
X
X
X
X
X
X
X
X
X
X
X
-
Urinalysis
X
if clinically indicated
X
X
X
-
Pregnancy test (minimum 
sensitivity 25 mIU/mL) for 
FCBP with regular or no 
menstrual cycles
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 28 days
X
X
X
-
Pregnancy test (minimum 
sensitivity 25 mIU/mL) for 
FCBP with irregular 
menstrual cycles
-10 to -14 days and -24 hours prior to first dose 
weekly for 28 days after first dose, then every 14 days
X
14 and 
28 days 
after last 
dose
X
-
Pregnancy counseling for 
all subjects on POM as part 
of study treatment
X
X
-
-
-
-
X
-
X
X
X
X
-
Antiviral prophylaxis
-
Initiate within 1 week of starting DARA and continue for 3 months following last dose of 
DARA.
-
TE prophylaxis for all 
subjects on POM as part of 
study treatment
-
Continuous during POM treatment
-
-
-
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
41
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
Table 4:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-up Period
Events
-28 to -1 
C 1-2
(±3 days)
C 3-6
(±3 days)
≥ C7 
(±3
days) 
EOT (≤7 
days from 
trt discon 
decision)
28 days 
(+3) 
after 
EOT
90 days 
(+3) 
after 
last 
DURVA
/DARA 
dose
SPM follow-
up every 6 
months (±2 
weeks) after 
90 day 
follow-up 
visita
D 
1b
D 
2g
D
8
D 
15
D 
22
D 1
D 15
D 1
EFFICACY AND OTHER ASSESSMENTS
ECOG Performance status
X
X
-
-
-
-
X
-
X
X
-
-
-
Assessment of response 
(IMWG Uniform Response 
Criteria)
c
-
C2
-
-
-
-
X
-
X
X
-
-
-
Serum and urine protein 
electrophoresis
X
X
-
-
-
-
X
-
X
X
-
-
-
Serum and urine 
immunofixation
X
X
-
-
-
-
X
-
X
X
-
-
-
Serum free light chains 
assay
X
X
-
-
-
-
X
-
X
X
-
-
-
Quantitative serum 
immunoglobulin
X
X
-
-
-
-
X
-
X
X
-
-
-
EMP clinical assessment
X
X
-
-
-
-
X
-
X
X
-
-
-
EMP radiological 
assessment (only required if 
history of or clinical 
indication of EMPs only 
assessable radiographically)
X
Day 1 starting at C3, then every 3 cycles thereafter
-
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
42
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
Table 4:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-up Period
Events
-28 to -1 
C 1-2
(±3 days)
C 3-6
(±3 days)
≥ C7 
(±3
days) 
EOT (≤7 
days from 
trt discon 
decision)
28 days 
(+3) 
after 
EOT
90 days 
(+3) 
after 
last 
DURVA
/DARA 
dose
SPM follow-
up every 6 
months (±2 
weeks) after 
90 day 
follow-up 
visita
D 
1b
D 
2g
D
8
D 
15
D 
22
D 1
D 15
D 1
Skeletal Survey for bone 
lesions
X
(within 60 
days prior to 
first dose is 
acceptable)
Repeated during treatment if clinically indicated to confirm response or PD
-
Bone marrow aspirate 
and/or biopsy sampling for 
cytogenetics, % plasma 
cells
X 
BMA and 
BMB 
cytogenetics
, % plasma 
cells
- BMA and BMB at time of CR confirmation for % plasma cells 
-
Beta2-microglobulin
X
X
-
-
-
-
X
-
X
X
-
-
-
STUDY TREATMENT (DURVA, DARA, POM, dex)
Pre- and post-DARA 
infusion medications
d
-
X
X
X
X
X
X
X
-
-
-
-
DARA IV administration
-
X
e
Xe
Xe
Xe
Xe
Xe
Xe
-
-
-
-
DURVA IV administration
-
C1D2
C2D1
f
-
-
Xf
-
Xf
-
-
-
-
Oral POM (if applicable)
-
Days 1-21/28-day cycle
-
-
-
-
Oral/IV dex (if applicable)
-
Days 1, 8, 15, 22/28-day cycle
-
-
-
-
Study treatment (DURVA, 
DARA POM, dex) 
accountability/compliance
-
X
X
X
X
X
X
X
X
X
-
-
-
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
43
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
Table 4:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-up Period
Events
-28 to -1 
C 1-2
(±3 days)
C 3-6
(±3 days)
≥ C7 
(±3
days) 
EOT (≤7 
days from 
trt discon 
decision)
28 days 
(+3) 
after 
EOT
90 days 
(+3) 
after 
last 
DURVA
/DARA 
dose
SPM follow-
up every 6 
months (±2 
weeks) after 
90 day 
follow-up 
visita
D 
1b
D 
2g
D
8
D 
15
D 
22
D 1
D 15
D 1
Blood sample for DURVA 
PK (only for subjects in the 
D2 Simon Stage 1)
-
C2
C1
C1
C1
C1
C4,C6
-
C10, 
C14
-
-
-
-
Blood sample for DARA 
PK (only for subjects in the 
D2 Simon Stage 1)
C1
C1
C1
C1
-
-
-
X
X
X
-
AE = adverse event; BMA = bone marrow aspirate; BMB = bone marrow biopsy; C = Cycle; CrCl = creatinine clearance; dex = dexamethasone; D= Day; 
DARA = daratumumab; DURVA= durvalumab; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group;  EMP = extramedullary 
plasmacytomas; EOI = End of Infusion; EOT = End of Treatment; FCBP = female of child-bearing potential; h = hours; HIV = human immunodeficiency 
virus; IAT = Indirect Antiglobulin Test; IMWG = International Myeloma Working Group; IRT= integrated response technology; IV = intravenous; min = 
minutes; PD = progressive disease; PK = pharmacokinetics POM = pomalidomide; PR = partial response; SD =  stable disease; SPM = second primary 
malignancy; trt discon = treatment  discontinuation.
a Only required for subjects who received POM as part of study treatment
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
44
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
b On Cycle 1 Day 1 (C1D1), safety laboratory assessments must be performed locally to confirm subject continues to meet the required safety laboratory values 
prior to initiating study treatment.  However, if screening assessments were performed within 72 hours of C1D1, safety laboratory and physical examinations 
need not be repeated at C1D1.
c Per IMWG Uniform Response Criteria all response categories and progressive disease require 2 consecutive assessments.
d Preinfusion medications to be given before all daratumumab infusions (if necessary, oral preinfusion medications may be administered at the subject’s home on 
the day of the infusion, provided they are given within 3 hours prior to the infusion); postinfusion medications to be given on the first and second days 
following all daratumumab infusions. 
e Every effort should be made to keep subjects on the planned dosing schedule. However, doses given within 3 days of the scheduled dose are permitted, as long 
as the interval between doses is at least 5 days. Blood pressure is to be measured at the following time points on C1D1 and C1D8: immediately before the start 
of the infusion; at 30 minutes, 1 hour, 90 minutes, 2 hours, and 3 hours 30 minutes after the start of the infusion; at the end of the infusion; and 30 minutes and 
1 hour after the end of the infusion. For all other DARA infusions, blood pressure will be measured immediately before the infusion start and at the end of the 
infusion.
f First DURVA infusion:  blood pressure and pulse will be monitored, as follows (based on a 60-minute infusion): Prior to the beginning of the infusion 
(measured once from approximately 30 minutes before up to 0 minutes [i.e., the beginning of the infusion]); approximately 30 minutes during the infusion 
(halfway through infusion); at the end of the infusion (approximately 60 minutes ±5 minutes). If the infusion takes longer than 60 minutes, then BP and pulse 
measurements should follow the principles as described above or be taken more frequently if clinically indicated.  For DURVA infusions on C2D1 onward, a 
+24 hours window is allowed and may be implement per investigator discretion.
Subsequent DURVA infusions:  vital signs will be measured prior to the start of the infusion. Subjects should be carefully monitored and blood pressure and 
other vital signs should be measured during and post infusion as per institution standard and as clinically indicated. Any clinically significant changes in vital 
signs should be entered onto an unscheduled vital signs CRF page. 
g Only applicable on Cycle 1.
h For subjects who have POM + dex added to the D2 regimen upon PD, hematology should be monitored (centrally and/or locally) weekly for the first 8 weeks
following addition of POM regardless of the cycle at which POM is added. If these assessments are only done locally or if the local results are used in making
any treatment-related decision or AE reporting, these local results must be entered as an unscheduled visit into the eCRF.
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
45
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
6.
PROCEDURES
Any questions regarding the protocol should be directed to the Celgene Medical Monitor or 
designee.
6.1.
Screening Period
The Screening Phase begins when the ICF is signed. Screening evaluations will be performed for 
all subjects to determine study eligibility. These evaluations must be completed within 28 days 
of first dosing unless noted otherwise below. 
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
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 AE reporting must be entered as 
an unscheduled visit into the electronic case report form (eCRF). 
The following will be performed at screening as specified in Table 4, after informed consent has 
been obtained:

Interactive Response Technology (IRT) Registration

Complete medical history (all relevant medical conditions diagnosed/occurring prior 
to screening should also be included)

Demographics (age, sex, race, and if allowed by local regulations, ethnicity, and date 
of birth, will be collected in the eCRF and/or IRT system)

Prior disease history (if available the date of initial diagnosis, staging at time of 
diagnosis [Appendix D], cytogenetics at diagnosis to be collected)

Prior disease therapies (including surgery, radiation, systemic or any other therapy for 
the subject’s disease)

Prior and concomitant medication evaluation (including those taken ≤ 28 days before 
screening, except for those taken for disease)

Prior and concomitant procedures evaluation (including all procedures occurring 
≤28 days before screening)

Adverse events 

Physical examination, including assessment for potential venous thromboembolism 
events (VTEs) (can be source documented only), 

Forced expiratory volume test (subjects with chronic obstructive pulmonary disease 
[COPD])

Vital signs (including blood pressure, temperature, and heart rate)
Approved
6.0
v
Approved
1.0
v


Durvalumab (MEDI4736)
Protocol MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
46
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021

Height and weight 

12-lead ECG (performed and reviewed locally)

Hepatitis panel

HIV-1 antibody 

Hematology panel including complete blood count (CBC) with differential, including 
red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count 
(with differential), platelet count, mean corpuscular volume (MCV)

Coagulation parameters (prothrombin time/international normalized ratio, activated 
partial thromboplastin time, fibrinogen)

Chemistry panel including sodium, potassium, calcium, corrected serum calcium, 
chloride, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, 
alkaline phosphatase (ALP), bilirubin (total, direct, and indirect), AST, ALT, lactate 
dehydrogenase (LDH), magnesium, bicarbonate, lipase, gamma glutamyltransferase 
(GGT), uric acid, triglycerides, cholesterol, phosphorus and amylase.  (NOTE: Tests 
for AST, ALT, ALP, direct bilirubin, indirect bilirubin, and total bilirubin must 
be conducted and assessed concurrently)

Thyroid function tests (thyroid stimulating hormone [TSH], free T4, free T3)

Estimation of renal function will be assessed using the CrCl calculated based on the 
Cockcroft-Gault formula 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 
(local laboratory).

Urinalysis (color, appearance, specific gravity, pH, protein, glucose, ketones, blood, 
bilirubin)

Females of childbearing potential 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 to 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

Counseling about pregnancy precautions and the potential risks of fetal exposure 

Eastern Cooperative Oncology Group (ECOG) Performance Status (see Appendix C)

Efficacy assessments / tumor evaluations (see Section 6.4). 

Beta-2 microglobulin test
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6.2.
Treatment Period
The subject will begin the treatment period upon confirmation of eligibility. The subject must 
start treatment within 28 days of signing the ICF. For all visits an administrative window of ± 3 
days is permitted. Safety laboratory testing at a local laboratory may be performed up to 3 days 
before the study treatment administration day. Results of these laboratory tests must be evaluated 
before each study treatment administration. 
Treatment cycles are 28 days in duration, the treatment and schedule will be as described in 
Section 7.2. Day 2 assessments should only be performed during Cycle 1.
The following evaluations will be performed at the frequency specified in Table 4. The 
evaluations should be performed prior to dosing on the visit day, unless otherwise specified. 

Interactive Response Technology (IRT) Registration:

Subject may be randomized in the IRT up to 3 days prior to initiating study 
treatment on Cycle 1 Day 1 (C1D1)

Concomitant medications evaluation

Concomitant procedures evaluation

Adverse event (continuously)

Second primary malignancy (SPM) monitoring for subjects receiving POM as part of 
study treatment

Physical examination, including assessment for potential VTEs (can be source-
documented only) 

Vital signs

Weight 

12-lead ECG (C1D1 and C6D1 immediately after DARA infusion)

Blood Type, Rh, and IAT should be done before the first dose of daratumumab. 
Subject RBC phenotyping (standard or extended) or genotyping is an alternative 
option to the IAT test, if locally required. Either method must be completed prior to 
first daratumumab infusion. Subjects will receive a patient identification wallet card 
for the study that includes the blood profile (ABO, Rh, and IAT or phenotyping) 
determined before the first infusion of daratumumab along with information on the 
IAT interference for healthcare providers/blood banks. See Section 6.8 for additional 
details.

Hematology panel

For subjects who have POM + dex added to the D2 regimen upon PD, the weekly 
hematology assessments for the first 8 weeks following addition of POM may be 
done centrally and/or locally. If these assessments are only done locally or if the 
local results are used in making any treatment-related decision or AE reporting, 
these local results should be entered as an unscheduled visit into the eCRF.
Approved
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
Coagulation parameters 

Chemistry panel 

Thyroid function tests:

Cycles 1 to 4: TSH, free T4, free T3

Cycle 5 onward: TSH, if TSH is abnormal, then reflex testing for free T4 and free 
T3

Renal function (CrCl)

Urinalysis (only if clinically indicated)

Urine (or serum) pregnancy test for FCBP (negative results required for study 
treatment [DURVA, DARA, POM, or dex] administration)

Counseling about pregnancy precautions and the potential risks of fetal exposure for 
subjects receiving POM 

Continuous thromboembolism prophylaxis treatment for subjects receiving POM as a 
part of study treatment

ECOG Performance status 

Efficacy assessments (see Section 6.4)

Beta-2 microglobulin test on Day 1 of each cycle

Blood sampling for PK assessments (see Section 6.5)

Study treatment (durvalumab, daratumumab, POM, or dex) 
accountability/compliance.
6.2.1.
End of Treatment
An End of Treatment (EOT) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason within 7 days after the decision to permanently discontinue treatment 
has been made. 
The following evaluations will be performed as specified in Table 4.

IRT registration

Concomitant medications evaluation (monitored until 90 days after last dose of 
DURVA or DARA, whichever is later)

Concomitant procedures evaluation (monitored until 90 days after last dose of 
DURVA or DARA, whichever is later)

Adverse event evaluation (monitored until 90 days after last dose of DURVA or 
DARA, whichever is later)
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
SPM monitoring for subjects who received POM as part of study treatment
(monitored until the last subject completes the 90 day follow-up visit)

Physical examination, including assessment for potential VTEs (can be source-
documented only) 

Vital signs 

Weight

12-lead ECG

Hematology panel

Coagulation parameters 

Chemistry panel

Thyroid function tests (TSH, free T4, free T3)

Renal function (CrCl)

Urinalysis

Urine (or serum) pregnancy test for FCBP

Counseling about pregnancy precautions and the potential risks of fetal exposure for 
subjects receiving POM 

ECOG Performance Status

Efficacy assessments will be performed according to the schedule defined in the 
Table of Events and do not need to be performed specifically for the EOT visit except 
as specified in Section 6.4.

Beta-2 microglobulin test 

Blood sampling for PK assessments (see Section 6.5)

Study treatment (durvalumab, daratumumab, POM, or dex) 
accountability/compliance.
6.3.
Follow-up Period
6.3.1.
Safety Follow-up
All subjects will be followed for 90 days after the last dose of DURVA or DARA, whichever is 
later, for AEs, including adverse events of special interest (AESI), reporting, as well as serious 
adverse events (SAEs) made known to the investigator at any time thereafter that are suspected 
of being related to study treatment (DURVA, DARA, POM, or dex), as described in
Section 10.1.
Approved
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Celgene Corporation
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Subjects are to return to the study site 28 (+3) days after the EOT visit and 90 (+3) days after the 
last dose of durvalumab for safety follow-up visits procedures as specified in Table 4.

Concomitant medications evaluation (monitored until 90 days after last dose of 
DURVA or DARA, whichever is later)

Concomitant procedures evaluation (monitored until 90 days after last dose of 
DURVA or DARA, whichever is later)

Adverse event (including AESIs) evaluation (monitored until 90 days after last dose 
of DURVA or DARA, whichever is later)

SPM monitoring for subjects who received POM as part of study treatment
(monitored until the last subject completes the 90 day follow-up visit)

Vital signs

Weight

Hematology panel

Chemistry panel

Thyroid function tests (TSH, free T4, free T3)

Renal function (CrCl)

Urinalysis

Urine (or serum) pregnancy test for FCBP

Counseling about pregnancy precautions and the potential risks of fetal exposure for 
subjects receiving POM.
6.3.2.
Second Primary Malignancy Follow-up
After the 90 days post last dose of DURVA or DARA follow-up visit, all subjects who received 
POM as part of study treatment will be continue to be followed for SPMs every 6 months until 
the end of the trial (once last subject completes the 90 day post treatment follow-up visit).
6.4.
Efficacy Assessments
6.4.1.
Laboratory Assessments for Efficacy Parameters
All laboratory assessments for efficacy will be performed centrally.
If screening assessments are performed within 3 days of C1D1, efficacy laboratory assessments 
need not be repeated at C1D1:

Serum protein electrophoresis (sPEP) and urine protein electrophoresis (uPEP) tests 
(performed on 24-hour urine collection) are required at screening, on Day 1 of each 
cycle, and at the EOT Visit. 

Serum and urine immunofixation tests are required at screening, on Day 1 of each 
cycle, and at the EOT Visit.
Approved
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Celgene Corporation
Confidential and Proprietary
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
Quantitative serum immunoglobulin assessment includes IgG, IgA, and IgM for all 
subjects, and IgE or IgD only for subjects with the respective MM sub-type (IgE or 
IgD) and is required at screening, on Day 1 of each cycle, and at the EOT Visit.

Serum free light chains assay is required at screening, on Day 1 of each cycle, and at 
the EOT Visit.

Corrected serum calcium will be assessed as part of the safety serum chemistry 
assessments performed at screening, on Day 1 of each cycle, and at the EOT Visit.
6.4.2.
Bone Marrow Aspiration and/or Biopsy
A bone marrow aspirate (BMA) and biopsy (BMB) is mandatory at the following time points:

At screening, BMA and BMB for percent plasma cells, cytogenetics
 
assessments

During treatment:

BMA and BMB at the time of complete response (CR) confirmation for percent 
plasma cells 
The analysis of bone marrow for percentage of plasma cells will be performed locally. The bone 
marrow samples for cytogenetics 
 will be submitted to a central laboratory.
6.4.3.
Bone Lesion Assessment
Bone lesion assessment by x-ray (skeletal survey) or CT Scan will be performed at screening and 
when clinically indicated to confirm response or PD. The same method (x-ray or CT Scan) 
should be used throughout the study. All films will be analyzed locally by the site 
investigator/radiologist. If a bone lesion assessment by x-ray or CT Scan was performed within 
60 days prior to the start of Cycle 1, it may be used for the screening assessment.  
If assessment is done by x-ray, the following are the minimum plain radiological films required 
for the skeletal (bone) survey: 

Lateral skull 

Anteroposterior (AP) and lateral cervical spine 

AP and lateral thoracic spine 

AP and lateral lumbar spine 

Posteroanterior chest 

AP pelvis 

AP upper extremities, shoulder to elbow 
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
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. 
6.4.4.
Extramedullary Plasmacytoma Assessments 
Clinical assessment for extramedullary plasmacytoma assessments (EMPs) will be performed at 
screening, on Day 1 of every cycle, and at the EOT Visit. 
For EMPs that are only assessable radiographically (by x-ray and/or conventional [spiral] 
CT/magnetic resonance imaging [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 the EOT Visit, 
and when clinically indicated to confirm a response (≥ PR) or PD. The radiographic modality 
used at screening (eg, X-ray) will be repeated at each assessment time point throughout the 
study. All scans will be reviewed locally only.
6.4.5.
Assessment of Response
Starting from Cycle 2, response will be assessed by the investigators using the International 
Myeloma Working Group (IMWG) Uniform Response Criteria (Rajkumar, 2011) (Appendix B)
at every cycle on Day 1 and at the EOT Visit. Response must be based on the central laboratory 
data to ensure consistency across investigative sites.
NOTE: Per IMWG Uniform Response Criteria all response categories and progressive disease 
require 2 consecutive assessments except for radiographic or bone marrow assessments
6.5.
Pharmacokinetics
Serum samples will be collected to assay concentrations of DURVA and DARA.
On PK sampling days, dosing and sample collection information including dosing date, dosing 
time (24 hour clock), and actual PK blood sampling time (24 hour clock) should be accurately 
documented on the appropriate eCRF pages.
6.5.1.
Pharmacokinetics of Durvalumab
All subjects enrolled in Phase 2 Stage 1 (including subjects enrolled in the D2 safety run-in
phase) will participate in the Durvalumab PK sample collections at the following time points: 

C1D2: predose (-30 to -5 minutes prior to dose), end of infusion (EOI) (+30 minutes), 

C1D8

C1D15 

C1D22

Additional Durvalumab PK samples to be collected to match 
 
predose (-30 to -5 minutes prior to dose) on C2D1, C4D1, C6D1, C10D1, C14D1 and 
EOT.
Approved
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Celgene Corporation
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6.5.2.
Pharmacokinetics of Daratumumab
All subjects enrolled in Phase 2 Stage 1 (including subjects enrolled in the D2 safety run-in 
phase) will participate in the Daratumumab PK sample collections at the following time points: 

C1D1: predose (-30 to -5 minutes prior to dose), and EOI (+30 minutes)

C1D8: predose (-30 to -5 minutes prior to dose), and EOI (+30 minutes)

C1D15: predose (-30 to -5 minutes prior to dose), and EOI (+30 minutes)

C1D22: predose (-30 to -5 minutes prior to dose), and EOI (+30 minutes)

EOT

28 days after EOT 

90 days after last DARA or DURVA dose.
Approved
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6.8.
Blood Type, Rh and Indirect Antiglobulin Test (IAT)
Blood Type, Rh, and IAT should be done before the first dose of daratumumab. Subject RBC 
phenotyping (standard or extended) or genotyping is an alternative option to the IAT test, if 
locally required. Either method must be completed prior to first daratumumab infusion.
Daratumumab interferes with the Indirect Antiglobulin Test (IAT), which is a routine pre-
transfusion test performed to identify a patient’s antibodies to minor antigens so that suitable 
donor blood can be given for transfusion.  Daratumumab does not interfere with ABO/RhD 
typing. CD38 is expressed at very low levels on erythrocytes. Daratumumab binds to the CD38 
on erythrocytes, which results in a positive IAT (Indirect Coombs Test).  This positive result 
masks the detection of antibodies to minor antigens and may prevent or delay blood banks from 
issuing donor blood for transfusion. This effect occurs during daratumumab treatment and for up 
to 6 months after treatment ends. Subjects will receive a patient identification wallet card for the 
study that includes the blood profile (ABO, Rh, and IAT or phenotyping) determined before the 
first infusion of daratumumab along with information on the IAT interference for healthcare 
providers/blood banks. Subjects are to carry this card throughout the treatment period and for at 
least 6 months after treatment ends. Blood banks can eliminate the daratumumab interference 
with IAT by treating reagent RBCs with dithiothreitol (DTT) (Chapuy, 2015).
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
a.
Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) 
or genotypically matched units
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b. Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is 
needed emergently as per local blood bank practice.
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in daratumumab studies. For additional details, refer to the 
Daratumumab IB.
Approved
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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Products
Investigational product supply will be managed by IRT. All IP must be stored in accordance with 
the product label in a secured area to prevent unauthorized access. 
United States:
Durvalumab (MEDI4736) and Pomalidomide will be supplied by Celgene and labeled 
appropriately as investigational material. Labels will bear Celgene’s name and address, the 
protocol number, product name, dosage form and strength, medication identification kit/number, 
lot number, expiry date, dosing instructions, storage conditions, the quantity of IP contained, and 
required caution statements and/or regulatory statement as applicable. 
Daratumumab (Darzalex) and dexamethasone will not be supplied by Celgene; instead it will be 
obtained by the sites according to local clinical study agreement and in accordance with local 
guidelines. Additional information may be included on the label as needed or applicable. 
Canada:
Durvalumab (MEDI4736), Daratumumab (Darzalex), and Pomalidomide will be supplied by 
Celgene and labeled appropriately as investigational material. Labels will bear Celgene’s name 
and address, the protocol number, product name, dosage form and strength, medication 
identification kit/number, lot number, expiry date, dosing instructions, storage conditions, the 
quantity of IP contained, and required caution statements and/or regulatory statement as 
applicable. 
Dexamethasone will not be supplied by Celgene; instead it will be obtained by the sites
according to local clinical study agreement and in accordance with local guidelines. Additional 
information may be included on the label as needed or applicable.
Outside the United States and Canada: 
Durvalumab (MEDI4736), Daratumumab (Darzalex), Pomalidomide, and dexamethasone will be 
supplied by Celgene and labeled appropriately as investigational material. Labels will bear 
Celgene’s name and address, the protocol number, product name, dosage form and strength, 
medication identification kit/number, lot number, expiry date, dosing instructions, storage 
conditions, the quantity of IP contained, and required caution statements and/or regulatory 
statement as applicable. 
7.1.1.
Durvalumab (MEDI4736)
Durvalumab will be supplied by Celgene in single use vials in single count cartons. Each 10R 
vial will be supplied as a vialed liquid solution containing 500mg (nominal) of IP at a 
concentration of 50 mg/mL. Durvalumab should be stored in accordance with the product label. 
Sites to supply the following:

IV infusion bags of normal saline (0.9% [w/v] sodium chloride injection, 250 mL 
size). Saline bags must be latex-free and can be made of polypropylene, polyethylene, 
polyolefin copolymers, or polyvinyl chloride. Infusion lines should contain a 0.2-μm 
in-line filter. 
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
Since the compatibility of MEDI4736 with other IV medications and solutions, other 
than normal saline, is not known, the MEDI4736 solution should not be infused 
through an IV line in which other solutions or medications are being administered. 
For additional information on preparation and storage please refer to the pharmacy 
manual. 
7.1.2.
Daratumumab (Darzalex)
Daratumumab (Darzalex) will be supplied by Celgene (except in the US) in single use vials in 
single count cartons. Daratumumab is a colorless to pale yellow, preservative-free solution and 
will be supplied in 20mL vials (20 mg/mL) and/or 5mL vials (20 mg/mL).
For additional information on preparation and storage please refer to the pharmacy manual. 
7.1.3.
Pomalidomide (POM)
Pomalidomide will be supplied by Celgene in appropriate strengths for oral administration. 
Investigational product will contain a 21 day supply of POM. Pomalidomide should be stored in 
accordance with the product label. 
For additional information and storage, please refer to the pharmacy manual. 
7.1.4.
Dexamethasone (Dex)
For sites outside the US and Canada, Celgene will provide commercial supplies of 
Dexamethasone 2 mg and 4 mg tablets for oral administration and 20 mg for IV administration. 
Dexamethasone should be stored in accordance with the product label.  
For additional information and storage, please refer to the pharmacy manual. 
7.2.
Treatment Administration and Schedule
The first day of study treatment dosing (DARA and/or DURVA and/or POM and/or dex) is 
considered Day 1 of a cycle.
7.2.1.
Treatment Administration
On days when DARA and DURVA are dosed on the same day, the DARA infusion should be 
administered first, followed by the DURVA infusion.
On days when DARA, DURVA and POM are dosed on the same day, the DARA infusion should 
be administered first, followed by the DURVA infusion, then POM administration.
7.2.1.1.
Durvalumab (MEDI4736)
7.2.1.1.1. Durvalumab Product Dose Preparation/Administration
The IV infusion for subjects will be approximately 1 hour in duration.
For detailed information on durvalumab dose preparation and administration please refer to the 
pharmacy manual. 
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7.2.1.1.2. Monitoring During/After Durvalumab Infusion
First DURVA infusion
For the first DURVA infusion (C1D2), blood pressure and pulse will be monitored, as follows
(based on a 60-minute infusion):

Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [i.e., the beginning of the infusion])

Approximately 30 minutes during the infusion (halfway through infusion) 

At the end of the infusion (approximately 60 minutes ±5 minutes)
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the 
principles as described above or be taken more frequently if clinically indicated.
Subsequent DURVA infusions
For the subsequent DURVA infusion, vital signs will be measured prior to the start of the 
infusion. Subjects should be carefully monitored and blood pressure and other vital signs should 
be measured during and post infusion as per institution standard and as clinically indicated. Any 
clinically significant changes in vital signs should be entered onto an unscheduled vital signs 
CRF page. 
In the event of a ≤ Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and reinitiated at 
50% of the initial rate until completion of the infusion. For patients with a ≤ Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate. 
Acetaminophen/paracetamol and/or an antihistamine (eg, diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the 
investigator. If the infusion-related reaction is ≥ Grade 3 or higher in severity, study drug will be 
discontinued.
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit patients to an intensive care unit if necessary.
7.2.1.2.
Daratumumab (Darzalex)
Refer to the full prescribing information for daratumumab (Darzalex PI) and Summary of 
Product Characteristics [SmPC] for the EU.
For detailed information on DARA dose preparation and administration please refer to the 
pharmacy manual.
Guidance on preinfusion and postinfusion medications for infusion reaction prophylaxis in 
relation to DARA dosing is given in Table 6 and can be used in conjunction with site’s standard 
of care for DARA infusions.
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Table 6:
Daratumumab Preinfusion and Postinfusion Medications
Time point
Medication
Subjects NOT receiving dex as 
part of study regimen
Subjects receiving 
dex as part of 
study regimen
Preinfusion (~1 hr 
prior to every 
DARA 
administration)
Oral montelukast
(if approved and 
available)
per investigator discretion prior to 
first infusion
per investigator 
discretion prior to 
first infusion
IV corticosteroid 
methylprednisolone 100 mg or 
equivalent dose of an intermediate-
acting or long-acting corticosteroid.
Following the second infusion, the 
dose of corticosteroid may be 
reduced (methylprednisolone 60 mg 
intravenously.
not applicable
a
oral antipyretics 
acetaminophen 650 to 1000 mg
b
acetaminophen 650 
to 1000 mg
oral or IV 
antihistamine 
diphenhydramine 25 to 50 mg or 
equivalentb
diphenhydramine 25 
to 50 mg or 
equivalent
Postinfusion 
Medication 
(1st and 2nd day 
after every DARA 
administration)
oral corticosteroid
c
20 mg methylprednisolone or 
equivalent dose of a corticosteroid 
in accordance with local standards 
Not applicablea,d
a Not applicable since dexamethasone is already given as part of the study treatment see Section 7.2.2.1.1
b If necessary, oral preinfusion medications may be administered at the subject’s home on the day of the infusion, 
provided they are given within 3 hours prior to the infusion
c For subjects with a history of obstructive pulmonary disorder, consider prescribing post-infusion medications such 
as short and long-acting bronchodilators, and inhaled corticosteroids. Following the first four infusions, if the 
patient experiences no major infusion reactions, these additional inhaled post-infusion medications may be 
discontinued.
d For subjects receiving dexamethasone ≤20 mg/week (> 75 years or with dex dose reduced) and given as pre-
infusion medication, may receive low-dose methylprednisolone (≤20 mg) PO (or equivalent in accordance with 
local standards) for the prevention of delayed infusion-related reactions, as clinically indicated.
7.2.1.3.
Pomalidomide
Refer to the POM IB for details on dosing and method of administration for POM. 
7.2.1.4.
Dexamethasone
Refer to the full prescribing information and labeling for dexamethasone contained in the 
respective current PI, SmPC, or equivalent document for the specific region/country.
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7.2.2.
Treatment Schedule
7.2.2.1.
Daratumumab Plus Durvalumab Treatment Schedule
Initial dosing will begin with Cohort 1. See section 3.1 for dosing rules.

Intravenous DARA at the dose depending on the assigned cohort:  Cycles 1 to 2 on 
Days 1, 8, 15, 22, Cycle 3 to 6 on Days 1 and 15, then on Day 1 for Cycle 7 onward 
of a 28-day cycle

Cohort 1: 16 mg/kg

Cohort -1: 16 mg/kg

Intravenous DURVA at the dose depending on the assigned cohort on Day 2 of 
Cycle 1, then Day 1 of Cycle ≥ 2 of a 28-day cycle.  For all DURVA infusion after 
Cycle 1, a +1 day window is allowed (subject may either receive the DURVA 
infusion on same day as the DARA infusion or on the next day per the investigator’s 
discretion).

Cohort 1: 1500 mg

Cohort -1: 750 mg
 
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7.2.3.
Overdose
Overdose, as defined for this protocol, refers to DURVA, DARA, POM, and dex dosing only. 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of DURVA, DARA, POM, or dex assigned to a given subject, regardless of any associated 
AEs or sequelae.

For oral, any amount over the protocol-specified dose

For IV, 10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as any amount 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 eCRF. See Section 10 for the reporting of AEs associated with overdose.
7.2.4.
Dose Modifications and Interruptions
Subjects will be evaluated for AEs at each visit with the NCI CTCAE Version 4.03 or higher as a 
guide for the grading of severity.  
If the treatment has been interrupted and the next cycle is delayed beyond Day 28 of the prior 
cycle, then Day 1 of the next cycle will be defined as the first day that study treatment is 
resumed. 

If DURVA is permanently discontinued, then the subject must be permanently 
discontinued from all study treatments.

If DARA is withheld or permanently discontinued, then DURVA, POM, and dex 
dosing may be continued.

If POM dosing is withheld or permanently discontinued, then DURVA, DARA, and 
dex dosing may be continued. 

If dex dosing is withheld or permanently discontinued, then DURVA, DARA, and 
POM dosing may be continued. 
7.2.4.1.
Dose Modification Instructions for Durvalumab
Refer to Appendix E for detailed instructions for DURVA dose modifications and toxicity
management.
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7.2.4.2.
Dose Modification Instructions for Daratumumab
For dose modification instructions for DARA, refer to the full prescribing information (Darzalex 
PI).
7.2.4.3.
Dose Modification Instructions for Pomalidomide
Guidelines for POM dose interruptions and reductions are provided in Table 7 and Table 8
outlines the dose reduction steps for POM. Refer to the POM IB for additional details.
Table 7:
Dose Modification Instructions for Pomalidomide
Toxicity
Dose Modification
Neutropenia
Absolute neutrophil count (ANC) 
< 500/μL or febrile neutropenia
Interrupt pomalidomide treatment for remainder of cycle. Add 
granulocyte-colony stimulating factor (G-CSF) (at the discretion 
of the treating physician) When ANC value returns to ≥500/μL, 
resume pomalidomide at 1 dose level lower
Thrombocytopenia
Platelet count < 25,000/μL
Interrupt pomalidomide treatment for remainder of cycle.  When 
platelet count returns to ≥ 50,000/μL, resume pomalidomide at 1 
dose level lower
Grade 2-3 skin rash
Pomalidomide interruption or discontinuation should be 
considered at the physician’s discretion
Angioedema, Grade 4 rash, 
exfoliative or bullous rash
Permanently discontinue pomalidomide
For other Grade 3/4 toxicities judged 
to be related to pomalidomide
Interrupt pomalidomide treatment and restart treatment at 1 mg 
less than the previous dose when toxicity has resolved to 
≤Grade 2 at the physician’s discretion.
ANC = absolute neutrophil count; G-CSF = granulocyte-colony stimulating factor 
To initiate a new cycle of pomalidomide following a dose interruption, the neutrophil count must 
be ≥ 500/μL, the platelet count must be ≥ 50,000/μL, and nonhematologic AEs must be resolved 
or improved as outlined in Table 7. 
Table 8:
Pomalidomide Dose Reduction Steps
Dose Level
Oral pomalidomide
Dose
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 POM.
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7.2.4.4.
Dose Modification Instructions for Low-dose Dexamethasone
Guideline for low-dose dex dose interruptions and reductions are outlined in Table 9 and 
Table 10.  For the full prescribing information refer to the respective current Prescribing 
Information, SmPC, or equivalent document for the specific region/country for dex.
Table 9:
Dose Modifications 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 1 dose level if symptoms persist.
Dyspepsia ≥ Grade 3
Interrupt dose until symptoms are controlled.  Add H2 
blocker or equivalent and decrease 1 dose level when dosing 
is resumed.
Edema ≥ Grade 3
Use diuretics as needed and decrease dose by 1 dose level.
Confusion or mood alteration ≥ Grade 
2
Interrupt dose until symptoms resolve.  When dosing is 
resumed, decrease dose by one dose level.
Muscle weakness (steroid myopathy) 
≥ Grade 2
Interrupt dose until muscle weakness ≤ Grade 1.  When 
dosing is resumed, decrease dose by 1 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
Interrupt dexamethasone dosing until the adverse event 
resolves to ≤ Grade 2. Decrease by 1 dose level when 
dexamethasone dosing is resumed.
If recovery from toxicities is prolonged beyond 14 days, then the dose of dexamethasone will be 
decreased by 1 dose level when dose is restarted.
Table 10:
Low-Dose Dexamethasone Dose Reduction Steps
Dose Level
≤ 75 years old
Dose
> 75 years old
Dose 
Starting Dose
40 mg
20 mg
Dose Level -1
20 mg
12 mg
Dose Level -2 
10 mg
8 mg
Dexamethasone should be discontinued if subject is unable to tolerate the lowest dose level. No 
dose re-escalation is permitted for dexamethasone.
7.3.
Method of Treatment Assignment
Assignment of subjects will be based on current open cohorts and available slots. Slots will be 
assigned on a first come-first serve basis and will be valid for 48 hours following assignment. 
Unconfirmed eligibility following 48 hours from slot assignment may result in forfeiture and 
subsequent reassignment of the slot.
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If 
 the D2
 Arms are open, the randomization will follow a 1:1 ratio to D2
Arms.  However, subjects who do not meet the additional eligibility requirement for receiving 
POM will be enrolled into the D2 Arm even when both arms are open.
Celgene trial staff will review specific eligibility criteria for all screened subjects prior to 
randomization of subjects via the IRT.
An IRT will be used to track subject assignments to the treatment arms and dose levels.
7.4.
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.
7.5.
Investigational Product Accountability and Disposal
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for investigational product return, disposal, and/or destruction including responsibilities for the 
site versus Celgene (or designee).
7.6.
Investigational Product Compliance
Accurate recording of all study treatment administration (DURVA, DARA, POM, and dex) will 
be made in the appropriate section of the subject’s eCRF and source documents. The investigator 
or designee is responsible for accounting for all study-specific treatment (DURVA, DARA, 
POM, and dex) either administered or in their custody during the course of the study. 
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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease progression. 
Supportive care, including but not limited to anti-emetic medications, may be administered at the 
discretion of the investigator.   
See Appendix E for additional details on DURVA toxicity management.
All concomitant treatments, including blood and blood products, used from 28 days prior to first 
dose of study treatment until 90 days after last dose of DURVA or DARA, whichever is later,
must be reported on the eCRF. 
For information regarding other drugs that may interact with IP and affect its metabolism, PK, or 
excretion, please see the IBs and/or local package inserts.
8.1.
Permitted Concomitant Medications and Procedures
Subjects with myeloma-associated bone disease may receive bisphosphonate therapy prior to 
study entry, unless such therapy is contraindicated.  The use of bisphosphonates is permitted 
throughout the study.
Platelet/RBC transfusions and hematopoietic growth factors are also permitted during the study.  
However, prophylactic use of transfusions or hematopoietic growth factors to prevent a potential 
DLT should be avoided unless deemed medically necessary by the treating physician for subject 
safety.  
Concurrent use of hormones for noncancer-related conditions (eg, insulin for diabetes and 
hormone replacement therapy) is acceptable.
8.2.
Prohibited Concomitant Medications and Procedures
The following medications are considered exclusionary during the study. The sponsor must be 
notified if a subject receives any of these during the study.
1. The prophylactic use of hematopoietic growth factors or platelet/RBC transfusions will 
not be allowed during the first cycle (DLT evaluation period); however, it is permitted at 
the Investigator’s discretion after a subject completes the first cycle or within the first 
cycle if a hematological DLT has already been declared for that subject. Subjects who 
fail absolute neutrophil count, hemoglobin or platelet eligibility criteria at screening 
should not be retested for the study after being treated with growth factors or 
platelet/RBC transfusion.
2. Any investigational anticancer therapy.
3. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment. 
4. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
tumor necrosis factor alpha (TNF-α) blockers. Pre- and post-infusion medication for 
infusion reaction prophylaxis as outlined in Table 6 is permitted. Use of 
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immunosuppressive medications for the management of IP-related AEs or in subjects 
with contrast allergies is acceptable. In addition, use of inhaled, topical, intranasal 
corticosteroids or local steroid injections (eg, intra-articular injection) is permitted. 
Temporary uses of corticosteroids for concurrent illnesses (eg, food allergies, CT scan 
contrast hypersensitivity, moderate to severe infusion-related reactions, etc) are 
acceptable upon discussion and agreement with the medical monitor. 
5. Live attenuated vaccines during the study through 30 days after the last dose of 
durvalumab.
6. Herbal and natural remedies are to be avoided.
7. Strong inhibitors of CYP1A2 (eg, ciprofloxacin, enoxacin, and fluvoxamine) should be 
avoided for subjects receiving POM.
8.3.
Required Concomitant Medications and Procedures

Infusion reaction prophylaxis: Guidance on preinfusion and postinfusion 
medications for infusion reaction prophylaxis in relation to DARA dosing is detailed 
in Table 6.

Antiviral prophylaxis: All subjects must initiate antiviral prophylaxis to prevent 
herpes zoster reactivation within 1 week of starting DARA and continue for 3 months 
following last dose of DARA.

Thromboembolism prophylaxis: low-dose aspirin, low molecular weight heparin, or 
other equivalent antithrombotic or anticoagulant will be given to all subjects who 
receive POM as a part of study treatment.
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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
All analyses will use descriptive statistics. The analyses will be done by cohorts and arms. 
Subjects treated with the recommended dose in the Phase 2 portion of D2 will be combined with 
the corresponding dose cohort in the safety run-in phase as one single dose cohort for efficacy 
and safety analysis. Safety and efficacy data for subjects after addition of POM + dex following 
confirmed PD will be analyzed separately.
9.2.
Study Population Definitions
The following 5 populations will be used for analysis: 

Safety Population: all enrolled subjects who take at least 1 dose of any study 
treatment. All safety analyses will be based on this population

Dose-limiting Toxicity Evaluable Population: all subjects from the Safety Population 
who meet the minimum exposure criterion and have sufficient safety evaluations, or 
experience a DLT during the first treatment cycle.

Full Analysis Population: all subjects who are enrolled in this study.

Efficacy Evaluable (EE) Population: all enrolled subjects who take at least 1 dose of 
study treatment and who have measurable disease at baseline and at least one 
postbaseline efficacy assessment.

Pharmacokinetic Population: includes all subjects who receive at least 1 dose of study 
treatment and have at least 1 measureable plasma exposure. If any subjects are found 
to be noncompliant with respect to dosing, have incomplete data, or encounter other 
circumstances that would affect the evaluation of the PK, a decision will be made on 
a case-by-case basis as to the inclusion of his PK data in the statistical analysis.
9.3.
Sample Size and Power Considerations
Sample size for D2 arm is calculated based on Simon's 2-stage design (Simon, 1989). The null 
hypothesis that the true overall response rate (ORR) is < 30% will be tested against a one-sided 
alternative. In the first stage, 32 subjects will be accrued. If there are 11 or fewer responses in 
these 32 subjects (11/32 = 34.4%), the study will be stopped. Otherwise, 68 additional subjects 
will be accrued to a total of 100. The null hypothesis will be rejected if 39 or more responses are 
observed in 100 subjects (39/100 = 39%). This design yields a Type I error rate of 0.05 and 
power of 80% when the true overall response rate is 45%.
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Number of observed responses in 32 subjects
80% Confidence Interval
10/32
31.3% (20.4%, 44.0%)
11/32
34.4% (23.1%, 47.2%)
12/32
37.5% (25.9%, 50.4%)
13/32
40.6% (28.7%, 53.5%)
14/32
43.8% 31.6%, 56.6%)
15/32
46.9% (34.6%, 59.6%)
16/32
50.0% (37.4%, 62.6%)
17/32
53.1% (40.4%, 65.5%)
18/32
56.3% (43.4%, 68.4%)
19/32
59.4% (46.5%, 71.3%)
20/32
62.5% (49.6%, 74.1%)
9.4.
Background and Demographic Characteristics
Summaries for the demographics and baseline characteristics will be carried out for each dose 
cohort and overall for the full analysis population. Age, height, weight, and other continuous 
baseline disease characteristics will be summarized using descriptive statistics, while gender, 
race, and other categorical variables will be provided using frequency tabulations. 
9.5.
Medical History
Medical history data will be summarized for full analysis population using frequency tabulations 
by the Medical Dictionary for Regulatory Activities (MedDRA) Version 18 or higher system 
organ class and preferred term.
9.6.
Concomitant Medications and Procedures
All concomitant medications and procedures documented during the study will be summarized 
for full analysis population using frequency tabulations. The Anatomical Therapeutic Chemical 
(ATC) coding scheme of the World Health Organization (WHO) will be used to group 
medications into relevant categories for these tabulations.
9.7.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized for full analysis population using frequency and 
percent by treatment arm and dose cohort and follow-up phases. A summary of subjects enrolled 
by site will be provided. Protocol deviations will be summarized using frequency tabulations.
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9.8.
Efficacy Analysis
9.8.1.
Response (International Myeloma Working Group Criteria)
Tumor response, including PD, will be assessed by the investigators using the International 
Myeloma Working Group Criteria (IMWG) criteria. 
The ORR will be calculated as the percent of responders (count of subjects with at least a PR, 
divided by the number of subjects in the EE Population). The ORR together with the proportions 
in each response category based on the IMWG criteria (ie, CR, Very Good Partial Response 
[VGPR], PR, Stable Disease [SD], and Progressive Disease [PD]) will be tabulated by dose 
cohort and arm. A 95% confidence interval of the ORR of D2 for all subjects treated with the 
RP2D
.
All response related analysis will be carried out for the efficacy evaluable population
9.8.2.
Time-to-Response
Time-to-response (for responders only, per IMWG criteria) is calculated as the time from the 
first date of dosing of study treatment to the first date of documented response (PR or better).
Time-to-response will be summarized using descriptive statistics or listed by dose cohort and 
arm.
9.8.3.
Duration of Response
Duration of response (for responders only, per IMWG criteria) is defined as time from the 
earliest date of documented response (PR or better) to the earliest date when disease progression 
was confirmed.  Duration of response will be summarized using Kaplan Meier statistics as 
appropriate or listed by dose cohort and arm.
9.8.4.
Progression-free survival (PFS)
Progression-free survival will be calculated as the time between the enrollment and PD, as 
determined by the investigator using the IMWG criteria, or death, whichever occurred earlier. 
Subjects who do not have a PFS event will be censored on the last adequate response assessment 
date. Progression-free survival will be summarized for full analysis population using Kaplan-
Meier statistics as appropriate or listed by dose cohort and arm.
9.9.
Safety Analysis
All safety analyses will be conducted using the Safety Population. All analyses will be presented 
by dose cohort and arm. 
Adverse events will be coded according to the MedDRA Version 18 or higher.  The intensity of 
AEs will be graded according to the NCI CTCAE Version 4.03 or higher.
Treatment-emergent AEs are defined as AE occurring or worsening on or after the first treatment 
of the study treatment and within 90 days after last dose of durvalumab. Treatment-emergent 
AEs, AEs leading to study treatment discontinuation, AEs leading to dose reduction/interruption, 
AEs related to study treatment, SAEs, and AEs leading to death will be summarized by system 
organ class, and preferred term for each treatment arm and dose cohort. A summary of AEs with 
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NCI CTCAE Grade 3 or higher, as well as the most frequent preferred terms, and AESIs 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. Deaths within 90 days after the last dose of 
durvalumab will be summarized separately. 
Clinical laboratory values will be graded according to NCI CTCAE Version 4.03 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.
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”. Shifts from baseline to worst during the treatment in the overall ECG interpretation 
will be displayed in cross–tabulations.
The number of subjects who develop anti-drug antibody against durvalumab and/or 
daratumumab will be summarized.
Graphical displays will be provided where useful to assist in the interpretation of results.
9.10.
Interim Analysis
The Phase 2 portion of this study uses the Simon's 2-stage design (Simon, 1989). Once the RP2D 
is confirmed after the safety run-in portion, a cohort of 32 subjects (including subject enrolled in 
the safety run-in portion) will be enrolled at the RP2D to determine the safety and preliminary 
efficacy of D2. If there are 11 or fewer responses in these 32 subjects (11/32=34.4%), the study 
will be stopped. Otherwise, 68 additional subjects will be accrued for a total of 100. 
9.11.
Other Topics
9.11.1.
Pharmacokinetic Analysis
Noncompartmental PK parameters such as Tmax, Cmax, and AUC will be estimated from the 
serum DURVA and DARA concentration-time profiles. All concentration data and PK 
parameters will be summarized for PK population descriptively. The relationship between 
exposure and response (eg, toxicity 
) may be explored if appropriate.
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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An 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 in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a 
preexisting condition) should be considered an AE. A diagnosis or syndrome should be recorded 
on the AE page of the case report form (CRF) rather than the individual signs or symptoms of the 
diagnosis or syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF (See Section 7.2 for the definition of overdose). Any sequela of an 
accidental or intentional overdose of an investigational product should be reported as an AE on 
the AE CRF. If the sequela of an overdose is an SAE, then the sequela must be reported on an 
SAE report form and on the AE CRF. The overdose resulting in the SAE should be identified as 
the cause of the event on the SAE report form and CRF but should not be reported as an SAE 
itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for DURVA, DARA, 
POM or dex overdose. Actual treatment should depend on the severity of the clinical situation 
and the judgment and experience of the treating physician.
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 
until 90 days after the last dose of DURVA or DARA, whichever is later, as well as those SAEs 
made known to the Investigator at any time thereafter that are suspected of being related to study 
IPs (durvalumab, daratumumab, POM, dex). Adverse events and SAEs will be recorded on the 
AE page of the CRF and in the subject’s source documents. All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form. 
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs as to: 
10.2.1.
Seriousness
An SAE is any AE occurring at any dose that:

Results in death;
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
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);

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.
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 start of treatment on study); must be 
documented in the source document and the CRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 

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 CRF and the SAE Report Form 
must be completed.
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For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/ intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, 
Version 4.03 or higher); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
Adverse events that are not defined in the CTCAE should be evaluated for severity/intensity 
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

Grade4 =Life-threatening– extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable

Grade5 =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.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IPs (DARA, 
DURVA, POM, dex) and the occurrence of an AE/SAE as Not Suspected or Suspected as 
defined below:
Not suspected:
A causal relationship of the adverse event to IPs (daratumumab, 
durvalumab, POM, dex) administration is unlikely or remote, 
or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed 
event.
Suspected:
There is a reasonable possibility that the administration of IPs 
(daratumumab, durvalumab, POM, dex) caused the adverse 
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event. ‘Reasonable possibility’ means there is evidence to 
suggest a causal relationship between the IP 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 IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with IPs (daratumumab, durvalumab, POM, dex) as 
a result of an AE or SAE, as applicable (eg, discontinuation, interruption, or dose reduction of 
IPs, as appropriate) and report if concomitant and/or additional treatments were given for the 
event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
aresults in discontinuation from the study; or

requires treatment, modification/ interruption of IPs (daratumumab, durvalumab, 
POM, dex) dose, or any other therapeutic intervention; or

is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
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 
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).
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10.4.
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. 
The exposure of any pregnant female (eg, caregiver, pharmacist, study coordinator or monitor) to 
POM is also an immediately reportable event.
10.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated β-subunit of human chorionic 
gonadotropin [β-hCG] or positive pregnancy test in a female subject of childbearing potential 
regardless of disease state) occurring while the subject is on study treatment, or within 90 days 
after last dose of DURVA / DARA or 28 days after last dose of POM whichever occurs later are 
considered immediately reportable events. Investigational product is to be discontinued 
immediately and the subject instructed to return any unused portion the Investigator. The 
pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug 
Safety immediately by email, phone or 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 IPs (DARA, DURVA, POM, or dex) 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.
10.4.2.
Male Subjects
If a female partner of a male subject taking IPs (DARA, DURVA, POM, or dex) becomes 
pregnant, the male subject taking IPs (DARA, DURVA, POM, or dex) should notify the 
Investigator, and the pregnant female partner should be advised to call their healthcare provider 
immediately.
10.5.
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 
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Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg, via email), using the SAE Report Form, or approved equivalent 
form. This instruction pertains to initial SAE reports as well as any follow-up reports.
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 IPs [DARA, DURVA, POM, or 
dex]) that occur during the study (from the time the subject signs informed consent until 90 days 
after the last dose of DURVA or DARA, whichever is later) or any SAE made known to the 
Investigator at anytime thereafter that are suspected of being related to IPs (DARA, DURVA, 
POM, or dex). Serious adverse events 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 Institutional 
Review Board/Ethics Committee (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.
10.5.1.
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.
10.6.
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 DURVA, DARA and POM, based on the IB.
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 
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 (dexamethasone) based on the 
EU SmPC. Events of 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.
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Celgene or its authorized representative shall notify the Investigator of the following 
information: 

Any AE suspected of being related to the use of IPs (DARA, DURVA, POM, or dex) 
in this study or in other studies that is both serious and unexpected (ie, suspected 
unexpected serious adverse reaction [SUSAR]);

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
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 14.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
10.7.
Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of durvalumab (MEDI4736) and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of durvalumab.
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-mediated adverse event (imAE) is defined as an adverse event 
that is associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate etiology. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an imAE diagnosis. Appropriate efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of 
the imAE.
If the Investigator has any questions in regards to an adverse event (AE) being an imAE, the 
Investigator should promptly contact the Medical Monitor.
Further information on these AESIs (eg, presenting symptoms) can be found in the current 
version of the durvalumab Investigator Brochure (Section 5.5.2 Summary of Risks). 
10.7.1.
Second Primary Malignancies
Second primary malignancies (SPMs) will be monitored as events of interest and must be 
reported as SAEs for subjects receiving POM (see Section 10.5). This includes any second 
primary malignancy, regardless of causal relationship to study treatment (DARA, DURVA, 
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POM, or dex), occurring at any time for the duration of the study, from the time of signing the 
ICF until the until the end of the trial (once the last subject completes the 90 day post treatment 
follow-up visit), as well as, those SPMs made known to the investigator at any time thereafter 
that are suspected of being related to study treatment (DARA, DURVA, POM, dex). Events of 
second primary malignancy are to be reported using the SAE report form and must be considered 
“Important Medical Events” if no other serious criteria apply; these events must also be 
documented in the appropriate page(s) of the CRF (ie, AE and SPM CRF) and subject’s source 
documents. Documentation on the diagnosis of the SPM must be provided at the time of 
reporting as a SAE (eg, any confirmatory histology or cytology results, x-rays, CT scans). 
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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the IP(s):

Progressive Disease

Adverse Event

Withdrawal by subject

Death

Lost to follow-up

Other (including pregnancy, to be specified on the eCRF).
The reason for discontinuation of treatment should be recorded in the eCRF and in the source 
documents.
The decision to discontinue a subject from treatment 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.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Completion of Study

Screen failure

Withdrawal by subject

Death

Lost to follow-up

Other (to be specified on the eCRF).
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This 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/contract 
research organization 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(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.
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13.
REGULATORY CONSIDERATIONS
13.1.
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 Council for
Harmonisation (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.
13.2.
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, 
including obligations of confidentiality of Celgene information. 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 
form (ICF) 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.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement. Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene. Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 
5 business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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13.3.
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 ICF 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 ICF must be revised. Study 
subjects participating in the study when the amended protocol is implemented must be 
reconsented with the revised version of the ICF. The revised ICF 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.
13.4.
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 ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
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.
Any substantial amendment to the protocol will be submitted to Competent Regulatory Authority
in each country and will not be implemented until it has been approved.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, 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.
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Investigational product 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 ICF should also be revised.
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. 
13.7.
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.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely 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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14.
DATA HANDLING AND RECORDKEEPING
14.1.
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.
14.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). 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.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. 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 ICFs 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 subinvestigators 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 or institution should take measures to prevent accidental or premature destruction of 
these documents.
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15.
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 SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study. All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting.  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. During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
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.
15.2.
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/ECs, regulatory authorities (eg, Food and Drug Administration 
[FDA], European Medicines Agency [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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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications. Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement. 
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results. At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance. This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and 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. 
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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17.
REFERENCES
Badros AZ, Kocoglu MH, Ma N, Rapoport AP, Lederer E, Philip S, et al.  A Phase II Study of 
Anti PD-1 Antibody Pembrolizumab, Pomalidomide and Dexamethasone in Patients with 
Relapsed/Refractory Multiple Myeloma (RRMM). 57th ASH Annual Meeting and Exposition; 
Orlando, FL, USA; Dec 5–8, 2015. Abstract 506.
Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Bladé J, et al. International 
Myeloma Working Group consensus approach to the treatment of multiple myeloma patients 
who are candidates for autologous stem cell transplantation. Blood. 2011;117(23):6063–73.
Chauhan D, Singh AV, Brahmandam M, Carrasco R, Bandi M, Hideshima T, et al. Functional 
interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. 
Cancer Cell. 2009;16(4):309–23.
Chapuy, C, Nicholson R, Aguad MD, Maria D. Aguad,Chapuy B, Laubach J, Richardson PG, et 
al. Resolving the daratumumab interference with blood compatibility testing. Transfusion. 2015; 
55:1545-1554
Darzalex™[Prescribing Information]. Horsham, PA: Janssen Biotech, Inc; November 2015. 
https://www.darzalex.com/shared/product/darzalex/darzalex-prescribing-information.pdf
Darzalex™ [Summary of Product Characteristics]. 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004077/huma
n_med_001979.jsp&mid=WC0b01ac058001d12
Durie BG, Salmon SE.  A clinical staging system for multiple myeloma. Correlation of measured 
myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 
1975;36(3):842-54.
Empliciti™[Prescribing Information] Princeton, NJ: Bristol-Myers Squibb Company November 
2015. http://packageinserts.bms.com/pi/pi_empliciti.pdf
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 
v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, 
France: International Agency for Research on Cancer; 2013. Available from: 
http://globocan.iarc.fr, accessed on 24Feb2016.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70
Greipp P, San Miquel J, Durie BG, Crowley JJ, Barlogie B, et al.  International staging system 
for multiple myeloma. J Clin Oncol. 2005;23(15):3412-20.
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Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, et al. SEER Cancer 
Statistics Review, 1975-2012, National Cancer Institute. Bethesda,MD,  
http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted 
to the SEER web site, April 2015.
Imnovid™ [Summary of Product Characteristics] Celgene Corporation; 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002682/WC500147717.pdf
 
Krejcik J, Casneuf T, Nijhof I, Verbist B, Bald J, Plesner T, et al. Immunomodulatory Effects 
and Adaptive Immune Response to Daratumumab in Multiple Myeloma [abstract]. Blood, 2015 
ASH Annual Meeting Abstracts. 2015;126:abstract 3037.
Laubach J, Garderet L, Mahindra A, Gahrton G, Caers J, Sezer O, et al. Management of 
relapsed multiple myeloma: recommendations of the International Myeloma Working 
Group. Leukemia (2016), 1–13. 
Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, et al. Molecular profiling of 
diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host 
inflammatory response. Blood 2005;105(5):1851-61.
NCCN Clinical Practice Guidelines in Oncology – (NCCN Guidelines®): Multiple Myeloma, 
Version 3.2016. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. 
Available from: http://www.nccn.org/Accessed on 24 Feb 2016. To view the most recent and 
complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE 
CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are 
trademarks owned by the National Comprehensive Cancer Network, Inc.
Oken, MM, Creech, RH, Tormey, DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-
55.
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Plesner T, Arkenau HT, Gimsing P Krejcik1 J, Lemech C, Minnem M, et al.  Daratumumab in 
Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and 
Refractory Multiple Myeloma: Updated Results of a Phase 1/2 Study (GEN503). 57th ASH 
Annual Meeting and Exposition; Orlando, FL, USA; Dec 5–8, 2015. Abstract 507.
Postow MA, Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol 
Educ Book. 2015:76-83. 
Pomalyst® [Prescribing Information]. Summit, NJ: Celgene Corporation; April 2015. 
http://www.pomalyst.com/wp-content/uploads/2013/08/prescribing_information.pdfRajkumar 
SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al.  Consensus 
recommendations for the uniform reporting of clinical trials: report of the International Myeloma 
Workshop Consensus Panel 1. Blood 2011;117(18):4691-5.
Ray A, Das DS, Song Y, Richardson P, Munshi NC, Chauhan D, Anderson KC. Targeting PD1–
PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer 
cells and multiple myeloma cells. Leukemia. 2015;29(6),1441–4.
San Miguel J, Mateos MV, Shah J, Ocio E, Rodriquez-Otero P, Reece D et al.  Pembrolizumab 
in Combination with Lenalidomide and Low-Dose Dexamethasone for Relapsed/Refractory 
Multiple Myeloma (RRMM): Keynote-023. 57th ASH Annual Meeting and Exposition; Orlando, 
FL, USA; Dec 5–8, 2015. Abstract 505.
Shields JD, Kourtis IC, Tomei AA, Roberts JM, Swartz MA. Induction of lymphoidlike stroma 
and immune escape by tumors that express the chemokine CCL21. Science. 
2010;328(5979):749-52.
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 
1989;10(1):1-10.
Tamura H, Ishibashi M, Yamashita T, Tanosaki S, Okuyama N, Kondo A, et al. Marrow stromal 
cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in 
multiple myeloma. Leukemia. 2013;27(2):464–72.
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18.
APPENDICES
Appendix A: Table of Abbreviations
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase 
ANC
Absolute neutrophil count
ASCT
autologous stem cell transplantation
AST
Aspartate aminotransferase
AUC
Area under the curve
β-hCG
β-subunit of human chorionic gonadotropin
BM
Bone marrow
BMA
Bone marrow aspirate
BMB
Bone marrow biopsy
BUN
Blood urea nitrogen
CBC
Complete blood count
CD
Cluster of differentiation
Cmax
Maximum plasma concentration of drug
CNS
Central nervous system
COPD
chronic obstructive pulmonary disease
CR
Complete response
CrCl
Creatinine clearance
CRF
Case report form
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4
D2
Durvalumab + daratumumab
DARA
Daratumumab
dex
Dexamethasone
DLT
Dose-limiting toxicity
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Abbreviation or 
Specialist Term
Explanation
DRT
Dose Review Team
DURVA
Durvalumab
EC
Ethics Committee
eCRF
electronic case report form
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EE
Efficacy Evaluable (population)
EEA
European Economic Area
EMA
European Medicines Agency 
EMP
Extramedullary plasmacytoma
EOI
End of infusion 
EOT
End of Treatment
EU
European Union
Fc
Fragment crystallizable 
FCBP
Female of child-bearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HIV
Human immunodeficiency virus
IAT
Indirect Antiglobulin Test
IB
Investigator’s Brochure 
ICF
Informed consent form
ICH
International Council for Harmonisation
IgA
immunoglobulin A
IgD
immunoglobulin D
IgE
immunoglobulin E
IgG
immunoglobulin G 
IgM
immunoglobulin M
IMiDs®
immunomodulatory drugs
IMWG
International Myeloma Working Group
IND
Investigational New Drug
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Abbreviation or 
Specialist Term
Explanation
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ILD
Interstitial lung disease 
imAE
Immune-mediated adverse event
IV
Intravenous
LEN
lenalidomide
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MM
Multiple myeloma
MR
Minimal response
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NK
Natural Killer
NOAEL
No observed adverse effect level
ORR
Overall response rate
PCP
Pneumocystis carinii pneumonia 
PD
Progressive disease
PD-1
Programmed cell ceath-1
pDCs
Plasmacytoid dendritic cells
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival
PI
Prescribing Information; proteasome inhibitor
PK
Pharmacokinetics
POM
Pomalidomide
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Abbreviation or 
Specialist Term
Explanation
PR
Partial response
Q4W
Every four weeks
RBC
Red blood cell count
RP2D
recommended phase 2 doses 
RRMM
Relapsed and refractory multiple myeloma
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Stable Disease
SmPC
Summary of product characteristics
SOP
Standard operating procedure
sPEP
Serum protein electrophoresis
SPM
Second primary malignancy 
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal elimination half-life
TNF
Tumor necrosis factor
Tregs
regulatory T cells
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
uPEP
Urine protein electrophoresis
US/USA
United States/United States of America
VGPR
Very Good Partial Response 
VTE
Venous thromboembolism
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Appendix B: International Myeloma Working Group Uniform Response 
Criteria
Response Category
a
Response Criteria
Stringent Complete 
Response (sCR)
CR as defined below, plus
Normal serum free light chain (FLC) ratio and
Absence of clonal plasma cells by immunohistochemistry or 2- to 4-color 
flow cytometry
Complete Response 
(CR)
Negative immunofixation of serum and urine and
Disappearance of any soft tissue plasmacytomas and
≤ 5% plasma cells in bone marrow
In patients in whom the only measurable disease is by serum FLC levels: 
CR in such patients indicates a normal FLC ratio of 0.26 to 1.65 in 
addition to CR criteria listed above. 
Very Good Partial 
Response (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
In patients in whom the only measurable disease is by serum FLC levels: 
VGPR in such patients requires a > 90% decrease in the difference 
between involved and uninvolved FLC levels.
Partial Response (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 not measurable, 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 
chain assay is also unmeasurable, a ≥ 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.
Stable Disease (SD)
Not meeting criteria for CR, VGPR, PR, or PD
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Response Category
a
Response Criteria
Progressive disease (PD)
Requires only one of the following:
Increase of 25% from lowest response value in any of the
following:

Serum M-component (absolute increase must be ≥ 0.5 g/dL), 
and/or

Urine M-component (absolute increase must be ≥ 200 mg/24 h), 
and/or
Only in patients without measurable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels (absolute 
increase must be ≥ 10 mg/dL)
Only in patients without measurable serum and urine M protein levels and 
without measurable disease by FLC levels, bone marrow plasma cell 
percentage (absolute percentage must be ≥ 10%)
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) 
that can be attributed solely to the plasma cell proliferative disorder
Additional Response Criteria
Molecular Complete 
Response
CR plus negative allele-specific oligonucleotide polymerase chain 
reaction (ASO-PCR), sensitivity 10-5
Immunophenotypic 
Complete Response 
Stringent CR plus
Absence of phenotypically aberrant plasma cells (clonal) in BM with a 
minimum of 1 million total BM cells analyzed by multiparametric flow 
cytometry (with > 4 colors)
Minimal Response (MR)
in patients with relapsed 
refractory myeloma 
adopted from the European 
Group for Blood and 
Marrow Transplantation 
(EBMT) criteria
≥ 25% but ≤ 49% reduction of serum M-protein and reduction in 24-hour 
urine M-protein by 50%-89%
In addition to the above criteria, if present at baseline, 25%-49% 
reduction in the size of soft tissue plasmacytomas is also required
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response)
a All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before 
the institution of any new therapy; CR, sCR, VGPR, PR, and SD categories also require no known evidence of 
progressive or new bone lesions if radiographic studies were performed. VGPR and CR categories require serum 
and urine studies regardless of whether disease at baseline was measurable on serum, urine, both, or neither. 
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not 
be confirmed. For PD, serum M-component increases of more than or equal to 1 g/dL are sufficient to define 
relapse if the starting M-component is ≥ 5 g/dL.
Source: Rajkumar, 2011
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Appendix C: ECOG Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
ECOG Performance Status
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 out work of a 
light or sedentary nature, e.g., light house work, 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
Source: Oken,1982
Eastern Cooperative Oncology Group, Robert Comis, MD, Group Chair.
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Appendix D: Staging Systems for Multiple Myeloma
Table 11:
Staging Systems for Multiple Myeloma
Stage
Durie-Salmon Criteria
a
International Staging System (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, 1975
b Greipp, 2005
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Appendix E: Durvalumab Treatment Modification and Toxicity Management Guidelines
Note: The toxicity management guidelines in Appendix E-1, E-2, E-3, and E-4 prepared by the sponsor are to assist the 
investigator in the exercise of his/her clinical judgment in treating these types of toxicities and should be applied to 
management of adverse events related to study treatment and not ANY adverse event.
Appendix E-1: Durvalumab Treatment Modification and Toxicity Management Guidelines for Immune-mediated Adverse 
Events
Immune-mediated Reactions
These guidelines are provided as a recommendation to support investigators in the management of potential immune-mediated adverse events 
(imAEs). 
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible immune-mediated reactions. 
Investigators are advised to take into consideration the appropriate practice guidelines and other society guidelines (e.g., NCCN, ESMO) in the management 
of these events.  Refer to the section of the table titled “Other -Immune-Mediated Reactions” for general guidance on imAEs not noted in the “Specific 
Immune-Mediated Reactions” section.
Early identification and management of immune-mediated adverse events (imAEs) are essential to ensure safe use of the study drug.  Monitor patients closely 
for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse events. Patients with suspected imAEs  should be 
thoroughly evaluated to rule out any alternative etiologies (e.g., disease progression, concomitant medications, infections). In the absence of a clear alternative 
etiology, all such events should be managed as if they were immune-mediated.  Institute medical management promptly, including specialty consultation as 
appropriate. In general, withhold study drug/study regimen for severe (Grade 3) imAEs. Permanently discontinue study drug/study regimen for life-
threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid 
dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. 
Based on the severity of the imAE, durvalumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid should 
be tapered over ≥ 28 days.  More potent immunosuppressive agents such as TNF inhibitors (e.g., infliximab) should be considered for events not responding 
to systemic steroids. Alternative immunosuppressive agents not listed in this guideline may be considered at the discretion of the investigator based on clinical 
practice and relevant guidelines. With long-term steroid and other immunosuppressive use, consider need for Pneumocystis jirovecii pneumonia (PJP, 
formerly known as Pneumocystis carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose monitoring.
Dose modifications of study drug/study regimen should be based on severity of treatment-emergent toxicities graded per NCI CTCAE version in the 
applicable study protocol.
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; 
NCI National Cancer Institute; NCCN  National Comprehensive Cancer Network; ESMO European Society for Medical Oncology
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Immune-mediated Reactions
Pneumonitis/ 
Interstitial Lung 
Disease (ILD)
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade:
-
Monitor subjects for signs and symptoms of 
pneumonitis or ILD (new onset or worsening 
shortness of breath or cough).  Patients should be 
evaluated with imaging and pulmonary function 
tests including other diagnostic procedures as 
described below
-
Suspected pneumonitis should be confirmed with 
radiographic imaging and other infectious and 
disease-related aetiologies excluded, and 
managed as described below.
-
Initial work-up may include clinical evaluation, 
monitoring of oxygenation via pulse oximetry 
(resting and exertion), laboratory work-up and 
high-resolution CT scan. 
-
Consider Pulmonary and Infectious Diseases 
consults.
Grade 1 
No dose modification required. However, 
consider holding study drug/study regimen 
dosing as clinically appropriate and during 
diagnostic work-up for other etiologies
For Grade 1 
-
Monitor and closely follow up in 2-4 days for 
clinical symptoms, pulse oximetry (resting and 
exertion) and laboratory work-up and then as 
clinically indicated
Grade 2 
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1
•
If toxicity worsens then treat as Grade 3 
or Grade 4 
•
If toxicity improves to ≤Grade 1, then the 
decision to reinitiate study drug/regimen 
will be based upon treating physician’s 
clinical judgment and after completion of 
For Grade 2 
-
Monitor symptoms daily and consider 
hospitalization
-
Promptly start systemic steroids (e.g., prednisone 
1-2mg/kg/day PO or IV equivalent)
-
Reimaging as clinically indicated consider chess 
CT with contrast and repeat in 3-4 weeks
-
If no improvement within 2 to 3 days, additional 
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steroid taper. 
workup should be considered and prompt 
treatment with IV methylprednisolone 2-
4mg/kg/day started 
-
If no improvement within 2 to 3 days despite IV 
methylprednisolone at 2-4/g/kg/day, promptly 
start immunosuppressive therapy such as TNF 
inhibitors (e.g. infliximab at 5mg/kg IV once, 
may be repeated at 2 and 6 weeks after initial 
dose at the discretion of the treating provider). 
Caution: Important to rule out sepsis and refer to 
infliximab label for general guidance before using 
infliximab 
-
Consider as necessary discussing with study 
physician
Grade 3 or 4 
Permanently discontinue study drug/study 
regimen
For Grade 3 or 4 
-
Promptly initiate empiric IV methylprednisolone 
1 to 4 mg/kg/day or equivalent
-
Obtain Pulmonary and Infectious Disease 
Consults; consider discussing with study 
physician, as needed.
-
Hospitalize the patient
-
Supportive Care (e.g., oxygen, etc.)
-
If no improvement within 2 to 3 days, additional 
workup should be considered and prompt 
treatment with additional immunosuppressive 
therapy such as TNF inhibitors (e.g. infliximab at 
5mg/kg IV once, may be repeated at 2 and 6 
weeks after initial dose at the discretion of the 
treating provider ) started. Caution: rule out 
sepsis and refer to infliximab label for general 
guidance before using infliximab 
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Immune-mediated Reactions
Diarrhea/Colitis  
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade:
-
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, 
or changes in bowel habits such as increased 
frequency over baseline or blood in stool) or 
related to bowel perforation (such as sepsis, 
peritoneal signs and ileus)
-
When symptoms or evaluation indicate a 
perforation is suspected, consult a surgeon
experienced in abdominal surgery immediately 
without any delay
-
PERMANENTLY DISCONTINUE STUDY 
DRUG FOR ANY GRADE OF INTESTINAL 
PERFORATION 
-
Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression, other medications, infections 
including testing for clostridium difficile toxin, 
etc.)
-
Steroids should be considered in the absence of 
clear alternative etiology, even for low grade 
events, in order to prevent potential progression 
to higher grade event, including intestinal 
perforation
-
Use analgesics carefully; they can mask 
symptoms of perforation and peritonitis
Grade 1 
No dose modification
For Grade 1: 
-
Close monitoring for worsening symptoms
-
Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
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Immune-mediated Reactions
colitis diet),  loperamide, and other supportive 
care measures. 
-
If symptoms persist, consider checking 
lactoferrin; if positive, treat as Grade 2 below. If 
negative and no infection, continue Grade 1 
management.
Grade 2
Hold study drug/study regimen until 
resolution to ≤ Grade 1
•
If toxicity worsens then treat as Grade 3 
or Grade 4
•
If toxicity improves to ≤Grade 1, then 
study drug/study regimen can be 
resumed after completion of steroid 
taper   
For Grade 2: 
-
Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
colitis diet), and loperamide and/or budesonide 
-
Promptly start prednisone 1 to 2 mg/kg/day PO or 
IV equivalent 
-
If event is not responsive within 2 to 3 days or 
worsens despite prednisone at 1-2 mg/kg/day PO 
or IV equivalent, consult a GI specialist for 
consideration of further workup, such as imaging 
and/or colonoscopy to confirm colitis and rule out 
perforation. 
-
If still no improvement within 2 to 3 days despite 
1 to 2mg/kg IV methylprednisolone, promptly 
start immunosuppressive agents, such as 
infliximab at 5mg/kg IV, may be repeated at 2 
and 6 weeks after initial dose at the discretion of 
the treating provider. aCaution: Important to rule 
out bowel perforation and refer to infliximab 
label for general guidance before using infliximab  
-
Consider, as necessary, discussing with study 
physician if no resolution to ≤ Grade 1 in 3-4 
days
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Immune-mediated Reactions
Grade 3 or 4 
Grade 3

For patients treated with PDL-1 
inhibitors, hold study drug/study 
regimen until resolution to Grade 
≤1; study drug/study regimen can be 
resumed after completion of steroid 
taper. Permanently discontinue 
study drug/study regimen for Grade 
3 if toxicity does not improve to 
Grade ≤1 within 14 days.

Permanently discontinue study drug 
for 1) Grade 3 colitis in patients 
treated with CTLA-4 inhibitors or 
2) Any grade of intestinal 
perforation in any patient treated 
with ICI.  
Grade 4
Permanently discontinue 
study drug/study regimen.
For Grade 3 or 4:
-
Promptly initiate empiric IV methylprednisolone 
1 to 2  mg/kg/day or equivalent
-
Monitor stool frequency and volume and 
maintain hydration  
-
Urgent GI consult and imaging and/or 
colonoscopy as appropriate. If still no 
improvement within 2 days, promptly add further 
immunosuppressants (e.g., infliximab at 5mg/kg 
IV, may be repeated at 2 and 6 weeks after initial 
dose at the discretion of the treating provider ).  
Caution: Ensure a GI consult to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab. If 
perforation is suspected, consult a surgeon 
experienced in abdominal surgery immediately 
without any delay.
-
If perforation is suspected, consult a surgeon 
experienced in abdominal surgery immediately 
without any delay.
Hepatitis (Elevated 
LFTs)
Any Grade
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade
-
Monitor and evaluate liver function test: AST, 
ALT, ALP and total bilirubin 
-
Evaluate for alternative etiologies (e.g., viral 
hepatitis, disease progression, concomitant 
medications) 
Grade 1
-
No dose modification. If it worsens, 
For Grade 1: 
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Immune-mediated Reactions
Infliximab should not 
be used for 
management of 
Immune Related 
Hepatitis
treat as Grade 2
-     Continue LFT monitoring per protocol  
Grade 2
Hold Study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1 
•
If toxicity worsens then treat as  Grade 3 
or Grade 4.
•
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid taper.
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria (AST and/or ALT >3 × ULN + 
bilirubin >2 × ULN without initial 
findings of cholestasis (i.e., elevated 
alkaline P04) and in the absence of any 
alternative cause.b
  
For Grade 2:
-
Regular and frequent checking of LFTs (e.g.,
every 1-2 days) until LFT elevations  improve or 
resolve.  
-
If no resolution to  Grade ≤1 in 1-2 days, consider 
discussing with study physician, as needed.
-
If event is persistent (> 2-3 days) or worsens, 
promptly start prednisone 1-2mg/kg/day PO or IV 
equivalent. 
PLEASE SEE 
shaded area 
immediately 
below this section 
to find guidance 
for management 
of “Hepatitis 
(elevated LFTS)” 
in HCC patients
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Grade 3 or 4
  
For Grade 3
For elevations in transaminases ≤ 8 × ULN, 
or elevations in bilirubin ≤ 5 × ULN:
-Hold study drug/study regimen dose until 
resolution to Grade ≤1 or baseline
Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 or 
baseline  within 14 days, and after 
completion of steroid taper
Permanently discontinue study drug/study 
regimen if the elevations do not downgrade 
to ≤ Grade 1 or baseline 
For elevations in transaminases > 8 × ULN 
or elevations in bilirubin > 5 × ULN  
discontinue study drug/study regimen. 
For Grade 4:
Permanently discontinue study drug/study 
regimen.
For Grade 3 or 4:
-
Promptly initiate empiric IV methylprednisolone 
at 1 to 2 mg/kg/day or equivalent 
-
If still no improvement within 2 to 3 days despite 
1 to 2 mg/kg/day methylprednisolone IV or 
equivalent, promptly start treatment with an 
immunosuppressant therapy (i.e., mycophenolate 
mofetil 0.5 – 1 g every 12 hours then taper in 
consultation with hepatology consult).  Discuss 
with study physician if mycophenolate is not 
available. Infliximab should NOT be used.
-
Perform Hepatology Consult, abdominal workup, 
and imaging as appropriate.
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Immune-mediated Reactions
Hepatitis 
(elevated LFTs)
Infliximab should not 
be used for 
management of 
immune-related 
hepatitis.
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation
Any elevations in 
AST, ALT, or TB 
as described below
General Guidance
For Any Elevations Described:
−
Monitor and evaluate liver function test: AST, 
ALT, ALP, and TB.
−
Evaluate for alternative etiologies (e.g., viral 
hepatitis, disease progression, concomitant 
medications, worsening of liver cirrhosis [e.g., 
portal vein thrombosis]).
−
For HBV+ subjects: evaluate quantitative HBV 
viral load, quantitative HBsAg, or HBeAg
−
For HCV+ subjects: evaluate quantitative HCV 
viral load
−
Consider consulting Hepatologiy or Infectious 
Diseases specialists regarding changing or 
starting antiviral HBV if HBV viral load is >2000 
IU/ml
−
Consider consulting Hepatology or Infectious 
Diseases specialists regarding changing or 
starting antiviral HCV medications if HCV viral 
load has increased by ≥2-fold
−
For HCV+ with HBcAb+: Evaluate for both HBV 
and HCV as above
Isolated AST or 
ALT >ULN and 
≤5.0×ULN, whether 
normal or elevated at 
baseline)

No dose modifications.

If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat as 
described for elevations in the row below.

For all transaminase elevations, see 
instructions at bottom of shaded area if 
transaminase rise is not isolated but (at 
any time) occurs in setting of either 
THIS shaded area 
is guidance only for
management of 
“Hepatitis (elevated 
LFTs)” in 
hepatocellular 
carcinoma (HCC)
subjects
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Immune-mediated Reactions
increasing bilirubin or signs of 
DILI/liver decompensation
(Isolated AST or 
ALT >5.0×ULN and 
≤8.0×ULN, if 
normal at baseline)
(Isolated AST or 
ALT >2.0×baseline 
and ≤12.5×ULN, if 
elevated >ULN at 
baseline)

Hold study drug/study regimen dose until 
resolution to AST or ALT ≤5.0×ULN.

If toxicity worsens, then treat as 
described for elevations in the rows 
below.
If toxicity improves to AST or ALT 
≤5.0×ULN, resume study drug/study regimen 
after completion of steroid taper.
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria, in the absence of any alternative 
cause.b
−
Regular and frequent checking of LFTs (e.g., 
every 1 to 3 days) until elevations of these are 
improving or resolved.
−
Recommend consult hepatologist; consider 
abdominal ultrasound, including Doppler 
assessment of liver perfusion.
−
Consider, as necessary, discussing with study 
physician.
−
If event is persistent (>2-3 days) or worsens, and 
investigator suspects toxicity to be an AE, start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent.
−
If still no improvement within 2 to 3 days despite 
1 to 2 mg/kg/day of prednisone PO or IV 
equivalent, consider additional workup.
−
If still no improvement within 2 to 3 days despite 
1 to 2 mg/kg/day of IV methylprednisolone, 
consider additional abdominal workup (including 
liver biopsy) and imaging (i.e., liver ultrasound), 
and consider starting immunosuppressant agents 
(i.e., mycophenolate mofetil 0.5 – 1 g every 12 
hours then taper in consultation with hepatology 
consult).a Discuss with study physician if 
mycophenolate mofetil is not available. 
Infliximab should NOT be used.
Isolated AST or 
ALT >8.0×ULN and 
≤20.0×ULN, if 
normal at baseline)

Hold study drug/study regimen dose until 
resolution to AST or ALT ≤5.0×ULN

Resume study drug/study regimen if 
elevations downgrade to AST or ALT 
≤5.0×ULN within 14 days and after 
−
Regular and frequent checking of LFTs (e.g., 
every 1-2 days) until elevations of these are 
improving or resolved.
−
Consult hepatologist (unless investigator is 
hepatologist); obtain abdominal ultrasound, 
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Immune-mediated Reactions
(Isolated AST or 
ALT >12.5×ULN 
and ≤20.0×ULN, if 
elevated >ULN at 
baseline)
completion of steroid taper.

Permanently discontinue study 
drug/study regimen if the elevations do 
not downgrade to AST or ALT 
≤5.0×ULN within 14 days
including Doppler assessment of liver perfusion; 
and consider liver biopsy.
−
Consider discussing with study physician, as 
needed.
−
If investigator suspects toxicity to be immune-
mediated, promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day or 
equivalent.
−
If no improvement within 2 to 3 days despite 1 to 
2 mg/kg/day methylprednisolone IV or 
equivalent, obtain liver biopsy (if it has not been 
done already) and promptly start treatment with 
an immunosuppressive therapy (mycophenolate 
mofetil 0.5 – 1 g every 12 hours then taper in 
consultation with hepatologist). Discuss with study 
physician if mycophenolate is not available. 
Infliximab should NOT be used.
Isolated AST or 
ALT >20×ULN, 
whether normal or 
elevated at baseline

Permanently discontinue study 
drug/study regimen.
Same as above 
(except would recommend obtaining liver biopsy early)
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 
2×baseline, if >ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR):
-
Manage dosing for each level of transaminase rise as instructed for the next highest level of transaminase rise
-
For example manage dosing for second level of transaminase rise (i.e., AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT 
>2.0×baseline and ≤12.5×ULN, if elevated >ULN at baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0×ULN and 
≤20.0×ULN, if normal at baseline, or AST or ALT >12.5×ULN and ≤20.0×ULN, if  elevated >ULN at baseline)
-
For the third and fourth level of transaminase rises, permanently discontinue study drug/study regimen
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Immune-mediated Reactions
Nephritis or Renal 
Dysfunction (elevated 
serum creatinine) 
Any Grade
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade:
-
Consult a Nephrologist
-
Monitor for signs and symptoms that may be 
related to changes in renal function (e.g., routine 
urinalysis, elevated serum BUN and creatinine, 
decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, proteinuria, 
etc.) 
-
Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression, infections, recent IV contrast, 
medications, fluid status)
-
Consider using steroids in the absence of a clear 
alternative etiology even for low grade events 
(Grade 2), in order to prevent potential 
progression to higher grade events
Grade 1
No dose modification
For Grade 1: 
-      Monitor serum creatinine weekly and any 
accompanying symptom

If creatinine returns to baseline, resume 
its regular monitoring per study 
protocol.

If it worsens, depending on the severity, 
treat as Grade 2 or Grade 3 or 4 
-      Consider symptomatic treatment including 
hydration, electrolyte replacement, diuretics, etc.
Grade 2 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline
•
If toxicity worsens then treat as Grade 3 
or Grade 4
For Grade 2: 
-
Consider symptomatic treatment including 
hydration, electrolyte replacement, diuretics, etc. 
-
Carefully monitor serum creatinine every 2-3 
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Immune-mediated Reactions
•
If toxicity improves to ≤Grade 1 or 
baseline then resume study drug/study 
regimen after completion of steroid 
taper
days and as clinically warranted.
-
Consult Nephrologist and consider renal biopsy if 
clinically indicated.
-
If event is persistent beyond  3-5 days or worsens, 
promptly start prednisone 1 to 2 mg/kg/day PO or 
IV equivalent. 
-
If event is not responsive within 3-5 days or 
worsens despite prednisone at 1-2 mg/kg/day PO 
or IV equivalent, consider additional workup.   
-
When event returns to baseline, resume study 
drug/study regimen and routine serum creatinine 
monitoring per study protocol.
Grade 3 or 4 
Permanently discontinue study drug/study 
regimen
For Grade 3 or 4:
-
Carefully monitor serum creatinine on daily basis
-
Consult Nephrologist and consider renal biopsy if 
clinically indicated
-
Promptly start prednisone 1 to 2 mg/kg/day PO or 
IV equivalent 
-
If event is not responsive within 3-5 days or 
worsens despite prednisone at 1-2 mg/kg/day PO 
or IV equivalent, consider additional workup and 
prompt treatment with an immunosuppressant in 
consultation with a nephrologist 
Rash or Dermatitis 
(including Pemphigoid)
Any grade
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for 
definition of 
severity/grade 
depending on type of 
General Guidance
For any grade:
−
Monitor for signs and symptoms of dermatitis 
(rash and pruritus)
−
HOLD STUDY DRUG IF STEVENS-
JOHNSON SYNDROME (SJS), TOXIC 
EPIDERMAL NECROLYSIS (TEN),  OR 
OTHER  SEVERE CUTANEOUS ADVERSE 
REACTION (SCAR) IS SUSPECTED
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Immune-mediated Reactions
skin rash) 
−
PERMANENTLY DISCONTINUE STUDY 
DRUG IF SJS, TEN, OR SCAR IS 
CONFIRMED
Grade 1 
No dose modification
For Grade 1:
-
Consider symptomatic treatment including oral 
antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy (e.g., emollient, 
lotion, or institutional standard)
Grade 2
For persistent (> 1 week) Grade 2 events, 
hold scheduled study drug/study 
regimen until resolution to ≤ Grade 1 or 
baseline 

If toxicity worsens then treat as 
Grade 3 

If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper
For Grade 2:
-
Obtain Dermatology consult 
-
Consider symptomatic treatment including oral 
antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy
-
Consider moderate-strength topical steroid 
-
If no improvement of rash/skin lesions occurs 
within 3 days or is worsening despite 
symptomatic treatment and/or use of moderate 
strength topical steroid, consider discussing with 
study physician, as needed, and promptly start 
systemic steroids such as prednisone 1-2 
mg/kg/day PO or IV equivalent  
-
Consider skin biopsy if the event persistent for >1 
week or recurs
Grade 3
For Grade 3:
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline.
For Grade 3 or 4:
-
Consult Dermatology 
-
Promptly initiate empiric IV methylprednisolone 
1 to 2 mg/kg/day or equivalent
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Immune-mediated Reactions

If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper.

If toxicity worsens, then treat as Grade 4.
-
Consider hospitalization
-
Monitor extent of rash [Rule of Nines]
-
Consider skin biopsy (preferably more than 1) as 
clinically feasible
-
Consider, as necessary, discussing with Study 
Physician
Grade 4
For Grade 4:
Permanently discontinue study drug/study 
regimen 
Endocrinopathy
(e.g., hyperthyroidism, 
thyroiditis, 
hypothyroidism, type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, 
adrenal insufficiency )
Any Grade 
(Depending on the 
type of 
endocrinopathy, 
refer to NCI CTCAE 
applicable version in 
study protocol for 
for defining the CTC 
grade/severity) 
General Guidance
For Any Grade:
-
Consider consulting an Endocrinologist for 
endocrine events
-
Consider discussing with study physician, as 
needed
-
Monitor subjects for signs and symptoms of 
endocrinopathies.  Non-specific symptoms 
include headache, fatigue, behavior changes,  
mental status changes, photophobia, visual field 
cuts, vertigo, abdominal pain, unusual bowel 
habits, polydipsia, polyuria, hypotension and 
weakness.
-
Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression including brain metastases, 
infections)
-
Depending on the suspected endocrinopathy, 
monitor and evaluate thyroid function tests: TSH, 
free T3 and free T4 and other relevant endocrine 
and related labs (e.g., blood glucose and ketone 
levels, HgA1c).
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Immune-mediated Reactions
-
If a patient experiences an AE that is thought to 
be possibly of autoimmune nature (e.g., 
thyroiditis, pancreatitis, hypophysitis, diabetes 
insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody 
testing
-
Investigators should ask subjects with 
endocrinopathies who may require prolonged or 
continued hormonal replacement, to consult their 
primary care physicians or endocrinologists about 
further monitoring and treatment after completion 
of the study 
Grade 1
No dose modification
For Grade 1
-
Monitor patient with appropriate endocrine 
function tests
-
For suspected hypophysitis/hypopituitarism, 
consider consulting  an endocrinologist to guide 
assessment of early-morning ACTH, cortisol, 
TSH and free T4; also consider gonadotropins, 
sex hormones, and prolactin levels, as well as 
cosyntropin stimulation test (though it may not be 
useful in diagnosing early secondary adrenal 
insufficiency).
-
If TSH < 0.5X LLN, or TSH >2X ULN or 
consistently out of range in 2 subsequent 
measurements, include free T4 at subsequent 
cycles as clinically indicated and consider 
consultation of an endocrinologist.
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Immune-mediated Reactions
Grade 2, 3, or 4 

For Grade 2-4 endocrinopathies 
other than hypothyroidism and type 
1 diabetes mellitus, consider 
holding study drug/study regimen 
dose until acute symptoms resolve

Study drug/study regimen can be 
resumed once the patient stabilizes 
and after completion of steroid taper

Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g., adrenal 
insufficiency) can be retreated with 
study drug/study regimen if the 
patient is clinically stable as per 
Investigator or treating physician’s 
clinical judgement 

If toxicity worsens, then treat based 
on severity
For Grade 2, 3 or 4 
-
Consult Endocrinologist to guide evaluation of 
endocrine function, and, as indicated by 
suspected endocrinopathy and as clinically 
indicated, consider pituitary scan
-
For subjects with abnormal endocrine work up, 
except for those with isolated hypothyroidism or 
type 1 diabetes mellitus (DM), and as guided by 
an endocrinologist consider short-term, 
corticosteroids (e.g., 1-2mg/kg/day 
methylprednisolone or IV equivalent) and prompt 
initiation of treatment with relevant hormone 
replacement (e.g. hydrocortisone, sex hormones). 
-
Isolated hypothyroidism may be treated with 
replacement therapy, without study drug/study 
regimen interruption, and without corticosteroids.
-
Isolated type 1 DM may be treated with 
appropriate diabetic therapy, and without 
corticosteroids. Only hold study drug/study 
regimen in setting of hyperglycemia when 
diagnostic workup is positive for diabetic 
ketoacidosis.
-
For patients with normal endocrine work up (lab 
or MRI scans), repeat labs/MRI as clinically 
indicated.
Amylase/Lipase 
increased
Any Grade
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
General Guidance
For Any Grade:
-
For modest asymptomatic elevations in serum 
amylase and lipase, corticosteroid treatment is not 
indicated as long as there are no other signs or 
symptoms of pancreatic inflammation. 
-
Assess for signs/symptoms of pancreatitis 
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grade/severity)
-
Consider appropriate diagnostic testing (e.g., 
abdominal CT with contrast, MRCP if clinical 
suspicion of pancreatitis and no radiologic 
evidence on CT)
-
If isolated elevation of enzymes without evidence 
of pancreatitis, continue immunotherapy.  
Consider other causes of elevated amylase/lipase
-
If evidence of pancreatitis, manage according to 
pancreatitis recommendations
Grade 1
No dose modification
Grade 2, 3, or 4 
For Grade 2, 3, or 4
In consultation with relevant pancreatic 
specialist consider continuing study 
drug/study regimen if no clinical/radiologic 
evidence of pancreatitis ± improvement in 
amylase/lipase.
Acute Pancreatitis
Any Grade
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade:
-
Consider Gastroenterology referral
Grade 1
No dose modification
For Grade 1: 
-      IV hydration
-      Manage as per amylase/lipase increased 
(asymptomatic)
Grade 2, 3, or 4 
For Grade 2
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
For Grade 3 or 4 
For Grade 2, 3, or 4 
-
Promptly start systemic steroids prednisone 1 to 
2 mg/kg/day PO or IV equivalent.
-
IV hydration
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Permanently discontinue study drug/study 
regimen.
Neurotoxicity
(to include but not 
limited to non-
infectious meningitis, 
non-infective 
encephalitis, and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre)  
Any Grade 
(Depending on the 
type of 
neurotoxicity, refer 
to NCI CTCAE  
applicable version in
study protocol for 
defining the CTC 
grade/severity)
General Guidance
For Any Grade:
-
Patients should be evaluated to rule out any 
alternative etiology (e.g., disease progression, 
infections, metabolic syndromes and medications) 
-
Monitor subject for general symptoms (headache, 
nausea, vertigo, behavior change, or weakness)
-
Consider appropriate diagnostic testing (e.g. 
electromyogram and nerve conduction 
investigations)
-
Perform symptomatic treatment with neurological 
consult as appropriate
-
FOR TRANSVERSE MYELITIS, 
PERMANENTLY DISCONTINUE FOR ANY 
GRADE.
Grade 1
No dose modifications
For Grade 1:
See “Any Grade” recommendations above.
Grade 2

For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to  
Grade ≤1

For sensory neuropathy/neuropathic 
pain, consider holding study 
drug/study regimen dose until 
resolution to  Grade ≤1.

Permanently discontinue study 
drug/study regimen if Grade 2 
imAE does not resolve to Grade ≤1 
within 30 days. If toxicity worsens 
For Grade 2:
-
Consider, as necessary, discussing with the study 
physician 
-
Obtain Neurology Consult 
-
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (e.g., 
gabapentin, duloxetine)
-
Promptly start systemic steroids prednisone 1-2 
mg/kg/day PO or IV equivalent 
-
If no improvement within 2 to 3 days despite 1-2 
mg/kg/day prednisone PO or IV equivalent;
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then treat as Grade 3 or Grade 4 
consider additional workup and promptly treat 
with an additional immunosuppressive therapy 
(e.g. IV IG or other immunosuppressant 
depending on the specific imAE) 
Grade 3 or 4
For Grade 3 or 4:

Permanently discontinue study 
drug/study regimen
For Grade 3 or 4:
-
Consider, as necessary, discussing with study 
physician
-
Obtain Neurology Consult
-
Consider hospitalization
-
Promptly initiate empiric IV methylprednisolone 
1 to 2 mg/kg/day or equivalent 
-
If no improvement within 2 to 3 days despite IV 
corticosteroids, consider additional workup and 
promptly treat with additional 
immunosuppressants (e.g. IV IG or other 
immunosuppressant depending on the specific 
imAE) 
-
Once stable, gradually taper steroids over ≥ 28 
days
Peripheral 
neuromotor 
syndromes
(such as Guillain-Barre 
and Myasthenia Gravis)
Any Grade
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade:
-
The prompt diagnosis of immune-mediated 
peripheral neuromotor syndromes is important, 
since certain subjects may unpredictably 
experience acute decompensations which can 
result in substantial morbidity or in the worst 
case, death. Special care should be taken for 
certain sentinel symptoms which may predict a 
more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, and 
signs of respiratory insufficiency or autonomic 
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instability
-
Subjects should be evaluated to rule out any 
alternative etiology (e.g., disease progression, 
infections, metabolic syndromes and medications, 
etc.). It should be noted that the diagnosis of 
immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in 
subjects with underlying cancer, due to the 
multiple potential confounding effects of cancer 
(and its treatments) throughout the neuraxis. 
Given the importance of prompt and accurate 
diagnosis, it is essential to have a low threshold to 
obtain a Neurology consult
-
Neurophysiologic diagnostic testing (e.g., 
electromyogram and nerve conduction 
investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated 
upon suspicion of such conditions and may be 
best facilitated by means of a Neurology 
consultation 
-
It is important to consider that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. Subjects requiring 
treatment should be started with IV IG and 
followed by plasmapheresis if not responsive to 
IV IG
Grade 1
No dose modification
For Grade 1:
-
Consider discussing with the study physician, as 
needed.
-
Care should be taken to monitor subjects for 
sentinel symptoms of a potential decompensation 
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as described above
-
Consult a neurologist  
Grade 2
Hold study drug/study regimen dose until 
resolution to ≤ Grade 1
Permanently discontinue study drug/study 
regimen if it does not resolve to ≤ Grade 1 
within 30 days or if there are signs of 
respiratory insufficiency or autonomic 
instability
For Grade 2:
−
Consider discussing with the study physician, as 
needed 
-
Care should be taken to monitor subjects for 
sentinel symptoms of a potential decompensation 
as described above
-
Consult a neurologist
-
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (e.g., 
gabapentin, duloxetine, etc.)
MYASTHENIA GRAVIS
o
Steroids may be successfully used to treat 
Myasthenia Gravis. Important to consider 
that steroid therapy (especially with high 
doses) may result in transient worsening 
of myasthenia and should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist.
o
Subjects unable to tolerate steroids may 
be 
candidates 
for 
treatment 
with 
plasmapheresis or IV IG. Such decisions 
are best made in consultation with a 
neurologist, taking into account the 
unique needs of each patient.
o
If Myasthenia Gravis-like neurotoxicity 
present, consider starting acetylcholine 
esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if 
successful, can also serve to reinforce 
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the diagnosis.
o
Avoid medications that can worsen 
myasthenia gravis.
GUILLAIN-BARRE: 
o
Important to consider here that the use of 
steroids as the primary treatment of 
Guillain-Barre is not typically 
considered effective.
o
Subjects requiring treatment should be 
started with IV IG and followed by 
plasmapheresis if not responsive to IV 
IG.
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Grade 3 or 4
For Grade 3:
Hold study drug/study regimen dose until 
resolution to ≤ Grade 1
Permanently discontinue Study drug/study 
regimen if Grade 3 imAE does not resolve 
to ≤ Grade 1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability
For Grade 4:
Permanently discontinue study drug/study 
regimen 
For Grade 3 or 4 
-
Consider discussing with study physician, as 
needed
-
Recommend hospitalization
-
Monitor symptoms and consult a neurologist 
MYASTHENIA GRAVIS
o
Steroids may be successfully used to 
treat Myasthenia Gravis.  It should 
typically be administered in a monitored 
setting under supervision of a consulting 
Neurologist.
o
Subjects unable to tolerate steroids may 
be candidates for treatment with 
plasmapheresis or IV IG.
o
If Myasthenia Gravis-like neurotoxicity 
present, consider starting acetylcholine 
esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if 
successful, can also serve to reinforce 
the diagnosis.
GUILLAIN-BARRE: 
o
Important to consider here that the use of 
steroids as the primary treatment of 
Guillain-Barre is not typically 
considered effective.
o
Subjects requiring treatment should be 
started with IV IG and followed by 
plasmapheresis if not responsive to IV 
IG
o
Avoid medications that can worsen 
myasthenia gravis.
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Myocarditis
Any Grade
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity)
General Guidance
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis.
For Any Grade:
-
The prompt diagnosis of immune-mediated 
myocarditis is important, particularly in subjects 
with baseline cardiopulmonary disease and 
reduced cardiac function. 
-
Consider discussing with the study physician, as 
needed.
-
Monitor subjects for signs and symptoms of 
myocarditis (new onset or worsening chest pain, 
arrhythmia, shortness of breath, peripheral 
edema). As some symptoms can overlap with 
lung toxicities, simultaneously evaluate for and 
rule out pulmonary toxicity as well as other 
causes (e.g., pulmonary embolism, congestive 
heart failure, malignant pericardial effusion). 
Consult a Cardiologist  early, to promptly assess  
whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures.
-
Initial work-up should include clinical evaluation, 
BNP, cardiac enzymes, ECG, echocardiogram 
(ECHO), monitoring of oxygenation via pulse 
oximetry (resting and exertion), and additional 
laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess
wall motion abnormalities when needed.
-
Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression, other medications, or infections).
Grade 1
No dose modifications required unless 
clinical suspicion is high, in which case hold 
study drug/study regimen dose during 
diagnostic work-up for other etiologies. If 
For Grade 1:

Monitor and closely follow up in 2 to 4 days for 
clinical symptoms, BNP, cardiac enzymes, ECG, 
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study drug/study regimen is held, resume 
after complete resolution to Grade 0.
ECHO, pulse oximetry (resting and exertion), and 
laboratory work-up as clinically indicated.

Consider using steroids if clinical suspicion is 
high.
Grade 2, 3, or 4 
If Grade 2 -- Hold study drug/study regimen 
dose until resolution to Grade 0. If toxicity 
rapidly improves to Grade 0, then the 
decision to reinitiate study drug/study 
regimen will be based upon treating 
physician’s clinical judgment and after 
completion of steroid taper. If toxicity does 
not rapidly improve, permanently. 
discontinue study drug/study regimen.
If Grade 3-4, permanently discontinue study 
drug/study regimen.
For Grade 2-4:
−
Monitor symptoms daily, hospitalize.
−
Promptly start IV methylprednisolone 2 to 
4 mg/kg/day or equivalent after Cardiology 
consultation has determined whether and when to 
complete diagnostic procedures including a 
cardiac biopsy.
−
Supportive care (e.g., oxygen).
−
If no improvement within 2 to 3 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, 
promptly start immunosuppressive therapy such 
as TNF inhibitors (e.g., infliximab at 5 mg/kg IV, 
may be repeated at 2 and 6 weeks after initial 
dose at the discretion of the treating provider ). 
Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance 
before using infliximab. Infliximab is 
contraindicated for patients who have heart 
failure.
Myositis/Polymyositis 
Any Grade
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade:
−
Monitor patients for signs and symptoms of 
poly/myositis. Typically, muscle 
weakness/pain occurs in proximal muscles 
including upper arms, thighs, shoulders, hips, 
neck and back, but rarely affects the 
extremities including hands and fingers; also 
difficulty breathing and/or trouble 
swallowing can occur and progress rapidly. 
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Increased general feelings of tiredness and 
fatigue may occur, and there can be new-
onset falling, difficulty getting up from a fall, 
and trouble climbing stairs, standing up from 
a seated position, and/or reaching up.
−
If poly/myositis is suspected, a Neurology 
consultation should be obtained early, with 
prompt guidance on diagnostic procedures. 
Myocarditis may co-occur with 
poly/myositis; refer to guidance under 
Myocarditis. Given breathing complications, 
refer to guidance under Pneumonitis/ILD. 
Given possibility of an existent (but 
previously unknown) autoimmune disorder, 
consider Rheumatology consultation.
−
Consider, as necessary, discussing with the 
study physician.
−
Initial work-up should include clinical 
evaluation, creatine kinase, aldolase, LDH, 
BUN/creatinine, erythrocyte sedimentation 
rate or C-reactive protein level, urine 
myoglobin, and additional laboratory work-
up as indicated, including a number of 
possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist 
consultation is indicated and could guide 
need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase 
[such as anti-Jo-1], and/or signal-recognition 
particle antibodies). Confirmatory testing 
may include electromyography, nerve 
conduction studies, MRI of the muscles, 
and/or a muscle biopsy. Consider Barium 
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swallow for evaluation of dysphagia or 
dysphonia.
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., disease 
progression, other medications, or 
infections).
Grade 1
No dose modifications.
For Grade 1:
−
Monitor and closely follow up in 2 to 4 days 
for clinical symptoms and initiate evaluation 
as clinically indicated.
−
Consider Neurology consult.
−
Consider, as necessary, discussing with the 
study physician.
Grade 2
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study drug/study 
regimen if it does not resolve to Grade ≤1 
within 30 days or if there are signs of 
respiratory insufficiency.
For Grade 2:
−
Monitor symptoms daily and consider 
hospitalization.
−
Obtain Neurology consult, and initiate 
evaluation.
−
Consider, as necessary, discussing with the 
study physician.
−
If clinical course is rapidly progressive 
(particularly if difficulty breathing and/or 
trouble swallowing), promptly start IV 
methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input 
from Neurology consultant 
−
If clinical course is not rapidly progressive, 
start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent); if no 
improvement within 2 to 3  days, continue 
additional work up and start treatment with 
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IV methylprednisolone 2 to 4 mg/kg/day
−
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 
2 to 3 days, consider starting another
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg IV, may 
be repeated at 2 and 6 weeks after initial dose at 
the discretion of the treating provider). Caution: 
It is important to rule out sepsis and refer to 
infliximab label for general guidance before 
using infliximab.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve to 
Grade ≤1 within 30 days or if there are signs 
of respiratory insufficiency.
For Grade 4:
Permanently discontinue study drug/study 
regimen.
For Grade 3 or 4
−
Monitor symptoms closely; recommend 
hospitalization.
−
Obtain Neurology consult.
−
Consider discussing with the study physician, 
as needed.
−
Promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with 
receiving input from Neurology consultant.
−
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 
2 to 3 days, consider starting another
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg IV, may 
be repeated at 2 and 6 weeks after initial dose at 
the discretion of the treating provider). Caution: 
It is important to rule out sepsis and refer to 
infliximab label for general guidance before 
using infliximab.
−
Consider whether patient may require IV IG, 
plasmapheresis.
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AChE = acetylcholine esterase; ACTH = adrenocorticotropic hormone; ADL = activities of daily living; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; ASCO = American Society of Clinical Oncology; AST = aspartate aminotransferase; BNP = brain natriuretic peptide; BUN = blood urea nitrogen; CT = 
computed tomography; CTCAE =  Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; FDA = Food and Drug Administration, GI = gastrointestinal; 
HgA1c = hemoglobin A1c; IG = immunoglobulin; ILD = interstitial lung disease; imAE = immune-mediated adverse event; IV = intravenous; LDH = lactate dehydrogenase; LFT 
= liver function test; LLN = lower limit of normal; MRI = magnetic resonance imaging; NCI = National Cancer Institute; NCCN = National Comprehensive Cancer Network; 
PJP = Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO = by mouth; T3 = triiodothyronine; T4 = thyroxine; TB = total bilirubin; TNF = 
tumor necrosis factor; TSH = thyroid stimulating hormone; ULN = upper limit of normal.
a ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD.
b FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation.
c NCCN Clinical Practice Guidelines in Oncology “Management of Immunotherapy-Related Toxicities” Version 1.2020 – December 2019 
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Appendix E-2: Durvalumab Treatment Modification and Toxicity Management Guidelines for Infusion-related Reactions
Infusion-Related Reactions
Severity 
Grade of the 
Event (Refer 
to NCI 
CTCAE 
applicable 
version in 
study protocol 
for defining 
the CTC 
grade/severity) 
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade:
-
Management per institutional standard at the discretion of investigator
-
Monitor subjects for signs and symptoms of infusion-related reactions 
(e.g., fever and/or shaking chills, flushing and/or itching, alterations in 
heart rate and blood pressure, dyspnea or chest discomfort, skin rashes 
etc.) and anaphylaxis (e.g., generalized urticaria, angioedema, 
wheezing, hypotension, tachycardia)
Grade 1 or 2
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until 
resolution of the event
The infusion rate of study drug/study regimen may be 
decreased 50% or temporarily interrupted until 
resolution of the event 
Subsequent infusions may be given at 50% of the initial 
infusion rate
For Grade 1 or Grade 2:
-
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator 
-
Consider premedication per institutional standard prior to subsequent 
doses
-
Steroids should not be used for routine premedication of ≤Grade 2 
infusion reactions
Grade 3/4
Permanently discontinue study drug/study regimen
For Grade 3 or 4:
Manage severe infusion-related reactions per institutional standards 
(e.g., IM epinephrine, followed by IV diphenhydramine and famotidine, 
and IV glucocorticoid)
CTCAE = Common Terminology Criteria for Adverse Events; IM = Intramuscular; IV = Intravenous; NCI = National Cancer Institute.
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Appendix E-3: Durvalumab Treatment Modification and Toxicity Management Guidelines for Non-Immune-Mediated 
Reactions
Non-immune Mediated Reactions
(Note:  As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with 
Study Physician” 
CTC 
Grade/Severity
Grade of the Event
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity)
Dose Modification 
Toxicity Management 
Any Grade
Note: dose modifications are not required for adverse events not deemed to be related to 
study treatment (i.e., events due to underlying disease) or for laboratory abnormalities not 
deemed to be clinically significant.
Treat accordingly as per institutional 
standard 
Grade 1
No dose adjustment 
Treat accordingly as per institutional 
standard 
Grade 2
Hold study drug/study regimen until resolution to ≤Grade 1 or baseline
Treat accordingly as per institutional 
standard 
Grade 3
Hold study drug/study regimen until resolution to ≤Grade 1 or baseline
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to ≤Grade 1 or baseline 
within 14 days, resume study drug/study regimen administration. Otherwise, discontinue 
study drug/study regimen
Treat accordingly as per institutional 
standard 
Grade 4
Discontinue Study drug/study regimen (Note: for Grade 4 labs, decision to discontinue 
would be based on accompanying clinical signs/symptoms and as per Investigator’s 
clinical judgment and in consultation with the sponsor.) 
Treat accordingly as per institutional 
standard 
AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST 
= aspartate aminotransferase; CT = computed tomography; GI = gastrointestinal; IDS=Infectious Disease Service; ILD = interstitial lung disease; IM = 
intramuscular; imAE = immune-mediated adverse event; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events; PO = by mouth; TNF = tumor necrosis factor; TSH = thyroid stimulating hormone; ULN = upper limit of normal.
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Physician.”
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Appendix E-4: Durvalumab Treatment Modification and Toxicity Management Guidelines for Other–immune-mediated 
Reactions
Other-immune-mediated Reactions
Severity Grade of 
the Event (Refer to 
NCI CTCAE 
applicable version 
in study protocol 
for defining the 
CTC 
grade/severity)
Dose Modification 
Toxicity Management 
Any Grade
Note: It is possible that events with an inflammatory or immune mediated mechanism 
could occur in nearly all organs, some of them are not noted specifically in these 
guidelines (e.g. immune thrombocytopenia, haemolytic anaemia, uveitis, vasculitis).
−
The study physician may be 
contacted for immune-mediated 
reactions not listed in the 
“specific immune-mediated 
reactions” section
−
Thorough evaluation to rule out 
any alternative etiology (e.g., 
disease progression, concomitant 
medications, and infections)
−
Consultation with relevant 
specialist
−
Treat accordingly, as per 
institutional standard.
Grade 1
No dose adjustment 
Monitor as clinically indicated
Grade 2

Hold study drug/study regimen until resolution to ≤Grade 1 or baseline.

If toxicity worsens, then treat as Grade 3 or Grade 4.

Study drug/study regimen can be resumed once event stabilizes to Grade ≤1 after 
completion of steroid taper. Consider whether study drug/study regimen should be 
permanently discontinued in Grade 2 events with high likelihood for morbidity 
and/or mortality when they do not rapidly improve to Grade <1 upon treatment with 
systemic steroids and following full taper
For Grade 2, 3, or 4
Treat accordingly, as per institutional 
standard, appropriate clinical practice 
guidelines, and other society guidelines 
(e.g., NCCN, ESMO)  
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Other-immune-mediated Reactions
Severity Grade of 
the Event (Refer to 
NCI CTCAE 
applicable version 
in study protocol 
for defining the 
CTC 
grade/severity)
Dose Modification 
Toxicity Management 
Grade 3
Hold study drug/study regimen
Grade 4
Permanently discontinue study drug/study regimen 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study 
Physician.”
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Protocol MEDI4736-MM-003
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MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
Appendix F: Guideline for Asthma Eligibility Criteria
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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.
UserName: 
Title:  
Date: Monday, 11 January 2021, 10:09 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
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Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MM-003
Celgene 
Confidential and Proprietary
3
MEDI4736-MM-003 Amendment 4.0 Final: 07 Jan 2021
1.
JUSTIFICATION FOR AMENDMENT
The primary purpose of Protocol Amendment 4.0 is to update the Durvalumab Treatment 
Modification and Toxicity Management Guidelines to reflect consistency with the Durvalumab 
Toxicity Management Guidelines, Version 17 Nov 2020.
Title Page (updated)
1. Contact Information updated.
Appendix E-1 (updated)
2. Appendix E-1: Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Immune-mediated Adverse Events, was updated to reflect consistency 
with Durvalumab Toxicity Management Guidelines, Version 17 Nov 2020.
Appendix E-2 (updated)
3. Appendix E-2: Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Infusion-related Reactions, was updated to reflect consistency with
Durvalumab Toxicity Management Guidelines, Version 17 Nov 2020.
Appendix E-3 (updated)
4. Appendix E-3: Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Non-immune-mediated Reactions, was updated to reflect consistency with
Durvalumab Toxicity Management Guidelines, Version 17 Nov 2020.
Appendix E-4 (created)
5. Appendix E-4: Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Other-immune-mediated Reactions, was created to reflect consistency 
with Durvalumab Toxicity Management Guidelines, Version 17 Nov 2020.
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EDMS Doc. Number: 24364021 - 21588738
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MM-003
Celgene Corporation
Confidential and Proprietary
3
MEDI4736-MM-003 Amendment 3.0 Final: 19 Dec 2019
1.
JUSTIFICATION FOR AMENDMENT
The primary purpose of this Protocol Amendment 3.0 is to update the Toxicity Management 
Guidelines (TMGs).  
Durvalumab IB Version 15 dated 08 Oct 2019 and Durvalumab Toxicity Management 
Guidelines, Version 4.03, dated 17 Oct 2019, necessitated the update to Appendix E-1 of this 
Protocol.
Title Page (updated)
1. Contact Information updated.
Appendix E (updated)
2. Appendix E-1: Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Immune-mediated Adverse Events, was updated to match Durvalumab 
Toxicity Management Guidelines, Version 4.03, dated 17 Oct 2019 and Durvalumab IB 
Version 15 dated 08 Oct 2019.
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EDMS Doc. Number: 22423923 - 21588738
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MM-003
Celgene 
Confidential and Proprietary
3
MEDI4736-MM-003 Amendment 2.0 Final: 15 Dec 2017
1.
JUSTIFICATION FOR AMENDMENT
Protocol Amendment 2 is written to update the Toxicity Management Guidelines (TMGs) and to 
reflect that on 05 Sep 2017 the United States (US) Food and Drug Administration (FDA) placed 
a Partial Clinical Hold on this study. The decision by the FDA was based on risks identified in 
other trials for an anti-programmed cell death-1 (PD-1) antibody, pembrolizumab, in patients 
with multiple myeloma in combination with immunomodulatory agents.
Significant changes included in this amendment are summarized below:
Discontinuation of enrollment of new subjects

Only those subjects already enrolled and treated who are receiving clinical benefit, 
based on the discretion of the investigator, can remain on treatment after being 
informed and reconsented on the safety concerns with the combination of a 
programmed cell death-1 (PD-1) pathway inhibitor and an immunomodulatory agent.

Changes to the protocol have been made in the Protocol Summary, Section 1 and 
Section 3.2 to reflect discontinuation of enrollment.
Updates to the Toxicity Management Guidelines (TMGs)

Updates have been made to the general dose modification and TMGs in Appendix E-
1 to include revised Durvalumab Toxicity Management Guidelines.
Other changes:

Correction of typographical errors and updated tables and table footnotes with revised 
text throughout the document.
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EDMS Doc. Number: 21590718 - 21588738
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MM-003
Celgene 
Confidential and Proprietary
3
MEDI4736-MM-003 Amendment 1.0 Final: 21 Dec 2016
1.
JUSTIFICATION FOR AMENDMENT
Protocol Amendment 1.0 was written to 
 
 
correct the dosing of daratumumab (DARA) in the protocol summary to 
correspond with Sections 7.2.2.1 and 7.2.2.1.1 of the protocol (the protocol summary incorrectly 
stated a dose level of DARA 8 mg/kg).
The amendment also includes several other updates, minor clarifications and corrections:

Updated status of DARA regulatory approvals to include the European Union
(Sections 1.2.2, 1.3.1, 1.3.4 and 7.2.1.2)

Dose Review Team composition to include study specific consultants, as required 
(Protocol summary and Section 3.1.3)

Includes a minimum number of doses of POM and dexamethasone (dex) for the dose 
limiting toxicity evaluation for subjects who receive POM + dex as part of their 
regimen. This is to ensure alignment with the other MEDI4736 protocols (Section 
3.1.4). 

Minor updates to safety laboratory assessments; added End of Treatment (EOT) visit 
to urinalysis timepoints (Table 4) and phosphorus to the biochemistry panel (Section 
6.1)

Clarifies that Day 2 assessments are only required during Cycle 1 (Table 4, Section 
6.2)

Updated protocol to require weekly hematology assessments for eight weeks when 
POM is added to study treatment upon disease progression on the durvalumab 
(DURVA) + DARA (D2) regimen (Table 4, Section 6.2)

Clarification on alternative options to the Indirect Antiglobulin Test (IAT) test 
(Sections 6.2 and 6.8)

The pharmacokinetic (PK) window of assessments was updated to logistically 
facilitate PK collection (Section 6.5.1 and 6.5.2). Updates to PK
assessments to include an EOT (End of Treatment) assessment (Sections 6.5.1 and 
6.6.1).

Clarification with regards to pre- and post- DARA infusion medications (Protocol 
summary, Sections 7.2.1.2 and 7.2.2.1.1)
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EDMS Doc. Number: 21590718 - 21588738
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MM-003
Celgene 
Confidential and Proprietary
4
MEDI4736-MM-003 Amendment 1.0 Final: 21 Dec 2016

Update to Durvalumab Treatment Modification and Toxicity Management Guidelines 
19 Aug 2016 Version (Appendix E).

Correction of minor spelling/grammatical errors
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