Conditions: Multiple Myeloma
Keywords: PD1 PD-1 PDL1 PD-L1
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 77
Healthy volunteers: no

Brief summary:
This is a study of pembrolizumab (MK-3475) in combination with lenalidomide and low-dose dexamethasone in participants with refractory or relapsed and refractory Multiple Myeloma (rrMM), and in combination with carfilzomib and low-dose dexamethasone in participants with relapsed or refractory Multiple Myeloma (rMM).

This study was being done to find the maximum tolerated dose (MTD)/maximum administered dose (MAD) and recommended Phase 2 dose (RP2D), and to evaluate the safety and tolerability of pembrolizumab when given in combination with standard of care (SOC) treatments in participants with rrMM or rMM. Preliminary efficacy data will also be assessed. There was no primary hypothesis associated with this study.

On 03-Jul-2017, the United States Food and Drug Administration (US FDA) placed the rrMM cohort of this protocol on clinical hold based on safety data from two other pembrolizumab protocols: MK-3475-183 (NCT02576977) and MK-3475-185 (NCT02579863) presented to the Data Monitoring Committee.

On 15-Sep-2017, the US FDA placed the rMM cohort of this study on partial clinical hold. Enrollment was stopped and will not be reopened. Participants who are deriving clinical benefit were allowed to continue receiving study treatment until protocol-specific end of treatment, and then progress into long term safety and survival follow up. Participants who are not deriving clinical benefit, must stop study treatment and move into the long term safety and survival follow up.

Detailed description:

Arms:
arm 1: Participants in Part 1 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 2 mg/kg once every 2 weeks (Q2W) (Days 1 and 15) in combination with lenalidomide 25 mg (Days 1-21) and dexamethasone 40 mg once weekly (Q1W) during Cycle 1 (28-day cycle). arm 2: Participants in Part 1 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 2 mg/kg Q2W (Days 1 and 15) in combination with lenalidomide 10 mg (Days 1-21) and dexamethasone 40 mg Q1W during Cycle 1 (28-day cycle). arm 3: Participants in Part 2 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 200 mg Q2W (Days 1 and 15) in combination with lenalidomide 25 mg (Days 1-21) and dexamethasone 40 mg Q1W during Cycle 1 (28-day cycle). arm 4: Participants in Part 2 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 200 mg Q2W (Days 1 and 15) in combination with lenalidomide 25 mg (Days 1-21) and dexamethasone 20 mg Q1W during Cycle 1 (28- day cycle). arm 5: Participants in Part 2 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 200 mg Q2W (Days 1 and 15) in combination with lenalidomide 10 mg (Days 1-21) and dexamethasone 40 mg Q1W during Cycle 1 (28-day cycle). arm 6: Participants in Part 3 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 200 mg Q2W (Days 1 and 15) in combination with lenalidomide 25 mg (Days 1-21) and dexamethasone 40 mg Q1W weekly during each 28-day cycle. arm 7: Participants in Part 3 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 200 mg Q2W (Days 1 and 15) in combination with lenalidomide 25 mg (Days 1-21) and dexamethasone 20 mg Q1W weekly during each 28-day cycle. arm 8: Participants in Part 3 with relapsed or refractory multiple myeloma (rMM) received pembrolizumab 200 mg Q3W in combination with carfilzomib 56 mg/m\^2 (Days 1, 2, 8, 9, 15, 16) and dexamethasone 20 mg once or twice weekly (Days 1, 2, 8, 9, 15, 16, 22, 23) during each 28-day cycle.

Interventions: intervention 1: Pembrolizumab intervention 2: Lenalidomide intervention 3: Dexamethasone intervention 4: Carfilzomib
Intervention descriptions: intervention 1: Intravenous (IV) infusion intervention 2: Oral capsule intervention 3: Oral tablet IV infusion intervention 4: IV infusion

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02036502
10-Mar-2020
Document Date: 
A Phase I Multi-Cohort Trial of Pembrolizumab (MK-3475) 
in Combination with Backbone Treatments for Subjects with 
Multiple Myeloma


Product:  MK-3475 
1
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase I Multi-Cohort Trial of Pembrolizumab (MK-3475) in Combination with Backbone 
Treatments for Subjects with Multiple Myeloma
IND NUMBER:  118604
EudraCT NUMBER:  2013-003512-44 
 
 
05FW09


Product:  MK-3475 
2
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 12
SUMMARY OF CHANGES................................................................................................ 15
1.0
TRIAL SUMMARY.................................................................................................. 17
2.0
TRIAL DESIGN........................................................................................................ 18
Trial Design ........................................................................................................... 18
Trial Diagram........................................................................................................ 21
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 22
Primary Objective(s) & Hypothesis(es).............................................................. 22
Secondary Objective(s) & Hypothesis(es)........................................................... 22
Exploratory Objectives......................................................................................... 22
4.0
BACKGROUND & RATIONALE.......................................................................... 23
Background ........................................................................................................... 23
Pharmaceutical and Therapeutic Background .................................................... 23
Pre-clinical and Clinical Trials ........................................................................... 24
Ongoing Clinical Trials....................................................................................... 24
Rationale for IMiDs as a Combination Agent: ................................................... 29
Rationale for Lenalidomide and Low-dose Dexamethasone in Multiple 
Myeloma ............................................................................................................. 29
Rationale for Proteasome Inhibitors as a Combination Agent............................ 31
Rationale for Carfilzomib and Low-dose Dexamethasone in Multiple 
Myeloma ............................................................................................................. 31
Rationale................................................................................................................ 32
Rationale for the Trial and Selected Subject Population .................................... 32
Rationale for Evaluating anti-PD-1 Therapy in Multiple Myeloma............ 32
Rationale for Dose Selection/Regimen............................................................... 33
Rationale for Endpoints ...................................................................................... 34
Safety Endpoints.......................................................................................... 34
Efficacy Endpoints....................................................................................... 34
Biomarker Research..................................................................................... 35
Future Biomedical Research........................................................................ 36
 
 
05FW09


Product:  MK-3475 
3
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
5.0
METHODOLOGY ................................................................................................... 37
Entry Criteria........................................................................................................ 37
Diagnosis/Condition for Entry into the Trial ...................................................... 37
Subject Inclusion Criteria.................................................................................... 37
Subject Exclusion Criteria .................................................................................. 42
Trial Treatment(s) ................................................................................................ 46
Dose Selection/Modification .............................................................................. 49
Dose Selection ............................................................................................. 49
Dose Modification (Escalation/Titration/Other).......................................... 49
5.2.1.2.1
Guidelines for Dose Modification ........................................................ 49
5.2.1.2.2
Dose Modification Guidelines for Pembrolizumab.............................. 50
5.2.1.2.3
Dose Modification Guidelines for Lenalidomide (after DLT 
Evaluation Period) ................................................................................ 56
Lenalidomide Dose Adjustments for Hematologic Toxicities 
during Multiple Myeloma Treatment............................................. 56
Other Grade 3 and 4 Lenalidomide Toxicities in MM................... 57
Recommended Lenalidomide Dose Adjustments for Subjects 
with Impaired Renal Function........................................................ 58
5.2.1.2.4
Dose Modification Guidelines for Dexamethasone.............................. 58
Dose Modification Guidelines for Dexamethasone for Elderly 
Subjects > 75 Years of Age............................................................ 59
Supportive Care Guidelines Specific to Dexamethasone............... 60
5.2.1.2.5
Cohort 2: Dose Modification Guidelines for Carfilzomib.................... 60
Timing of Dose Administration.......................................................................... 62
Definition of Disease Progression....................................................................... 62
Guidelines for Study Drug Administration......................................................... 62
Rules for Dose Determination and Confirmation ............................................... 63
Dose Determination ..................................................................................... 63
Dose Confirmation....................................................................................... 64
Expansion Cohort......................................................................................... 66
Definition of Dose Limiting Toxicities............................................................... 67
Replacement of Subjects in DLT Evaluation Period .......................................... 68
Trial Blinding/Masking....................................................................................... 69
 
 
05FW09


Product:  MK-3475 
4
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Randomization or Treatment Allocation............................................................ 69
Stratification.......................................................................................................... 69
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 69
Acceptable Concomitant Medications ................................................................ 69
Concomitant Medications for Cohort 2 Carfilzomib................................... 70
Prohibited Concomitant Medications.................................................................. 70
Rescue Medications & Supportive Care............................................................. 71
Supportive Care Guidelines ................................................................................ 71
Supportive Care Guidelines Specific to Lenalidomide....................................... 72
Hematologic Toxicity .................................................................................. 72
Venous Thromboembolism.......................................................................... 72
Lactose Intolerance...................................................................................... 73
Allergic Reactions........................................................................................ 73
Tumor Lysis Syndrome................................................................................ 73
Hepatotoxicity.............................................................................................. 73
Second Primary Malignancies ..................................................................... 74
Supportive Care Guidelines Specific for Carfilzomib [Cohort 2] ...................... 74
“First-Dose-Like Effect”.............................................................................. 74
Tumor Lysis Syndrome................................................................................ 74
Renal Function............................................................................................. 75
Hydration ..................................................................................................... 75
Other Adverse Events on Combination Therapy................................................ 75
Diet/Activity/Other Considerations..................................................................... 76
Diet...................................................................................................................... 76
Blood Donation................................................................................................... 76
Contraception...................................................................................................... 76
Dose Determination, Dose Confirmation, and Expansion Cohort 1............ 76
Expansion Cohort 2...................................................................................... 78
Use in Pregnancy ................................................................................................ 81
Use in Nursing Women....................................................................................... 81
Subject Withdrawal/Discontinuation Criteria................................................... 81
Subject Replacement Strategy............................................................................. 82
 
 
05FW09


Product:  MK-3475 
5
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Beginning and End of the Trial ........................................................................... 83
Clinical Criteria for Early Trial Termination ................................................... 83
6.0
TRIAL FLOW CHART ........................................................................................... 84
Trial Flow Chart Dose Determination, Dose Confirmation, and Cohort 1 
(rrMM Subjects Allocated to Pembrolizumab Q2W, Lenalidomide and 
Low-dose Dexamethasone)................................................................................... 84
Trial Treatment Administration Schedule Dose Determination, Dose 
Confirmation, and Cohort 1 ................................................................................ 87
Pembrolizumab PK and Anti-pembrolizumab Antibodies Procedures during 
Dose Determination, Dose Confirmation and Cohort 1...................................... 88
Trial Flow Chart Cohort 2 – (2L rMM Subjects Allocated to Triplet with 
Pembrolizumab Q3W, Carfilzomib and Low-dose Dexamethasone) .............. 90
Trial Treatment Administration Schedule Cohort 2 ........................................... 93
Pembrolizumab PK and Anti-pembrolizumab Antibodies Procedures during 
Cohort 2 .............................................................................................................. 94
7.0
TRIAL PROCEDURES ........................................................................................... 95
Trial Procedures ................................................................................................... 95
Administrative Procedures.................................................................................. 95
Informed Consent......................................................................................... 95
7.1.1.1.1
General Informed Consent.................................................................... 95
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 96
Inclusion/Exclusion Criteria ........................................................................ 96
Subject Identification Card .......................................................................... 96
Medical History ........................................................................................... 96
Prior and Concomitant Medications Review............................................... 96
7.1.1.5.1
Prior Medications.................................................................................. 96
7.1.1.5.2
Concomitant Medications..................................................................... 96
Disease Details and Treatments................................................................... 97
7.1.1.6.1
Disease Details...................................................................................... 97
7.1.1.6.2
Prior Treatment Details......................................................................... 97
7.1.1.6.3
Subsequent Antineoplastic Therapy Status........................................... 97
Assignment of Screening Number............................................................... 97
 
 
05FW09


Product:  MK-3475 
6
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Assignment of Randomization Number....................................................... 97
Trial Compliance (Medication/Diet/Activity/Other) ................................... 97
Clinical Procedures/Assessments........................................................................ 98
Adverse Event (AE) Monitoring.................................................................. 98
Physical Exam.............................................................................................. 99
7.1.2.2.1
Full Physical Exam ............................................................................... 99
7.1.2.2.2
Directed Physical Exam........................................................................ 99
Vital Signs.................................................................................................... 99
Electrocardiogram (ECG)............................................................................ 99
Assessment of LVEF using ECHO.............................................................. 99
Eastern Cooperative Oncology Group (ECOG) Performance Scale ......... 100
Assessment of Disease and Tumor Imaging.............................................. 100
7.1.2.7.1
Criteria for Assessment of Disease..................................................... 100
Myeloma Disease Measurements................................................. 100
7.1.2.7.2
Imaging for Subjects with Myeloma Bone Disease............................ 100
7.1.2.7.3
Disease Assessment of Immunotherapeutic Agents ........................... 101
7.1.2.7.4
Timing of Disease Assessments ......................................................... 101
7.1.2.7.5
Initial Disease Assessment.................................................................. 101
7.1.2.7.6
Disease Assessment During Trial....................................................... 102
7.1.2.7.7
Confirmation Assessments ................................................................. 102
7.1.2.7.8
Biopsy Collection and Correlative Studies Blood Collection ............ 103
Laboratory Procedures/Assessments ................................................................ 105
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 105
Pharmacokinetic/Pharmacodynamic Evaluations...................................... 107
7.1.3.2.1
Blood Collection for Pembrolizumab................................................. 107
7.1.3.2.2
Blood Collection for Anti-Pembrolizumab Antibodies...................... 107
Future Biomedical Research...................................................................... 107
Other Procedures............................................................................................... 108
Withdrawal/Discontinuation...................................................................... 108
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................. 108
Blinding/Unblinding .................................................................................. 108
Calibration of Equipment........................................................................... 108
 
 
05FW09


Product:  MK-3475 
7
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Visit Requirements............................................................................................ 109
Screening Period ........................................................................................ 109
Treatment Period........................................................................................ 109
Post-Treatment Visits................................................................................. 110
7.1.5.3.1
Safety Follow-Up Visit....................................................................... 110
Efficacy Follow-Up Visits......................................................................... 110
7.1.5.4.1
Survival Follow-Up ............................................................................ 111
7.1.5.4.2
Follow-up After Allogeneic Stem Cell Transplantation..................... 111
Survival Status ........................................................................................... 111
Assessing and Recording Adverse Events ........................................................ 112
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor........................................................................................................ 113
Reporting of Pregnancy and Lactation to the Sponsor ..................................... 113
Immediate Reporting of Adverse Events to the Sponsor.................................. 114
Serious Adverse Events ............................................................................. 114
Events of Clinical Interest.......................................................................... 115
7.2.3.2.1
Adverse 
Events 
Follow-up 
post-Allogeneic 
Stem 
Cell 
Transplantation ................................................................................... 116
Protocol-Specific Exceptions to Serious Adverse Event Reporting.......... 116
Evaluating Adverse Events............................................................................... 117
Sponsor Responsibility for Reporting Adverse Events .................................... 120
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 120
Statistical Analysis Plan Summary ................................................................... 120
Efficacy Analyses ............................................................................................. 121
Safety Analyses................................................................................................. 121
Power and Sample Size..................................................................................... 121
Statistical Analysis Plan ..................................................................................... 122
Responsibility for Analyses .............................................................................. 122
Hypotheses/Estimation ..................................................................................... 122
Analysis Endpoints ........................................................................................... 122
Efficacy Endpoints..................................................................................... 122
Safety Endpoints........................................................................................ 123
 
 
05FW09


Product:  MK-3475 
8
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Analysis Populations......................................................................................... 123
Efficacy Analysis Populations ................................................................... 123
Safety Analysis Populations ...................................................................... 123
Statistical Methods............................................................................................ 124
Statistical Methods for Efficacy Analyses................................................. 124
Statistical Methods for Safety Analyses .................................................... 125
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses..................................................................................................... 126
Multiplicity ....................................................................................................... 126
Sample Size and Power Calculations................................................................ 126
Subgroup Analyses and Effect of Baseline Factors.......................................... 127
Interim Analysis................................................................................................ 127
Compliance (Medication Adherence)............................................................... 127
Extent of Exposure............................................................................................ 128
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 128
Investigational Product ...................................................................................... 128
Packaging and Labeling Information ............................................................... 129
Clinical Supplies Disclosure............................................................................... 129
Storage and Handling Requirements................................................................ 129
Returns and Reconciliation................................................................................ 129
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 129
Confidentiality..................................................................................................... 129
Confidentiality of Data ..................................................................................... 129
Confidentiality of Subject Records................................................................... 130
Confidentiality of Investigator Information...................................................... 130
Confidentiality of IRB/IEC Information........................................................... 130
Compliance with Financial Disclosure Requirements..................................... 131
Compliance with Law, Audit and Debarment ................................................. 131
Compliance with Trial Registration and Results Posting Requirements ...... 133
Quality Management System............................................................................. 133
Data Management............................................................................................... 134
 
 
05FW09


Product:  MK-3475 
9
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Publications ......................................................................................................... 134
11.0
LIST OF REFERENCES....................................................................................... 136
12.0
APPENDICES......................................................................................................... 143
Merck Code of Conduct for Clinical Trials...................................................... 143
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 145
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 151
Multiple Myeloma Diagnostic Criteria............................................................. 162
ECOG Performance Status................................................................................ 163
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 164
MM Disease Response Criteria ......................................................................... 165
List of Abbreviations .......................................................................................... 167
13.0
SIGNATURES......................................................................................................... 170
Sponsor's Representative ................................................................................... 170
Investigator.......................................................................................................... 170
 
 
05FW09


Product:  MK-3475 
10
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values..................................................... 39
Table 2
Adequate Organ Function Laboratory Values..................................................... 41
Table 3
Combination Trial Dosing Cohorts..................................................................... 47
Table 4
Dose Modification Guidelines for Hematological Drug-Related 
Adverse Events.................................................................................................... 50
Table 5
Dose Modification and Toxicity Management Guidelines for 
Immune-related AEs Associated with Pembrolizumab....................................... 52
Table 6
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines............................................................................................................ 55
Table 7
Platelet Counts: Thrombocytopenia in MM........................................................ 57
Table 8
Absolute Neutrophil Counts (ANC): Neutropenia in MM.................................. 57
Table 9
Lenalidomide Dose Reductions for Subjects with Other Grade 3 and 4 
Toxicities............................................................................................................. 58
Table 10
Dexamethasone Dose Reductions for Subjects with Grade 3 and 4 
Toxicities............................................................................................................. 59
Table 11
Dexamethasone Dose Reductions for Elderly Subjects > 75 Years of 
Age with Grade 3 and 4 Toxicities...................................................................... 59
Table 12
Supportive Care Guidelines Specific to Dexamethasone.................................... 60
Table 13
Dose Modifications for Toxicity during Carfilzomib Treatment........................ 61
Table 14
Dose Level Reductions for Carfilzomib.............................................................. 61
Table 15
Dose Confirmation Rules.................................................................................... 65
Table 16
Operating Characteristics of Design Based on the Toxicity Probability 
Interval (TPI) Approach ...................................................................................... 66
Table 17
Recommendations for the Management of Cytopenias ...................................... 72
Table 18
Recommendations 
for 
the 
Management 
of 
Venous 
Thromboembolism. ............................................................................................. 73
Table 19
Bone Marrow and Whole Blood Sample Collection (Dose 
Determination, Dose Confirmation, Cohort 1).................................................. 103
Table 20
Bone Marrow and Whole Blood Sample Collection (Cohort 2)....................... 104
Table 21
Laboratory Tests................................................................................................ 106
Table 22
Evaluating Adverse Events ............................................................................... 118
Table 23
Summary of Analysis Strategy for Key Efficacy Endpoints............................. 121
Table 24
Censoring Rules for the Analysis of DOR ........................................................ 124
Table 25
Analysis Strategy for Efficacy Variables .......................................................... 125
Table 26
Two-sided 95% Confidence Intervals of ORR with 30 Subjects...................... 127
Table 27
Product Descriptions ......................................................................................... 128
 
 
05FW09


Product:  MK-3475 
11
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
LIST OF FIGURES
Figure 1
Trial Design......................................................................................................... 21
Figure 2
Kaplan-Meier Graph of Overall Survival (ITT Population) ............................... 25
Figure 3
Kaplan-Meier Graph of Time to Progression Per IMWG 2011 Based 
on Confirmed Investigator Review (Primary Censoring Rule) (ITT 
Population) .......................................................................................................... 26
Figure 4
Kaplan-Meier Graph of Overall Survival (ITT Population) ............................... 27
Figure 5
Kaplan-Meier Graph of Time to Progression Per IMWG 2011 Based 
on Confirmed Investigator Review (Primary Censoring Rule) (ITT 
Population) .......................................................................................................... 28
Figure 6
Kaplan-Meier Estimates of Overall Survival (ASaT Population)....................... 29
Figure 7
Dose Determination Schema............................................................................... 64
 
 
05FW09


Product:  MK-3475 
12
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-3475-023-07
10-MAR-2020
To discontinue data collection following the database lock for the final 
analysis, as all participants remaining on study are in survival follow-up.
MK-3475-023-06
05-APR-2018
The treatment of subjects in Cohort 1 was discontinued based on a 
clinical hold placed on the study by the US FDA on 03-JUL-2017. The 
FDA determined that the risks of pembrolizumab plus pomalidomide or 
lenalidomide outweighed any potential benefit for patients with multiple 
myeloma.  Based on this decision, the treatment phase of Cohort 1 of 
KN023 is closed effective immediately.  All subjects stopped study 
treatment, completed the Discontinuation Visit, and moved into the long 
term safety and survival follow-up (every 12 weeks) per protocol. 
The enrollment of subjects into Cohort 2 was discontinued based on a 
partial clinical hold placed on the study by the US FDA on 15-SEP-2017. 
Enrollment was stopped and all subjects who derived clinical benefit 
from therapy are allowed to continue if reconsented. Those subjects who 
were already enrolled and deriving clinical benefit from therapy were 
allowed to continue if reconsented, and could continue on study until 
protocol-specific end of treatment, and then progress into long term 
safety and follow-up. Those subjects who were not deriving clinical 
benefit, stopped study treatment, completed the Discontinuation Visit. 
and moved into the long term safety and follow-up per protocol.
 
 
05FW09


Product:  MK-3475 
13
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Document
Date of Issue
Overall Rationale
MK-3475-023-05
28-NOV-2016
Removed biomarker bone marrow biopsy requirement for subjects 
enrolled to Dose Determination, Dose Confirmation and Cohort 1. 
Clarified that subjects in the US and Canada are to provide new bone 
marrow aspirate for biomarker analysis. Updated inclusion criteria to 
reflect this change and clarified bone marrow materials needed for 
disease assessment. PD-L1 testing using bone marrow core biopsies has 
been shown to be of limited utility due to its de-calcification impact on 
the PD-L1 antigen. Therefore, testing requirements were removed to 
reduce risk associated with this invasive procedure. 
MK-3475-023-04
23-MAY-2016
Clarification to insure patients who may have a history of pneumonitis 
are excluded from the study (when applicable).
MK-3475-023-03
07-APR-2016
Removed Doublet arm of pembrolizumab in combination with 
lenalidomide in rrMM, replaced with new triplet arm of pembrolizumab 
in combination with carfilzomib and dexamethasone in rMM (Cohort 2).
This change was derived from need to explore other standard of care 
combinations in Multiple Myeloma to assess preliminary safety and 
efficacy. The title of the protocol was changed to include the new 
combination, and new rationale for the treatment and inclusion/exclusion 
criteria for Cohort 2 were added. Supportive care guidance for 
carfilzomib was added, and the study flowchart was updated to 
accommodate new treatment schedule and PK/antibodies testing for 
Cohort 2.
 
 
05FW09


Product:  MK-3475 
14
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Document
Date of Issue
Overall Rationale
MK-3475-023-02
10-JUL-2014
The 5 mg/kg and 10 mg/kg doses were removed from dose escalation. 
The “Dose Escalation” was changed to “Dose Determination”.
Dose Confirmation was revised and 2 Expansion Arms (Doublet-
MK+Len and Triplet-MK+Len+Dex) using a fixed dose MK-3475 were 
added.  The statistical Section was also revised accordingly.
MK-3475-023-01
08-JAN-2014
First and second line patients were removed from the subject population. 
These changes were made based upon FDA comments
MK-3475-023-00
02-OCT-2013
Original protocol
 
 
05FW09


Product:  MK-3475 
15
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
Trial Summary
Updated duration of survival 
follow-up 
to 
12 
months 
following discontinuation visit.
To allow for early closure of 
the study.
2.1
Trial Design
Updated follow-up after stem 
cell transplant (SCT) to provide 
for completion of follow-up at 
the end of the trial.
Survival 
follow-up 
will 
continue for at least 12 months 
following 
the 
last 
discontinuation 
visit, 
which 
occurred in November of 2018.  
To date no subject remaining in 
follow-up has  had a SCT.
5.10
Beginning and End of Trial
Updated criteria for end of the 
trial 
to 
include 
Sponsor 
decision to close.
To broaden the criteria for 
ending the trial.
7.1.5.3.1
7.1.5.4.1
7.1.5.4.2
7.2.3.2.1
Safety Follow-up
Survival Follow-up
Follow-up 
After 
Allogenic 
Stem Cell Transplantation
Adverse 
Events 
Follow-up 
post-Allogeneic 
Stem 
Cell 
Transplantation
Updated criteria for completion 
of 
safety 
follow-up
after 
discontinuation and after SCT 
to include Sponsor decision to 
close the trial.
To broaden the criteria for 
ending safety follow-up.
 
 
05FW09


Product:  MK-3475 
16
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
4.1.1.1
Pembrolizumab
Updated 2 reference citation 
DocIDs.
To allow proper linking at 
finalization.
4.2.3.5 
7.1.1.1.2 
12.2
Future Biomedical Research
Consent and Collection of 
Specimens for Future 
Biomedical Research
Collection and Management of 
Specimens 
for 
Future 
Biomedical Research
Removed references to Future 
Biomedical 
Research 
“sub-
trial.”
Template update
7.1.5.4
Efficacy Follow-up Visits
Updated the heading name.
Template 
update 
for 
clarification.
7.1.5.4.2
Survival Follow-up
Added new template language 
on timing of survival follow-up
Template 
update 
for 
clarification.
 
 
05FW09


Product:  MK-3475 
17
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
1.0 TRIAL SUMMARY
Abbreviated Title
A Phase I Multi-Cohort Trial of Pembrolizumab (MK-3475) in 
Combination with Backbone Treatments for Subjects with Multiple 
Myeloma.
Trial Phase
I
Clinical Indication
Multiple Myeloma (MM)
Trial Type
Interventional
Type of control
No treatment control
Route of administration
IV, Oral
Trial Blinding
Unblinded Open-label
Treatment Groups
Dose Determination: pembrolizumab 2 mg/kg every 2 weeks (Days 1 
and 15) in combination with 10 mg or 25 mg lenalidomide (Days 1-21) 
and dexamethasone 40 mg weekly of a 28-day cycle;
Dose 
Confirmation: Pembrolizumab 200 mg every 2 weeks (Days 1 and 15)
in combination with 10 mg or 25 mg lenalidomide (Days 1-21) and 
dexamethasone 40 mg weekly of a 28 day cycle. Expansion Cohort:
Cohort 1 (rrMM): Pembrolizumab 200 mg every 2 weeks (Days 1 and 
15) in combination with 25 mg lenalidomide (Days 1-21) and 
dexamethasone 40 mg weekly of a 28 day cycle. Cohort 2 (rMM):
Pembrolizumab 200 mg every 3 weeks (Q3W) in combination with 
56 mg/m2 carfilzomib (Days 1, 2, 8, 9, 15, 16) and dexamethasone 20 
mg (Days 1, 2, 8, 9, 15, 16, 22, 23) of a 28 day cycle.
Number of trial subjects
Approximately 115 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 
66 months from the time the first subject signs the informed consent 
until the last subject’s last visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified 
contact. After a screening phase of 28 days, eligible subjects will 
receive assigned treatment appropriate for the trial stage in which they 
are enrolled as described above. The assigned treatment will continue 
until documented confirmed disease progression, unacceptable adverse 
event(s), intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw the subject, subject 
withdraws consent, pregnancy of the subject, noncompliance with trial 
treatment or procedure requirements, or for administrative reasons. 
Subjects with confirmed disease progression according to response 
criteria whom the investigator considers are deriving clinical benefit
may be considered to continue on treatment after consultation with the 
Sponsor. After the end of treatment, each subject will be followed for 30 
days for the occurrence of adverse events and spontaneously reported 
pregnancy as described under Section 7.2 of the protocol (serious 
adverse events will be collected for 90 days following the cessation of 
treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier). Subjects who 
discontinue for reasons other than progressive disease will move into 
the Follow-Up Phase to monitor disease status and should be assessed 
every 4 weeks (± 14 days) until: (1) the start of new anti-cancer 
treatment; (2) documented disease progression; (3) death; (4) withdraw 
of consent; or (5) the end of the trial, whichever occurs first. Every 
 
 
05FW09


Product:  MK-3475 
18
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
effort should be made to collect information regarding disease response 
assessment in the follow-up period. Prior to discontinuing patients from 
therapy, consult with Sponsor and submit the Treatment Termination & 
Disease Assessment Termination Form. Information regarding post-
study anti-myeloma treatment will be collected if new treatment is 
initiated. After documented disease progression or the start of new 
antineoplastic therapy, each subject will be followed up by telephone 
every 12 weeks (± 7 days) for at least 12 months after their 
discontinuation visit for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
On 
03-JUL-2017, 
the 
US 
FDA 
placed 
KN183 
(pembrolizumab/pomalidomide/dexamethasone 
for 
Refractory 
or 
Relapsed 
and 
Refractory 
Multiple 
Myeloma), 
KN185 
(pembrolizumab/lenalidomide/dexamethasone 
for 
treatment 
naïve 
multiple myeloma), and cohort 1 of KN023 on clinical hold based on 
safety data from KN183 and KN185 presented to the Data Monitoring 
Committee (DMC). The FDA determined that the risks of 
pembrolizumab plus pomalidomide or lenalidomide outweighed any 
potential benefit for patients with multiple myeloma.  Based on this 
decision, the treatment phase of KN183, KN185, and Cohort 1 of 
KN023 is closed effective immediately.  All subjects must stop study 
treatment, complete the Discontinuation Visit and move into the long 
term safety and survival follow-up (every 12 weeks) per protocol.
On 15-SEP-2017, the US FDA placed Cohort 2 of KN023 
(pembrolizumab/carfilzomib/dexamethasone), on partial clinical hold. 
Enrollment was stopped and all subjects who derived clinical benefit 
from therapy are allowed to continue if reconsented, at least verbally. 
Enrollment will not be reopened by the sponsor after a full safety and 
efficacy evaluation did not demonstrate any significant difference from 
historical controls. Those subjects who are already enrolled and deriving 
clinical benefit from therapy were allowed to continue if reconsented, at 
least verbally, and will continue on study until protocol-specific end of 
treatment, and then progress into long term safety and follow-up. Those 
subjects who are not deriving clinical benefit, must stop study treatment, 
complete the Discontinuation Visit and move into the long term safety 
and follow-up per protocol.
A list of abbreviations used in this document can be found in Section 12.8.
2.0 TRIAL DESIGN
Trial Design
This is an open-label, Phase I, multicenter, multi-cohort trial of pembrolizumab (also referred 
to as MK-3475) in combination with lenalidomide and low-dose dexamethasone in subjects 
with refractory or relapsed and refractory Multiple Myeloma (rrMM), and in combination 
with carfilzomib and low-dose dexamethasone in subjects with relapsed or refractory 
Multiple Myeloma (rMM). 
The trial will use a modified 3+3 design for Dose Determination followed by a toxicity 
probability interval (TPI) design for Dose Confirmation in subjects with rrMM. After the
 
 
05FW09


Product:  MK-3475 
19
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
MTD/MAD is defined the Expansion Cohort stage will be started. It is estimated that 
approximately up to 115 subjects (approximately 6-12 in Dose Determination, an additional 
7-13 in Dose Confirmation and 60-90 in Expansion Cohorts) will be enrolled to evaluate 
safety, tolerability and efficacy in this trial.  Dosing arms are described in Table 3, Section 
5.2.
During the Dose Determination stage, cohorts of approximately 3-6 subjects will be enrolled 
at 2 mg/kg of pembrolizumab in combination with 25 mg or 10 mg of lenalidomide and low-
dose dexamethasone in rrMM subjects. In this stage, if Dose Level 1 is not tolerated, de-
escalation to Dose Level -1A is permitted after the dose limiting toxicity (DLT) evaluation 
period of Dose Level 1 pembrolizumab 2 mg/kg in combination with lenalidomide 25 mg 
(Days 1-21) and weekly dexamethasone 40 mg. If Dose Level 1 is not tolerable, then the next 
cohort of subjects will be assigned to Dose Level -1A. 
At a safety interim analysis in June 2015 a preliminary MTD/MAD was identified as 
pembrolizumab 2 mg/kg in combination with lenalidomide 10 mg (Days 1-21) and weekly 
dexamethasone 40 mg, additional subjects were enrolled in the Dose Confirmation stage at a 
fixed dose of 200 mg pembrolizumab in combination with lenalidomide and low-dose
dexamethasone to determine the final MTD/MAD dose based on the TPI algorithm. The 
Dose Confirmation stage allowed for re-escalation of lenalidomide providing no additional 
toxicity was observed following the TPI algorithm. The final MTD/MAD was determined to 
be pembrolizumab 200 mg in combination with lenalidomide 25 mg (Days 1-21) and weekly 
dexamethasone 40 mg.
Once the final MTD/MAD was determined the Expansion Cohort stage started and
encompasses: 

Cohort 1: Subjects with refractory or relapsed and refractory multiple myeloma 
(rrMM) who have undergone at least 2 lines of prior treatment, are refractory to their 
last line of treatment. Subjects must have been previously exposed to an 
immunomodulatory drug (IMiDs) such as lenalidomide, pomalidomide or 
thalidomide and a proteasome inhibitor such as bortezomib, ixazomib or carfilzomib
and should be considered to be refractory or relapsed and refractory to an IMiD or a 
proteasome inhibitor or both.  Subjects will receive pembrolizumab in combination 
with lenalidomide and dexamethasone.  

Cohort 2: Subjects with relapsed or refractory multiple myeloma (rMM) and have 
received 1 to 3 lines of prior treatment.  Subjects will receive pembrolizumab in 
combination with carfilzomib and dexamethasone.  
The Expansion Cohorts (Section 5.2.5.3) will further evaluate safety and characterize 
preliminary efficacy for pembrolizumab in combination with SOC for each cohort. A safety 
run in for Cohort 2 will be conducted after 6 subjects are enrolled and one cycle completed to 
assess overall safety before expanding this cohort to its specified sample size.
 
 
05FW09


Product:  MK-3475 
20
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Study treatment with pembrolizumab in combination with SOC will continue until 
documented disease progression, unacceptable adverse event(s) (AEs), intercurrent illness 
that prevents further administration of treatment, investigator’s decision to withdraw the 
subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial 
treatment or procedure requirements, or administrative reasons. However, in the setting 
where a subject assessment shows confirmed PD per IMWG 2006 criteria, by investigator 
assessment, study drug may be continued upon Sponsor consultation, if the investigator 
considers the subject is deriving clinical benefit.  
After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events [SAEs] will be collected for 90 days following the 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier).
Subjects who undergo allogeneic stem cell 
transplant (allo-SCT) within 24 months after their last dose of pembrolizumab will be 
followed for events of clinical interest (ECI) for up to 18 months post-transplant, or until the 
end of the trial. Subjects who discontinue for reasons other than progressive disease will 
move into the Follow-Up Phase to monitor disease status and should be assessed every 4 
weeks (± 14 days) until: (1) the start of new anti-cancer treatment; (2) documented disease 
progression; (3) death; (4) withdraw of consent; or (5) the end of the trial, whichever occurs 
first. Every effort should be made to collect information regarding disease response 
assessment in the follow-up period.  Prior to discontinuing patients from therapy, consult 
with Sponsor and submit the Treatment Termination & Disease Assessment Termination 
Form. Information regarding post-study anti-myeloma treatment will be collected if new 
treatment is initiated. After documented disease progression or the start of new antineoplastic 
therapy, each subject will be followed by telephone every 12 weeks (± 7 days) for at least 
12 months following their discontinuation visit for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
The primary objectives of the trial are to establish an MTD or MAD in the Dose 
Determination and Dose Confirmation stages. The Expansion Cohorts will determine safety 
and tolerability of pembrolizumab in combination with SOC for each cohort. Secondary 
objectives include further evaluation of various efficacy parameters as objective response
rate (ORR) and disease control rate (DCR) of pembrolizumab in combination with SOC. 
Exploratory objectives will include the evaluation of other efficacy parameters as duration of 
response (DOR), progression-free survival (PFS), time to progression (TTP) and overall 
survival (OS); pharmacokinetic (PK) properties of pembrolizumab in combination with 
lenalidomide and low-dose dexamethasone or carfilzomib and low-dose dexamethasone; the 
analysis of PD-L1 expression and corresponding efficacy in each subject population; and the 
relationship of candidate efficacy/resistance biomarkers and antitumor activity with SOC for 
each cohort activity.
This trial will be conducted in conformance with Good Clinical Practices.
On 03-JUL-2017, the US FDA placed KN183, KN185, and cohort 1 of KN023 on clinical 
hold based on safety data from KN183 and KN185 presented to the DMC.  The FDA 
determined that the risks of pembrolizumab plus pomalidomide or lenalidomide outweighed 
 
 
05FW09


Product:  MK-3475 
21
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
any potential benefit for patients with multiple myeloma.  Based on this decision, the 
treatment phase of KN183, KN185, and Cohort 1 of KN023 is closed effective immediately.  
All subjects must stop study treatment, complete the Discontinuation Visit and move into the 
long-term safety and survival follow-up (every 12 weeks) per protocol.
On 15-SEP-2017, the US FDA placed Cohort 2 of KN023, on partial clinical hold. 
Enrollment was stopped and all subjects who derived clinical benefit from therapy are 
allowed to continue if reconsented, at least verbally. Enrollment will not be reopened by the 
sponsor after a full safety and efficacy evaluation did not demonstrate any significant 
difference from historical controls. Those subjects who are already enrolled and deriving
clinical benefit from therapy were allowed to continue if reconsented, at least verbally, and 
will continue on study until protocol-specific end of treatment, and then progress into long 
term safety and follow-up. Those subjects who are not deriving clinical benefit, must stop 
study treatment, complete the Discontinuation Visit and move into the long term safety and 
follow-up per protocol.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
No formal efficacy interim analyses are planned for this trial.
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Trial Design
 
 
05FW09


Product:  MK-3475 
22
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
For Dose Determination and Dose Confirmation Stages:
(1) Objective: To establish a maximum tolerated dose (MTD) or a maximum 
administered dose (MAD) of pembrolizumab when given in combination with 
lenalidomide and low-dose dexamethasone to subjects with refractory or relapsed and 
refractory multiple myeloma.
For Expansion Cohort Stage (Cohort 1 rrMM, Cohort 2 rMM):
(2) Objective: To determine the safety and tolerability of pembrolizumab in combination 
with SOC in subjects with multiple myeloma.
Secondary Objective(s) & Hypothesis(es)
The following secondary objective will be evaluated separately for Expansion Cohort 1 
(rrMM) and for Expansion Cohort 2 (rMM):
Objective: To evaluate objective response rate (ORR) and disease control rate (DCR) of 
pembrolizumab in combination with SOC in subjects with MM by investigator assessment.  
NOTE: The investigator assessment will be based on IMWG criteria (IMWG 2006) [1].
Exploratory Objectives 
The following objectives will be evaluated separately for Expansion Cohort 1 (rrMM) and 
for Expansion Cohort 2 (rMM): 
(1) Objective: To evaluate duration of response (DOR), progression-free survival (PFS) and 
time to progression (TTP) of pembrolizumab in combination with SOC in subjects with 
MM by investigator assessment.
NOTE: The investigator assessment will be based on IMWG criteria (IMWG 2006) [1].
(2) Objective: To evaluate Overall Survival (OS) of pembrolizumab in combination with 
SOC in subjects with MM.
The following exploratory objectives will be evaluated for all subjects enrolled in the study:
(3) Objective: To identify molecular (genomic, metabolic and/or proteomic) determinants of 
response or resistance to pembrolizumab and other treatments in this study, so as to 
define novel predictive and pharmacodynamic biomarkers and understand the mechanism 
of action of pembrolizumab. 
 
 
05FW09


Product:  MK-3475 
23
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
(4) Objective: To explore the PK profile of pembrolizumab in combination with standard of 
care in each study cohort.
4.0 BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death-ligand 1 (PD-L1) and programmed cell 
death-ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies.  Keytruda™ (pembrolizumab) is indicated for the treatment of 
patients across a number of indications.  Refer to the Investigators Brochure (IB) for detailed 
background information on pembrolizumab.
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [2].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [3] [4] [5] [6] [7].  In particular, the presence of CD8+ T-cells and the 
ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [8] 
[9].  The structure of murine PD-1 has been resolved [10].  PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of 
signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor 
tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [8] [11] [12] [13].  The mechanism by which 
PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins [14] [15].  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs, and Natural Killer cells [16] [17].  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
 
 
05FW09


Product:  MK-3475 
24
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
dendritic cells [18].  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors [14] [19] [20] [21].  Both ligands are type I transmembrane receptors 
containing both IgV- and IgC-like domains in the extracellular region and contain short 
cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 
inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at low 
levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas 
PD-L2 protein is only detectably expressed on antigen presenting cells found in lymphoid 
tissue or chronic inflammatory environments.  PD-L2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function 
in peripheral tissues [14].  Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL)
[22].  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2 without ADCC or CDC activity.
Pre-clinical and Clinical Trials
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively promoted CD8+ 
T-cell infiltration into the tumor and the presence of IFN-, granzyme B, and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector 
T-cell function in vivo [23] [24] [25] [26] [27] [28].  Experiments have confirmed the in vivo 
efficacy of PD-1 blockade as a monotherapy as well as in combination with chemotherapy in 
syngeneic mouse tumor models (see the Investigator’s Brochure [IB]).
Ongoing Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, non–small cell lung 
cancer, head and neck cancer, urothelial tract cancer, triple negative breast cancer, gastric 
cancer, and hematologic malignancies. For trial details please refer to the Investigator’s 
Brochure.
The external DMC met on 26-MAY-2017 and 09-JUN-2017 for a review of safety and 
survival data for all patients enrolled in KN183 and KN185 (cutoff date of 22-MAR-2017). 
Based on an imbalance of deaths in both studies, the eDMC recommended that Merck 
suspend enrollment and provide an updated complete safety and efficacy analysis. On 03-
 
 
05FW09


Product:  MK-3475 
25
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
JUL-2017, after review of the data provided to the external DMC the US FDA placed studies 
KN183, KN185 and a cohort of KN023 on full clinical hold.
A full safety and efficacy analysis based on a 02-JUL-2017 data cutoff date was conducted 
for studies KEYNOTE-183 and KEYNOTE-185. A summary of these results is presented 
below. 
KEYNOTE-183
KEYNOTE-183 is a Phase 3, randomized, controlled trial of pomalidomide and low-dose 
dexamethasone with or without pembrolizumab in patients with relapsed and refractory 
multiple myeloma who had received at least two prior lines of therapy. 
Using a data cutoff date of 02-JUN-2017, a complete evaluation of safety and efficacy was 
performed (Figure 2).  There were 249 randomized patients included in the analysis. The 
median follow-up was 8.1 months. For overall survival, there were 29 deaths on the 
pembrolizumab-containing investigational arm and 21 deaths on the control arm. The hazard 
ratio of the pembrolizumab-containing investigational arm compared to the control arm was 
1.61 (95% CI: 0.91, 2.85), increasing the relative risk of death by more than 50% compared 
to the control arm.
Figure 2
Kaplan-Meier Graph of Overall Survival (ITT Population)
The objective response rate was 34% in the investigational arm compared to 40% in the 
control arm. In an exploratory time to progression analysis, a hazard ratio of 1.14 (95% CI: 
0.75, 1.74) was observed (Figure 3).
 
 
05FW09


Product:  MK-3475 
26
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Figure 3
Kaplan-Meier Graph of Time to Progression Per IMWG 2011 Based on 
Confirmed Investigator Review (Primary Censoring Rule) (ITT Population)
There was an 18% increase of severe, Grade 3-5 toxicity (83% vs. 65%, investigational vs. 
control arm). The incidence of serious adverse events was 63% compared to 46% in the 
control arm.  The following non-disease progression causes of death were identified in the 
pembrolizumab arm: myocarditis, Stevens-Johnson syndrome, myocardial infarction, 
pericardial hemorrhage, cardiac failure, respiratory tract infection, neutropenic sepsis, sepsis, 
multiple organ dysfunction, respiratory failure, and unknown.
KEYNOTE-185
KEYNOTE-185 is a Phase 3, randomized, controlled trial of lenalidomide and low-dose 
dexamethasone with or without pembrolizumab in patients with newly diagnosed patients 
with multiple myeloma who are ineligible for autologous stem cell transplant. 
The data cutoff date of 02-JUN-2017 was used for these analyses (Figure 4).  There were 
301 randomized patients included in the analysis. The median follow-up was 6.6 months. For 
overall survival, there were 19 deaths on the pembrolizumab-containing investigational arm, 
and 9 deaths on the control arm.  The hazard ratio of the pembrolizumab-containing 
investigational arm compared to the control arm was 2.06 (95% CI: 0.93, 4.55), more than 
doubling the relative risk of death compared to the control arm.  
 
 
05FW09


Product:  MK-3475 
27
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Figure 4
Kaplan-Meier Graph of Overall Survival (ITT Population)
Additional efficacy analyses based on a 02-JUN-2017 data cutoff date demonstrated an 
objective response rate of 64% in the investigational arm compared to 62% in the control arm
(Figure 5). In an exploratory time to progression analysis, a hazard ratio of 0.55 (95% CI: 
0.20, 1.50) was observed.
 
 
05FW09


Product:  MK-3475 
28
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Figure 5
Kaplan-Meier Graph of Time to Progression Per IMWG 2011 Based on 
Confirmed Investigator Review (Primary Censoring Rule) (ITT Population)
In conclusion, the benefit-risk profile for KEYNOTE 183 and 185 is unfavorable for: 
(1)
the combination of pembrolizumab, pomalidomide and dexamethasone in relapsed 
refractory multiple myeloma, and 
(2)
the combination of pembrolizumab, lenalidomide and dexamethasone in newly 
diagnosed treatment naive multiple myeloma.
KEYNOTE-023
Cohort 1: Based on a data cutoff of 10-MAR-2017, a total of 62 subjects were enrolled in this 
cohort, including dose determination, dose confirmation, and dose expansion. The follow-up 
was 18.9 months. The median overall survival (Figure 6) was not reached and there was a 
total of 16 deaths. Additional efficacy analysis in response evaluable population 
demonstrated an objective response rate of 44.0%. 
 
 
05FW09


Product:  MK-3475 
29
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Figure 6
Kaplan-Meier Estimates of Overall Survival (ASaT Population)
Cohort 2: As of 2017-NOV-03 total of 10 subjects were enrolled in this cohort and no data 
has yet been published.
Rationale for IMiDs as a Combination Agent:
IMiDs (thalidomide, lenalidomide, and pomalidomide) are a class of immunomodulatory 
agents, which are a mainstay in myeloma therapy and in the case of lenalidomide is currently
under investigation in diffuse large B cell lymphoma, and could be rationally combined with 
anti-PD-1 therapy.  IMiDs acquire their designation as “Immunomodulators” designed as 
therapeutic immune stimulators derived from the parent compound thalidomide.  
Lenalidomide, and now pomalidomide, are approved therapies for multiple myeloma. The 
immunostimulatory properties of IMiDs could synergize with anti-PD-1 therapies. Published 
literature suggests that IMiDs have T-cell co-stimulatory and positive effects on antigen 
presenting cells (APCs). T-cell co-stimulation has been demonstrated by increased IFN-g and 
IL-2 production, which result in clonal T-cell expansion and increased natural killer (NK) 
cell activity [29].  There is also evidence of increased IL-12 production in the setting of T-
cell co-stimulation, which activates APCs [30]. 
Rationale for Lenalidomide and Low-dose Dexamethasone in Multiple Myeloma
Lenalidomide is a good choice among the three available IMiDs due to its better safety 
profile compared to thalidomide and broader use in earlier lines of therapy compared to the 
newer pomalidomide in Multiple Myeloma.  Clinical studies have shown that lenalidomide 
has single agent activity in relapsed or refractory MM, and synergistic effects when 
combined with dexamethasone [31] [32] [33] [34]. Two recent pivotal Phase III studies 
(MM-009 and MM-010) have robustly demonstrated the clinical benefit of lenalidomide plus 
high-dose dexamethasone over dexamethasone alone in subjects with relapsed or refractory 
MM [34] [35]. A combined analysis of the data from the two pivotal Phase III studies 
 
 
05FW09


Product:  MK-3475 
30
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
demonstrated that lenalidomide plus high-dose dexamethasone achieved an OR in of 
approximately 60%, including 15% of patients achieving CR, a median OS of 38 months, 
and a median TTP of 13.4 months [36].  According to the National Cancer Institute Common 
Toxicity Criteria, the most common Grade 3–4 adverse events associated with the use of 
lenalidomide plus dexamethasone in clinical trials that included subjects with MM have been 
cytopenias, fatigue, muscle cramps, rash, infection, insomnia, and venous thromboembolism 
(VTE) [31] [32] [33] [34] [35] [37] [38].  Such events are largely manageable through 
subject evaluation and monitoring, dose adjustment, or prophylactic intervention.
Lenalidomide in combination with dexamethasone is indicated for the treatment of subjects 
with multiple myeloma across all lines of therapy. The initial Phase III registration studies of 
lenalidomide were done in combination with high-dose dexamethasone versus high-dose 
dexamethasone alone. The dose of dexamethasone (which was defined as high-dose 
dexamethasone) used for the initial approval by the FDA, in combination with lenalidomide 
in relapse or refractory multiple myeloma, was 40 mg QD PO on Days 1-4, 9-12, and 17-20 
in the first 4 cycles, and on Days 1-4 in Cycle 5 and above in each 28-day treatment cycle. 
However, two recent Phase III randomized studies in newly diagnosed multiple myeloma 
show that combining lenalidomide with low-dose dexamethasone as compared to combining 
with high-dose dexamethasone was safer and more effective. Low-dose dexamethasone was 
defined as 40 mg p.o. on Days 1, 8 15 and 22. These results led to the FDA final approval of 
lenalidomide in combination with low-dose dexamethasone in multiple myeloma. 
The first randomized study (known as E4A03) sponsored by the US National Cancer Institute 
(NCI), and conducted by a network of researchers led by the Eastern Cooperative Oncology 
Group (ECOG), compared combination treatment of lenalidomide and either high- or low-
dose dexamethasone in 445 patients with newly diagnosed multiple myeloma [39]. The dose 
of dexamethasone considered low-dose in this trial was 40 mg on Days 1, 8, 15, and 22 (i.e.,
once weekly) in each 28-day cycle. The study found that patients in the study who received 
low-dose dexamethasone and lenalidomide had a one-year survival of 96 percent compared 
to 87 percent for patients treated with the standard or high-dose of dexamethasone and 
lenalidomide. 
In addition, there were fewer side effects associated with the low-dose
dexamethasone and lenalidomide. 
In the second randomized Phase III study (FIRST trial), 1,623 patients were enrolled to
compare the efficacy and safety of lenalidomide and low-dose dexamethasone (Rd) given 
continuously or for 18 cycles versus melphalan, prednisone, and thalidomide (MPT) in newly 
diagnosed multiple myeloma patients who were not candidates for stem cell transplant [40]. 
In the first arm of the study, lenalidomide plus low-dose dexamethasone were given 
continuously until progressive disease (Rd Continuous). In the second arm, lenalidomide 
plus low-dose dexamethasone were given for up to eighteen 28-day cycles. In the third arm, 
melphalan, prednisone, and thalidomide (MPT) were given for a maximum of twelve 42-day 
cycles. Patients in any of the lenalidomide arms received lenalidomide 25 mg once daily on 
Days 1 to 21 of 28-day cycles. Dexamethasone was administered at 40 mg once daily on 
Days 1, 8, 15, and 22 of each 28-day cycle. For patients over > 75 years old, the starting 
 
 
05FW09


Product:  MK-3475 
31
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
dose of dexamethasone was 20 mg orally once daily on Days 1, 8, 15, and 22 of repeated 28-
day cycles. 
Progression-free survival (PFS) was significantly longer with Rd Continuous than MPT: HR 
0.72 (95% CI: 0.61-0.85 p <0.0001).
The improvement in median PFS time in the Rd 
Continuous arm compared with the MPT arm was 4.3 months. Objective response rate 
(ORR) was higher with Rd Continuous compared with MPT (75.1% versus 62.3%); with 
complete responses in 15.1% of Rd Continuous arm patients versus 9.3% in the MPT arm. 
The median time to first response was 1.8 months in the Rd Continuous arm versus 2.8 
months in the MPT arm.
For the interim OS analysis, the median follow-up time for all 
patients was 45.5 months and the observed OS HR was 0.75 for Rd Continuous versus MPT 
(95% CI = 0.62, 0.90).
Rationale for Proteasome Inhibitors as a Combination Agent
Proteasome inhibitors (bortezomib, carfilzomib and ixazomib) are a class of drugs widely 
used across all lines of therapy in multiple myeloma, which could be rationally combined 
with anti-PD-1 therapy. Several clinical studies indicate proteasome inhibitor activity is 
enhanced when combined with immune-modulatory drugs [41] [42] [43] [44] [45]. 
Moreover, in immunotherapy animal models involving low-avidity antigens [46] [47], the 
proteasome inhibitor bortezomib activated NF-κB p65 in CD8+ T cells, stabilizing expression 
of T-cell receptor CD3ζ and IL2 receptor-α, while maintaining IFNγ secretion to improve 
FasL-mediated tumor lysis. Notably, bortezomib increased tumor cell surface expression of 
Fas in mice as well as human melanoma tissue from a responsive patient. In renal tumor-
bearing immunodeficient Rag2−/−
mice, bortezomib treatment after adoptive T-cell 
immunotherapy reduced lung metastases and enhanced host survival. Our findings highlight 
the potential of proteasome inhibitors to enhance antitumor T-cell function in the context of 
cancer immunotherapy.
Rationale for Carfilzomib and Low-dose Dexamethasone in Multiple Myeloma
Carfilzomib is a keto-epoxide tetrapeptide proteasome inhibitor recently approved for the 
treatment of relapsed or refractory MM in combination with lenalidomide and low-dose
dexamethasone or with low-dose dexamethasone alone. 
In the ASPIRE Phase 3 trial of 792 patients, carfilzomib in combination with lenalidomide 
and low-dose dexamethasone (KRd)
was superior to lenalidomide and low-dose 
dexamethasone (Rd) in terms of response rates, PFS, and OS [48]. Progression-free survival 
was significantly longer for KRd than Rd (median, 26.3 months, vs. 17.6 months in the 
control group; HR 0.69; 95% CI: 0.57 to 0.83; p = 0.0001). The 2-year overall survival rates 
were 73.3% and 65.0% in the carfilzomib and control groups respectively (HR 0.79; 95% CI:
0.63 to 0.99; p = 0.04). Objective response rate (ORR) was higher with KRd compared with 
Rd (87.1% versus 66.7%, p <0.001) 
Support for carfilzomib as a more potent proteasome inhibitor than bortezomib comes from a 
randomized Phase 3 trial (ENDEAVOR) in which carfilzomib-dexamethasone (Kd) was
 
 
05FW09


Product:  MK-3475 
32
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
compared with bortezomib-dexamethasone (Vd) in 929 subjects with relapsed MM [49].
Median progression-free survival was 18.7 months (95% CI: 15.6–not estimable) in the 
carfilzomib group versus 9.4 months (CI: 8·4–10·4) in the bortezomib group at a preplanned
interim analysis (HR 0.53; 95% CI: 0.44–0.65; p<0·0001). Objective response rate (ORR) 
was higher with Kd compared with Vd (77 % versus 63%, p<0.0001). At the time of the 
analysis overall survival data was still immature and subjects continued on follow up.
This Phase I trial will establish the safety and tolerability of pembrolizumab in combination 
with lenalidomide and low-dose dexamethasone in subjects with refractory or relapsed and 
refractory MM or in combination with carfilzomib and low-dose dexamethasone in subjects 
with relapsed or refractory MM.
Rationale
Rationale for the Trial and Selected Subject Population
Rationale for Evaluating anti-PD-1 Therapy in Multiple Myeloma
Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in the 
bone marrow leading to bone destruction and marrow failure.
It accounts for 10% of all 
hematological malignancies, with an incidence of 5 cases per 100,000/year and a median age 
at onset of 65 to 70 years [50] [51] [52] [53].  The American Cancer Society has estimated 
21,700 new cases of MM in the United States in 2012, with an estimated 10,710 deaths [54].
It is diagnosed by the presence of monoclonal plasma cell proliferation with more than 10% 
plasma cells in the bone marrow, presence of monoclonal proteins in serum, and/or in urine 
with one or more of end organ effects such as hypercalcemia, renal failure, anemia, or bone 
destruction (CRAB
features) [55] [56].  Multiple myeloma is responsive to 
immunomodulatory drugs like lenalidomide. Although, improvements in overall survival 
have been achieved with newer therapies such as proteasome inhibitors and 
immunomodulatory drugs (IMiDs), myeloma remains an incurable disease. Relapsed and 
refractory MM patients have an overall survival of ~12 months, but only 3 months if they 
receive no therapy following relapse; thus reflecting the poor outcome among these patients 
[57] [58] [59].
In Multiple Myeloma, PD-L1 is expressed on most MM plasma cells [60], and PD-L1 
overexpression enhanced MM invasiveness and rendered tumor cells less susceptible to 
cytotoxic T lymphocytes (CTLs).
This effect was alleviated by anti-PD-L1 antibody 
treatment, demonstrating the importance of the PD-1/PD-L1 pathway in this process [61]. In 
addition, a recent report demonstrated increased levels of PD-L1 on MM cells together with 
enhanced PD-1 expression on T cells with an “exhausted” phenotype. The 
immunosuppressive effects of myeloma are overcome by PD-L1 blockade [62].  A Phase 1 
clinical trial conducted in advanced hematologic malignancies using CT-011, a humanized 
antibody anti-PD-1, showed clinical responses in 6 of 17 subjects including HL and NHL 
while stable disease where observed in multiple myeloma patients [63]. 
 
 
05FW09


Product:  MK-3475 
33
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Rationale for Dose Selection/Regimen
The dose of pembrolizumab planned to be studied in this trial is 200 mg.  The dose recently 
approved in the United States and several other countries for treatment of melanoma subjects 
is 2 mg/kg Q3W.  Information on the rationale for selecting 200 mg is summarized below.
In KEYNOTE-001, an open-label Phase I study is being conducted to evaluate the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and antitumor activity of 
single agent pembrolizumab.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg and 10 mg/kg, administered every 2 weeks (Q2W) and dose 
expansion cohorts evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects with advanced 
solid tumors.  All dose levels were well tolerated, and no dose limiting toxicities were 
observed.  This first-in-human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels.  No maximum 
tolerated dose (MTD) has been identified.  In addition, two randomized cohort evaluations of 
melanoma subjects receiving pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W 
have been completed, and one randomized cohort evaluating 10 mg/kg Q3W versus 10 
mg/kg Q2W has also been completed.  The clinical efficacy and safety data demonstrate a 
lack of important differences in efficacy or safety profile across doses. 
An integrated body of evidence suggests that 200 mg every 3 weeks (Q3W) is expected to 
provide similar response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W.  Previously, 
a flat pembrolizumab exposure-response relationship for efficacy and safety has been found 
in subjects with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  Exposures 
for 200 mg Q3W are expected to lie within this range and will be close to those obtained with 
2 mg/kg Q3W dose.  
A population pharmacokinetic (PK) model, which characterized the influence of body weight 
and other patient covariates on exposure, has been developed.  The PK profile of 
pembrolizumab is consistent with that of other humanized monoclonal antibodies, which 
typically have a low clearance and a limited volume of distribution.  The distribution of 
exposures from the 200 mg fixed dose are predicted to considerably overlap those obtained 
with the 2 mg/kg dose and importantly will maintain individual patient exposures within the 
exposure range established in melanoma as associated with maximal clinical response.  
Pharmacokinetic properties of pembrolizumab, and specifically the weight-dependency in 
clearance and volume of distribution are consistent with no meaningful advantage to weight-
based dosing relative to fixed dosing.   
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the antitumor
effect of pembrolizumab is driven through immune system activation rather than through a 
direct interaction with tumor cells, rendering it independent of the specific tumor type.  In 
addition, available PK results in subjects with melanoma, NSCLC, and other tumor types 
support a lack of meaningful difference in pharmacokinetic exposures obtained at tested 
doses among tumor types.  Thus the 200 mg fixed dose regimen is considered an appropriate 
fixed dose for other tumor indications as well.  
 
 
05FW09


Product:  MK-3475 
34
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage.  The existing data suggest 
200 mg as the appropriate dose for pembrolizumab.
Rationale for Endpoints
Safety Endpoints
The primary objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in combination with lenalidomide and low-dose dexamethasone or 
carfilzomib and low-dose dexamethasone in subjects with MM.  The primary safety analysis 
will be based on subjects who experienced toxicities as defined by CTCAE criteria. Safety 
will be assessed by quantifying the toxicities and grades of AEs experienced by subjects who 
have received pembrolizumab, including SAEs and events of clinical interest (ECIs).
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0
(Appendix 12.6). The attribution to drug, time-of-onset, duration of the event, its resolution, 
and any concomitant medications administered will be recorded. Adverse events will be 
analyzed including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes.
Furthermore, the occurrence of specific immune-related adverse events (irAEs) will be 
collected and designated as immune-related events of clinical interest (ECIs) as described in 
Section 7.2.3.2.
Efficacy Endpoints
The efficacy objective of this trial is to evaluate the antitumor activity of pembrolizumab in 
combination with SOC for the different cohorts:

Dose Determination, Dose Confirmation, and Cohort 1: In combination with 
lenalidomide and low-dose dexamethasone in subjects with rrMM

Cohort 2: In combination with carfilzomib and low-dose dexamethasone in subjects 
with rMM
Efficacy will be assessed based on objective response rate (ORR) as assessed by the 
investigator per the International Myeloma Working Group criteria for multiple myeloma
(IMWG 2006 Criteria) (Appendix 12.7) [1].
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses, which may be functionally 
anergic. The response patterns seen with such an approach may extend beyond the typical 
time course of responses seen with cytotoxic agents, and can manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions. Standard 
response assessment criteria may not provide a comprehensive response assessment of
immunotherapeutic agents such as pembrolizumab. Although disease response assessment 
will be performed on day 1 of every 28-day treatment cycle for all cohorts, treatment 
 
 
05FW09


Product:  MK-3475 
35
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
decisions will be based on the Week 12 response assessment. For subjects with biochemical 
progression two consecutive assessments are needed to confirm PD, according to IMWG
2006. In the setting where a subject’s disease response assessment shows confirmed PD
according to the IMWG criteria, the subject may continue on study treatment if the 
investigator considers the subject is deriving clinical benefit from study treatment upon
consultation with the Sponsor.
Biomarker Research
Cancer immunotherapies are an important novel class of antitumor agents. However, much 
remains to be learned about how cancer immunotherapies work and how best to leverage 
these new drugs in treating patients.  Thus, to aid future patients, it is important to 
investigate the determinants of response or resistance to cancer immunotherapy as well as 
determinants of AEs in the course of our clinical trials. To that end we seek to define novel 
predictive/pharmacodynamic biomarkers and the best strategies of combination therapy with 
immuno-oncology drugs. To fully leverage the clinical data collected in this trial, we will 
also collect biospecimens (blood components, tumor material, etc.) to support biomarker 
analyses of cellular components (e.g., protein, DNA, RNA, metabolites) and other blood 
soluble molecules.  
Investigations may include but are not limited to: 
Germline (blood) for genetic analyses (e.g., SNP analyses, whole exome sequencing, 
whole genome sequencing):  
This research will evaluate whether genetic variation within a clinical trial population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations.
Finally, microsatellite
instability (MSI) may be evaluated as this is an important biomarker for some cancers (i.e., 
colorectal cancer).
Genetic (DNA) analyses from tumor:  
The application of new technologies, such as next-generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (i.e., mutations, 
methylation status, microsatellite instability etc).
Key molecular changes of interest to 
immune-oncology drug development are the mutational burden of tumors and the clonality of 
T-cells in the tumor microenvironment. Increased mutational burden (sometimes referred to 
as a ‘hyper-mutated’ state) is one of the major mechanisms of neo-antigen presentation in the 
context of a tumor. There is a potential that in the hyper-mutated state, the presence of neo-
antigen mutational patterns and the detection of increased T-cell clonality, both of which can 
be determined by use of next-generation sequencing methods, may correlate with response to 
pembrolizumab therapy and/or that the converse, the ‘hypomutated’ state (the absence of 
neo-antigens) may correlate with non-response. To conduct this type of research, it is 
 
 
05FW09


Product:  MK-3475 
36
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
important to identify tumor-specific mutations that occur across all genes in the tumor 
genome. Thus, genome-wide approaches may be used for this effort. Note that in order to 
understand tumor-specific mutations, it is necessary to compare the tumor genome with the 
germline genome. Microsatellite instability (MSI) may also be evaluated as this is an 
important biomarker for some cancers (i.e., colorectal cancer).
Tumor and blood RNA analyses: 
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/ immune 
phenotype. Specific immune-related gene sets (such as those capturing interferon-gamma 
transcriptional 
pathways)
may 
be 
evaluated 
and 
new 
signatures 
may 
be 
identified.  Individual genes related to the immune system may also be evaluated (e.g., IL-
10). MicroRNA profiling may also be pursued. 
Proteomics and immunohistochemistry (IHC) using blood or tumor:
Tumor and blood samples from this study may undergo proteomic analyses (e.g., PD-L1 
IHC). PD-L1 protein level, as assessed by IHC in tumor sections, has been shown to 
correlate with response to pembrolizumab in patients with NSCLC and melanoma, and a PD-
L1 IHC diagnostic is marketed for use with pembrolizumab in NSCLC.  Preliminary data 
indicates that this association may also be true in additional cancer types (i.e., TNBC, H&N 
and gastric). Additional tumor or blood-derived proteins may also correlate with response to 
pembrolizumab. Therefore, tumor tissue may be subjected to proteomic profiling using a 
variety 
of 
platforms 
that 
could 
include 
but 
are 
not 
limited 
to 
cytometry, 
immunohistochemistry, immunoassay, liquid chromatography/mass spectrometry.
This 
approach could identify novel protein biomarkers that could aid in patient selection for 
pembrolizumab (MK-3475) therapy. 
Other blood-derived biomarkers: 
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as enzyme-linked immunoassay 
measure such proteins in serum. Correlation of expression with response to pembrolizumab 
therapy may identify new approaches for predictive biomarkers in blood representing a major 
advance from today’s reliance on assessing tumor biomarkers. This research would serve to 
develop such assays for future clinical use. 
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on DNA, blood, and bone marrow
specimens collected during this clinical trial.  This research may include genetic analyses 
 
 
05FW09


Product:  MK-3475 
37
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of Future 
Biomedical Research are presented in Section 12.2 - Collection and Management of 
Specimens for Future Biomedical Research.  Additional informational material for 
institutional review boards/ethics committees (IRBs/ERCs) and investigational site staff is 
provided in Section 12.3.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with multiple myeloma (MM) of at least 18 years of age will be 
enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
Dose Determination Stage, Dose Confirmation Stage, Cohort 1:
1. Be willing and able to provide written informed consent/assent for the trial.
The 
subject may also provide consent/assent for Future Biomedical Research. However, 
the subject may participate in the main trial without participating in Future 
Biomedical research.
2. Be 18 years of age on the day of signing informed consent.
3. Has a confirmed diagnosis of multiple myeloma based on standard criteria (see Durie 
1986 for criteria [64]). See Appendix 12.4 for MM Diagnostic Criteria.
 
 
05FW09


Product:  MK-3475 
38
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
4. Currently has MM with measurable disease, defined as:
o
a monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 
g/dL and/or 
o
urine monoclonal protein levels of at least 200 mg/24 hours 
o
for subjects without measurable serum and urine M-protein levels, an 
abnormal free light chain ratio (normal value: 0.26 - 1.65) with involved FLC 
level ≥10 mg/dL (≥100 mg/L).
5. Must have undergone prior treatment with ≥ 2 treatment lines of anti-myeloma 
therapy and must have failed their last line of treatment defined as documented 
disease progression during or within 60 days of completing their last anti-myeloma 
therapy (refractory to last line of treatment). 
6. Prior anti-myeloma treatments must have included an IMiD (lenalidomide, 
pomalidomide
or thalidomide) AND proteasome inhibitor (bortezomib or 
carfilzomib) alone or in combination and subject must have failed therapy with an 
IMiD OR proteasome inhibitor defined as one of the following:

Refractory: Documented progressive disease on or within 60 days of 
completing treatment with an IMiD and/or proteasome inhibitor OR

Relapsed and refractory: In case of prior response [≥ partial response (PR)] to 
an IMiD or proteasome inhibitor, subjects must have relapsed within 6 months 
after stopping treatment with an IMiD and/or proteasome inhibitor containing 
regimen.
7. Be able to provide archival or newly obtained bone marrow material for disease 
assessment.  In addition, for subjects in the US and Canada, be able to provide newly 
obtained bone marrow aspirate for biomarker analysis.
8. Has a performance status of 0 or 1 on the ECOG Performance Scale.
9. Demonstrate adequate organ function as defined by the following table (Table 1). All 
screening labs should be performed within 7 days of treatment initiation.
 
 
05FW09


Product:  MK-3475 
39
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,000 /mcL
Platelets
≥75,000 / mcL 
Hemoglobin
≥8 g/dL 
Renal
Blood creatinine OR
Measured or calculated1 creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤ 1.5 X upper limit of normal (ULN) 
OR
≥ 60 mL/min for subject with creatinine 
levels > 1.5 X institutional ULN
Hepatic
Blood total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with 
total bilirubin levels > 1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN  
Coagulation
International 
Normalized 
Ratio 
(INR) 
or 
Prothrombin Time (PT)
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy as long as PT or 
PTT is within therapeutic range of 
intended use of anticoagulants
Activated Partial Thromboplastin Time (aPTT)
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy as long as PT or 
PTT is within therapeutic range of 
intended use of anticoagulants
1 Creatinine clearance should be calculated per institutional standard.
10. All subjects must agree to follow the regional requirements for lenalidomide counseling, 
pregnancy testing, and birth control and be willing and able to comply with the regional 
requirements (for example, periodic pregnancy tests, safety labs, etc.).
11. Female subjects of childbearing potential should have a negative urine or serum 
pregnancy test within 10-14 days prior to and again within 24 hours prior to receiving
the first dose of pembrolizumab, lenalidomide and dexamethasone.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Female subjects of childbearing potential should agree to ongoing pregnancy testing.
12. Female subjects of childbearing potential must be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.3).
Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 2 years.
NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
 
 
05FW09


Product:  MK-3475 
40
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
13. Male subjects must agree to use a latex condom during sexual contact with females of 
childbearing potential, even if they have had a successful vasectomy, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.
NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
14. Subject is able to swallow capsules and is able to take or tolerate oral medications on 
a continuous basis.
Cohort 2:
1. Be willing and able to provide written informed consent/assent for the trial.  The 
subject may also provide consent/assent for Future Biomedical Research. However, 
the subject may participate in the main trial without participating in Future 
Biomedical research.
2. Be 18 years of age on the day of signing informed consent.
3. Multiple myeloma with relapsing or refractory disease at study entry. 
4. Currently has MM with measurable disease, defined as:
o
a monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 
g/dL and/or 
o
urine monoclonal protein levels of at least 200 mg/24 hours or
o
for subjects without measurable serum and urine M-protein levels, an 
abnormal free light chain ratio (normal value: 0.26 - 1.65) with involved FLC 
level ≥10 mg/dL (≥100 mg/L).
5. Received prior treatment with 1 to 3 lines for multiple myeloma. (Induction therapy 
followed by stem cell transplant and consolidation/maintenance therapy will be 
considered as one line of therapy.)
6. Achieved a partial response to at least one prior regimen (defined as ≥ 50% decrease 
in tumor burden). 
NOTE: Prior treatment with carfilzomib is allowed if subject achieved at least a 
partial response to prior carfilzomib therapy, was not discontinued due to toxicity and 
had at least 6 months carfilzomib free treatment interval before entering the study.
NOTE: Prior treatment with bortezomib is allowed if subject achieved at least a 
partial response to prior bortezomib therapy, was not discontinued due to toxicity and 
had at least 6 months bortezomib free treatment interval before entering the study. 
 
 
05FW09


Product:  MK-3475 
41
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
7. Be able to provide archival or newly obtained bone marrow material for disease 
assessment.  In addition, for subjects in the US and Canada, be able to provide newly 
obtained bone marrow aspirate for biomarker analysis.
8. Has a performance status of 0 or 1 on the ECOG Performance Scale 
9. Left ventricular ejection fraction of at least 40%.
10.Demonstrate adequate organ function as defined by the following table (Table 2). All 
screening labs should be performed within 7 days of treatment initiation.
Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,000 /mcL
Platelets
≥75,000 / mcL 
Hemoglobin
≥8 g/dL 
Renal
Blood creatinine OR
Measured or calculated1 creatinine clearance
(GFR can also be used in place of creatinine or CrCl)
≤ 1.5 X upper limit of normal 
(ULN) OR
≥ 60 mL/min for subject with 
creatinine 
levels 
> 
1.5 
X 
institutional ULN
Hepatic
Blood total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for 
subjects with total bilirubin 
levels > 1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN  
Coagulation
International Normalized Ratio (INR) or Prothrombin 
Time (PT)
≤1.5 X ULN unless subject is 
receiving anticoagulant therapy 
as long as PT or PTT is within 
therapeutic range of intended 
use of anticoagulants
Activated Partial Thromboplastin Time (aPTT)
≤1.5 X ULN unless subject is 
receiving anticoagulant therapy 
as long as PT or PTT is within 
therapeutic range of intended 
use of anticoagulants
1 Creatinine clearance should be calculated per institutional standard.
11.Female subjects of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.
 
 
05FW09


Product:  MK-3475 
42
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
12.Female subjects of childbearing potential (Section 5.7.3) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.3 – Contraception, for 
the course of the study through 120 days after the last dose of study medication.
NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
13.Male subjects of childbearing potential (Section 5.7.3) must agree to use an adequate 
method of contraception as outlined in Section 5.7.3 – Contraception, starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.
NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
Dose Determination Stage, Dose Confirmation Stage, Cohort 1:
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment.
2. Has history of repeated infections, primary amyloidosis, hyperviscosity, plasma cell 
leukemia, POEMS syndrome or Waldenström's macroglobulinemia.
3. Has a diagnosis of immunosuppressive disorder or is on any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.
4. Has received a prior monoclonal antibody within 4 weeks prior to study Day 1 or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from a baseline AE or a Grade 
1 adverse event associated with agents administered more than 4 weeks earlier. 
5. Has had prior anti-myeloma therapy (including dexamethasone), targeted small 
molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 who has 
not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously 
administered agent.
NOTE:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the trial.
NOTE:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting therapy. 
 
 
05FW09


Product:  MK-3475 
43
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
NOTE: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the 
inclusion requirements for laboratory parameters defined in Table 1.
6. Has a known additional malignancy that is progressing or requires active treatment 
within the last 5 years. Exceptions include basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone 
potentially curative therapy.
7. Has known clinically active CNS involvement.
8. Has an active autoimmune disease or a documented history of autoimmune 
disease/syndrome that requires systemic steroids or immunosuppressive agents.  
Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to 
this rule.  Subjects that require intermittent use of bronchodilators or local steroid 
injections would not be excluded from the study.  Subjects with hypothyroidism 
stable on hormone replacement or Sjogren’s syndrome will not be excluded from the 
trial.
9. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
10. Has an active infection requiring intravenous systemic therapy.
11. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
12. Is pregnant or breastfeeding, or is expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or Screening Visit 
through 120 days after the last dose of trial treatment.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation 
or checkpoint pathways).
14. Has a known Human Immunodeficiency Virus (HIV), or known active Hepatitis B 
(HBV), or known active Hepatitis C (HCV) infection.
15. Has a clinically significant coagulopathy per investigator’s assessment.
16. Has known symptomatic congestive heart failure, unstable angina pectoris, or 
cardiac arrhythmia.
17. Has received or is planning for an allogeneic stem cell transplant. 
18. Has received autologous stem cell transplant within 12 weeks before the first 
infusion. 
 
 
05FW09


Product:  MK-3475 
44
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
19. Subjects with a prior history of Grade 4 rash associated with thalidomide treatment.
20. Has known hypersensitivity to thalidomide, lenalidomide or pomalidomide.
21. Has known gastrointestinal disease that may significantly alter the absorption of 
lenalidomide.
22. Is unable or unwilling to undergo antithrombotic prophylactic treatment.
23. Has received a live vaccine within 30 days prior to first dose.
24. Is or has an immediate family member (spouse or children) who is investigational 
site or sponsor staff directly involved with this trial, unless prospective IRB approval 
(by chair or designee) is given allowing exception to this criterion for a specific
subject.
Cohort 2:
1. Is currently participating and receiving study therapy or has participated in a study 
of an investigational agent and received study therapy or used an investigational 
device within 4 weeks of the first dose of treatment.
2. Subjects with smoldering multiple myeloma (SMM), monoclonal gammopathy of 
undetermined significance (MGUS), plasma cell leukemia or Waldenström's 
macroglobulinemia.
3. Has history of repeated infections, primary amyloidosis, hyperviscosity or
POEMS syndrome. 
4. Has a known history of immunosuppression or is receiving systemic steroid 
therapy or any other form of systemic immunosuppressive therapy within 7 days 
prior to the first dose of trial treatment.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
5. Has received a prior monoclonal antibody within 4 weeks prior to study Day 1 or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from a baseline AE or a 
Grade 1 adverse event associated with agents administered more than 4 weeks 
earlier. 
6. Significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 days prior to 
the first dose of treatment. 
NOTE:  Subjects with Grade 1 or Grade 2 (without pain) neuropathy are an 
exception to this criterion and may qualify for the trial.
 
 
05FW09


Product:  MK-3475 
45
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
7. Has had prior  anti-myeloma therapy (including dexamethasone), targeted small 
molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 who 
has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a 
previously administered agent. 
NOTE:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.  
NOTE: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the 
inclusion requirements for laboratory parameters defined in Table 2.
8. Has a known additional malignancy that is progressing or requires active 
treatment within the last 5 years.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or in situ cervical cancer that has undergone potentially curative therapy.
9. Has an active autoimmune disease that has required systemic treatment in the past 
2 years
(i.e.,
with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs).  Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.
10. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
11. Has an active infection requiring intravenous systemic therapy, antiviral or
antifungal agents within 14 days prior to the first dose of treatment.
12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
13. Is pregnant or breastfeeding, or is expecting to conceive or father children within 
the projected duration of the trial, starting with the pre-screening or Screening 
Visit through 120 days after the last dose of trial treatment.
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody 
(including ipilimumab or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways).
15. Has a known Human Immunodeficiency Virus (HIV), or known active Hepatitis 
B (HBV), or known active Hepatitis C (HCV) infection.
16. Has a clinically significant coagulopathy per investigator’s assessment.
 
 
05FW09


Product:  MK-3475 
46
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
17. Myocardial infarction within 4 months prior to randomization, NYHA Class III or 
IV heart failure, uncontrolled angina, history of severe coronary artery disease, 
severe uncontrolled 
ventricular arrhythmias, sick sinus syndrome, or 
electrocardiographic evidence of acute ischemia or Grade 3 conduction system 
abnormalities unless subject has a pacemaker.
18. Has received within the last 5 years or is planning for an allogeneic stem cell 
transplant.
19. Has received autologous stem cell transplant within 12 weeks before the first 
infusion. 
20. Has received a live vaccine within 30 days prior to first dose.
21. Known history of allergy to Captisol® (a cyclodextrin derivative used to 
solubilize carfilzomib).
22. Patients with hypersensitivity to carfilzomib, bortezomib, boron, or mannitol.
23. Contraindication to any of the required concomitant drugs or supportive 
treatments, including hypersensitivity to all anticoagulation and antiplatelet 
options, antiviral drugs, or intolerance to hydration due to pre-existing pulmonary 
or cardiac impairment.
24. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to the 
first dose of treatment.
25. Subjects with pleural effusions requiring thoracentesis or ascites requiring 
paracentesis within 14 days prior to the first dose of treatment.
Trial Treatment(s)
Trial treatment should be administered starting with Day 1 of the first 28-day cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatment may be administered up to 3 days before or after the scheduled day of 
administration due to administrative reasons. Subjects may continue on treatment until 
confirmed disease progression or until meeting other discontinuation criteria (Section 5.8).
The treatments to be used in this trial are outlined below in Table 3.
 
 
05FW09




Product:  MK-3475 
48
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
Pembrolizumab will be given as a fixed dose of 200 mg. 
Lenalidomide [Dose Determination, Dose Confirmation, Cohort 1]
The recommended starting dose of lenalidomide is 25 mg once daily on Days 1 through 21 of 
repeated 28-day cycles. If 25 mg dose of lenalidomide is not tolerated due to toxicity, the 
dose could be decreased according to Section 5.2.1.2.3 of this protocol.  Lenalidomide should 
be taken orally at about the same time each day, either with or without food. Lenalidomide 
capsules should be swallowed whole with water. The capsules should not be opened, broken, 
or chewed. Refer to local product label for more details.
Carfilzomib [Cohort 2]
The recommended starting dose of carfilzomib is 20 mg/m2/day on Days 1 and 2 of Cycle 1. 
If tolerated, the dose should be escalated to a target dose of 56 mg/m2/day starting on Day 8, 
and continuing on Day 9, 15, and 16 of Cycle 1, then on Days 1, 2, 8, 9, 15 and 16 of 
subsequent cycles. Dose modifications and dose reductions are outlined in Section 5.2.1.2.5.  
Carfilzomib will be administered intravenously as a 30 minute infusion on two consecutive 
days each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest 
period (Days 17 to 28). 
Treatment with carfilzomib requires pre-treatment medications; see Section 5.5.1.1 for 
specific details.  
Dexamethasone [All Subjects]
Dose Determination, Dose Confirmation, and Cohort 1:  The recommended dose of 
dexamethasone is 40 mg once weekly on Days 1, 8, 15, and 22 of each 28-day cycle. A 
dexamethasone dose of 20 mg once weekly on Days 1, 8, 15, and 22 in subjects aged >75 
years is recommended. Refer to local product label for more details.  
Cohort 2:  Dexamethasone 20 mg is taken by mouth or intravenously on Days 1, 2, 8, 9, 15, 
16, 22, and 23 of each 28-day cycle. Administer dexamethasone 30 minutes to 4 hours before 
carfilzomib on the day of the infusion.
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. The local product labels 
and institutional standards should be referenced for lenalidomide, carfilzomib and 
dexamethasone.
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
On 03-JUL-2017, the US FDA placed KN183, KN185, and cohort 1 of KN023 on clinical 
hold based on safety data from KN183 and KN185 presented to the DMC.  The FDA 
 
 
05FW09


Product:  MK-3475 
49
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
determined that the risks of pembrolizumab plus pomalidomide or lenalidomide outweighed 
any potential benefit for patients with multiple myeloma.  Based on this decision, the 
treatment phase of KN183, KN185, and Cohort 1 of KN023 is closed effective immediately.  
All subjects must stop study treatment, complete the Discontinuation Visit and move into the 
long-term safety and survival follow-up (every 12 weeks) per protocol.
On 15-SEP-2017, the US FDA placed Cohort 2 of KN023, on partial clinical hold. 
Enrollment was stopped and all subjects who derived clinical benefit from therapy are 
allowed to continue if reconsented, at least verbally. Enrollment will not be reopened by the 
sponsor after a full safety and efficacy evaluation did not demonstrate any significant 
difference from historical controls. Those subjects who are already enrolled and deriving 
clinical benefit from therapy were allowed to continue if reconsented, at least verbally, and 
will continue on study until protocol-specific end of treatment, and then progress into long 
term safety and follow-up. Those subjects who are not deriving clinical benefit, must stop 
study treatment, complete the Discontinuation Visit and move into the long term safety and 
follow-up per protocol.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
Dose Selection
The rationale for selection of doses to be used in this trial is provided in Section 4.2.2 –
Background and Rationale.
The amount required to prepare the pembrolizumab infusion solution will be based on the
subject’s weight in kilograms (kg) for Dose Determination. During Dose Confirmation and 
Expansion Cohort 1, a fixed dose of pembrolizumab will be given Q2W.  Subjects in 
Expansion Cohort 2 will receive pembrolizumab 200 mg Q3W.  Details on the dose 
calculation, reconstitution, preparation of infusion fluid, and administration are provided in 
the Pharmacy Manual.
Please refer to the local product label for dosing details of 
lenalidomide, carfilzomib and dexamethasone.
Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Guidelines for Dose Modification
During Dose Determination, if dose modifications are necessary during the DLT observation 
period due to drug-related AEs that do not meet DLT criteria, then this would be considered 
a DLT. Following the DLT evaluation period, for Grade 3 and 4 toxicities, the dose of 
pembrolizumab, lenalidomide, and dexamethasone could be modified as outlined in Table 4, 
Table 5, Table 7, Table 8, Table 9, Table 10 and Table 11. 
 
 
05FW09


Product:  MK-3475 
50
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
In Cohort 2, for the initial 6 subjects in the safety run in, carfilzomib dose modifications are 
allowed in accordance with Table 13 and Table 14. During the safety run in, any drug-
related AEs, which in the opinion of the investigator cannot be managed by the carfilzomib 
dose modifications outlined in Table 13 and Table 14, will be considered a DLT.  After the 
safety run in for the initial 6 subjects have been completed, the dose of pembrolizumab, 
carfilzomib and dexamethasone can be modified as outlined in Table 4, Table 5, Table 10, 
Table 13 and Table 14.  
Subjects who discontinue lenalidomide, carfilzomib or dexamethasone due to toxicity, may 
continue receiving pembrolizumab until unacceptable toxicity or progression.  Subjects who 
discontinue pembrolizumab due to untoward toxicities may not continue on the study 
receiving only lenalidomide or carfilzomib, and dexamethasone. 
After any study medication has been held for any reason, it may be restarted when clinically 
indicated according to any applicable dose modification guidelines and the dosing schedule 
conforms to the schedule of the normal dosing cycle.  Missed doses should be skipped, not 
delayed, if not given within the allowed window.  
5.2.1.2.2 Dose Modification Guidelines for Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for
drug-related toxicities and severe or life-threatening AEs as per Table 4 and Table 5 below. 
See Section 5.6.1 for supportive care guidelines, including use of corticosteroids.
Table 4
Dose Modification Guidelines for Hematological Drug-Related Adverse Events
Toxicity
Grade
Hold 
Treatment 
(Y/N)
Timing for 
restarting 
treatment
Discontinue Subject 
(after consultation 
with Sponsor)
Hematological Toxicity
1, 2, 3
No
N/A
N/A
4 
Yes
Toxicity 
resolves to 
Grade 0-1 or 
baseline
Toxicity does not 
resolve within 4 
weeks of last infusion
Permanent 
discontinuation 
should be considered 
for any severe or life-
threatening event
 
 
05FW09


Product:  MK-3475 
51
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than on body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 5.
 
 
05FW09


Product:  MK-3475 
52
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and 
symptoms of pneumonitis

Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (i.e. diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation (i.e. 
peritoneal signs and ileus).

Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
05FW09


Product:  MK-3475 
53
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
AST / ALT 
elevation or 
Increased 
Bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for participants with 
T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (e.g. propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
Permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (e.g. levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
renal dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
 
 
05FW09


Product:  MK-3475 
54
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All Other 
immune-related 
AEs
Intolerable/ 
Persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  GBS 
(Guillain-Barre 
Syndrome), SOTR 
(solid organ 
transplant 
rejection), 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
05FW09


Product:  MK-3475 
55
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 6. 
Table 6
Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise, dosing will be 
held until symptoms resolve and the subject
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration.
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable, in the opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration.
 
 
05FW09


Product:  MK-3475 
56
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Other allowed dose interruption for pembrolizumab 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record.
Subjects who experience a DLT in Cycle 1 should be discontinued from the study. However,
the subject may be allowed to continue if it has been determined that the subject is deriving 
clinical benefit from the study therapy. It should be noted that if the dose of pembrolizumab 
is interrupted due to toxicity, the lenalidomide/low-dose dexamethasone or carfilzomib/low-
dose dexamethasone may continue to be administered per standard of care based on 
investigator’s assessment as appropriate.
5.2.1.2.3 Dose Modification Guidelines for Lenalidomide (after DLT Evaluation
Period)
Dose modification guidelines are based on the recommendation provided by the myeloma 
expert panel review of the efficacy and toxicity of lenalidomide plus dexamethasone, and the 
guidance provided in the product label for lenalidomide [37] [65].
The criteria presented in this section below for dose modification are meant as general 
guidelines, and they are based on current US standards of clinical practice. Local standards 
and prescribing information may differ and should be followed. Lenalidomide dose 
modifications for toxicity must be performed as clinically indicated at the discretion of the 
investigator. For additional information please refer to lenalidomide local prescribing 
information.
Lenalidomide is administered once daily from Day 1 through Day 21 in each 28-day cycle. 
The lowest dose of lenalidomide allowed in this trial is 5 mg.  Therefore, if a subject
receiving 5 mg of lenalidomide experiences an AE related to lenalidomide and is in need of 
dose modification, the subject should discontinue lenalidomide and continue only 
pembrolizumab and dexamethasone. A maximum of three dose reductions of lenalidomide 
will be allowed in the order indicated in Table 9, where applicable. The duration of 
administration will remain the same.
A subject cannot be restarted on lenalidomide unless non-hematologic lenalidomide-related 
toxicities have returned to at least Grade 1 toxicity or baseline.
Lenalidomide Dose Adjustments for Hematologic Toxicities during 
Multiple Myeloma Treatment
Dose modification guidelines, as summarized below in Table 7 and Table 8, are 
recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 
4 toxicities judged to be related to lenalidomide. Please refer to local product label for 
additional guidelines.
 
 
05FW09


Product:  MK-3475 
57
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Table 7
Platelet Counts: Thrombocytopenia in MM
When Platelets
Recommended Course
Fall to <30,000/mcL
Return to ≥30,000/mcL
Interrupt lenalidomide treatment, follow 
CBC weekly
Restart lenalidomide at 15 mg daily
For each subsequent drop <30,000/mcL
Return to ≥30,000/mcL
Interrupt lenalidomide treatment
Resume lenalidomide at 5 mg less than the 
previous dose. Do not dose below 5 mg 
daily.
Table 8
Absolute Neutrophil Counts (ANC): Neutropenia in MM
When Neutrophils
Recommended Course1
Fall to <1,000/mcL
Return to ≥1,000/mcL and neutropenia is the 
only toxicity
Interrupt lenalidomide treatment, add G-
CSF, and follow CBC weekly
Resume lenalidomide at 25 mg daily
Return to ≥1,000/mcL and if other toxicity
Resume lenalidomide at 15 mg daily
For each subsequent drop <1,000/mcL
Return to ≥1,000/mcL
Interrupt lenalidomide treatment
Resume lenalidomide at 5 mg less than the 
previous dose. Do not dose below 5 mg 
daily.
1 If the subject is receiving Len 10 mg, the subject may resume Len at 5 mg. 
Other Grade 3 and 4 Lenalidomide Toxicities in MM
For other Grade 3 and 4 toxicities, hold treatment and restart at the physician’s discretion at 
next lower dose level when toxicity has resolved to ≤ Grade 2 as outlined below in Table 9.
 
 
05FW09


Product:  MK-3475 
58
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Table 9
Lenalidomide Dose Reductions for Subjects with Other Grade 3 and 4 Toxicities 
Modification
Dose 1, 2
Starting Dose 
Lenalidomide 25 mg every day for 21 days, every 28 days
Dose Reduction 1
Lenalidomide 15 mg every day for 21 days, every 28 days
Dose Reduction 2
Lenalidomide 10 mg every day for 21 days, every 28 days
Dose Reduction 3
Lenalidomide 5 mg every day for 21 days, every 28 days
1 Do not dose below 5 mg daily
2 If the subject is receiving Len 10 mg, the subject may resume Len at 5 mg.
Recommended Lenalidomide Dose Adjustments for Subjects with Impaired 
Renal Function
Renal function may be impaired in subjects with MM by immunoglobulin light chains, 
amyloidosis. MM subjects with normal renal function may develop renal dysfunction or 
renal impairment during treatment with lenalidomide and dexamethasone. If renal toxicity 
occurs during study treatment, drug should not be restarted unless the toxicity resolved to 
≤Grade 1.
5.2.1.2.4 Dose Modification Guidelines for Dexamethasone 
Dose Determination, Dose Confirmation, and Cohort 1: Dexamethasone will be given at 
40 mg QD PO on Days 1, 8, 15, and 22 (i.e., once weekly) in each 28-day cycle. If a subject 
experiences adverse events, up to two dose reductions of dexamethasone will be allowed. 
The duration of administration will remain the same; however, the weekly dose will be 
modified in the order indicated in Table 10 and Table 11. Additional supportive care 
guidelines specific to dexamethasone are indicated in Table 12.
A subject cannot be restarted on dexamethasone unless non-hematologic dexamethasone-
related toxicities have returned to at least Grade 1 toxicity or baseline.
Cohort 2: Dexamethasone will be given at 20 mg p.o. or IV on Days 1,2, 8, 9, 15, 16, 22, and 
23 in each 28-day cycle.  If a subject experiences dexamethasone-related adverse events, up 
to two dose reductions of dexamethasone will be allowed (in Table 10).  At the investigator’s 
discretion, dexamethasone could be tapered prior to complete discontinuation according to 
institutional practice. If the dexamethasone dose was reduced during the previous cycle, the 
reduced dose level will be continued on day 1 of the new cycle. If the reduced dose level was 
well tolerated for a complete cycle, the patient could, at the investigator’s discretion, be 
rechallenged with the dose level prior to the reduction at the start of the next cycle. 
Additional supportive care guidelines specific to dexamethasone are indicated in Table 12.
A subject cannot be restarted on dexamethasone unless non-hematologic dexamethasone-
related toxicities have returned to at least Grade 1 toxicity or baseline.
 
 
05FW09


Product:  MK-3475 
59
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Table 10
Dexamethasone Dose Reductions for Subjects with Grade 3 and 4 Toxicities
Dexamethasone: Dose Determination, Dose Confirmation, and Cohort 1
On Days 1, 8, 15, and 22  in each 28-day cycle
Starting Dose (mg)
Dose Reduction 1 (mg)
Dose Reduction 2 (mg)
40
20 
10 
Dexamethasone: Cohort 2
On Days 1, 2, 8, 9, 15, 16, 22, and 23  in each 28-day cycle
Starting Dose (mg)
Dose Reduction 1 (mg)
Dose Reduction 2 (mg)
20
12
8
Dose Modification Guidelines for Dexamethasone for Elderly Subjects > 75 
Years of Age 
Table 11
Dexamethasone Dose Reductions for Elderly Subjects > 75 Years of Age with 
Grade 3 and 4 Toxicities
Dexamethasone
Per Cohort Schedule
Starting Dose (mg)
Dose Reduction 1 (mg)
Dose Reduction 2 (mg)
20
10 
5
 
 
05FW09


Product:  MK-3475 
60
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Supportive Care Guidelines Specific to Dexamethasone
Table 12
Supportive Care Guidelines Specific to Dexamethasone
Body System
Symptom
Recommended Action
Gastrointestinal
Dyspepsia, gastric or duodenal 
ulcer, 
gastritis 
Grade 
1–2 
(requiring medical management)
Treat with H2 blockers, sucralfate, or omeprazole.  
If symptoms persist despite these measures, 
decrease dexamethasone dose by one dose level.
Gastrointestinal
> 
Grade 
3 
(requiring 
hospitalization or surgery)
Hold 
dexamethasone 
until 
symptoms 
are 
adequately controlled.  Restart and decrease one 
dose level of current dose along with concurrent 
therapy 
with 
H2 
blockers, 
sucralfate, 
or 
omeprazole.  If symptoms persist despite these
measures, discontinue dexamethasone and do not 
resume.
Gastrointestinal
Acute pancreatitis
Discontinue dexamethasone and do not resume.
Cardiovascular
Edema
>Grade 3 (limiting function and 
unresponsive 
to 
therapy 
or 
anasarca)
Diuretics as needed, and decrease dexamethasone 
dose by one dose level; if edema persists despite 
measures, decrease dose another dose level.  
Discontinue dexamethasone and do not resume if 
symptoms persist despite second reduction.
Neurology
Confusion or mood alteration 
>Grade 
2 
(interfering 
with 
function 
+/-
interfering 
with 
activities of daily living)
Hold dexamethasone until symptoms resolve.  
Restart with one dose level reduction.  If 
symptoms persist despite measures, discontinue 
dexamethasone and do not resume.
Musculoskeletal
Muscle weakness > Grade 2 
(symptomatic and interfering with 
function 
+/-
interfering 
with 
activities of daily living)
Decrease dexamethasone by one dose level.   If 
weakness persists despite measures, decrease 
dose 
by 
one 
dose 
level. 
 
Discontinue 
dexamethasone and do not resume if symptoms 
persist.
Metabolic
Hyperglycemia > Grade 3 or 
higher
Treatment with insulin or oral hypoglycemics as 
needed.  If uncontrolled despite measures, 
decrease dose by one dose level until levels are 
satisfactory.
5.2.1.2.5 Cohort 2: Dose Modification Guidelines for Carfilzomib
In Cohort 2, for the initial 6 subjects in the safety run in, carfilzomib dose modifications are 
allowed in accordance with Table 13 and Table 14. During the safety run in, any drug-
related AEs, which in the opinion of the investigator cannot be managed by the carfilzomib 
dose modifications outlined in Table 13 and Table 14, will be considered a DLT.  After the 
safety run in for the initial 6 subjects have been completed, the dose of pembrolizumab, 
carfilzomib and dexamethasone can be modified as outlined in Table 4, Table 5, Table 10, 
Table 13 and Table 14.
 
 
05FW09


Product:  MK-3475 
61
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Table 13
Dose Modifications for Toxicity during Carfilzomib Treatment
Hematologic Toxicity
Recommended Action
ANC less than 0.5 × 109/L
Withhold dose.  If recovered to greater than or equal 
to 0.5 × 109/L, continue at the same dose level.
For subsequent drops to less than 0.5 × 109/L, 
follow the same recommendations as above and 
consider 1 dose level reduction when restarting 
carfilzomib
Febrile neutropenia
(ANC less than 0.5 × 109/L and an oral temperature 
more than 38.5°C or two consecutive readings of 
more than 38.0°C for 2 hours)
Withhold dose.  If ANC returns to baseline grade 
and fever resolves, resume at the same dose level.
Platelets less than 10 × 109/L or evidence of bleeding 
with thrombocytopenia
Withhold dose. If recovered to greater than or equal 
to 10 × 109/L and/or bleeding is controlled, continue 
at the same dose level.
For subsequent drops to less than 10 × 109/L, follow 
the same recommendations as above and consider 1 
dose level reduction when restarting carfilzomib
Renal Toxicity
Recommended Action
Serum creatinine greater than or equal to 2 × baseline 
OR
Creatinine clearance less than 15 mL/min, or 
creatinine clearance decreases to less than or equal to 
50% of baseline, or need for dialysis
Withhold dose and continue monitoring renal 
function (serum creatinine or creatinine clearance)

If attributable to carfilzomib, resume when 
renal function has recovered to within 25% of 
baseline; start at 1 dose level reduction

If not attributable to carfilzomib, dosing may be 
resumed at the discretion of the physician
For patients on dialysis receiving carfilzomib, the 
dose is to be administered after the dialysis 
procedure
Other Hon-hematologic Toxicity
Recommended Action
All 
other 
severe 
or 
life-threatening 
non-
hematological toxicities (CTCAE Grades 3 and 4)
Withhold until resolved or returned to baseline
Consider restarting the next scheduled treatment at 
1 dose level reduction
Table 14
Dose Level Reductions for Carfilzomib
Carfilzomib
Nominal Dose 
Dose -1
Dose -2
Dose -3
20 mg/m2
15 mg/m2
11 mg/m2
-
56 mg/m2
45 mg/m2
36 mg/m2
27 mg/m2
 
 
05FW09


Product:  MK-3475 
62
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Timing of Dose Administration
Trial treatment should be administered starting with Day 1 of the first 28-day cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatment may be administered up to 3 days before or after the scheduled day of 
administration due to administrative reasons.
All trial treatments will be administered on an outpatient basis.
Definition of Disease Progression
A subject with unconfirmed progression of disease may continue trial treatment until 
progression of disease is confirmed at the next scheduled assessment (refer to Section 
7.1.2.6.1 for details).  Subjects may only receive trial treatment while waiting for 
confirmation of PD if the following criteria are met:

Absence of signs and symptoms indicating disease progression

No decline in ECOG performance status

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention.
If a subject is noted to have confirmed progression of disease by the respective response 
criteria, the subject should not receive further treatment with trial treatment unless allowed 
after Sponsor consultation.
Guidelines for Study Drug Administration
The study starts with a 3+3 Dose Determination stage to identify a preliminary MTD (or 
MAD) of the combination.  In this stage, pembrolizumab (2 mg/kg) will be evaluated in 
combination with lenalidomide and dexamethasone (Table 3).
After identification of a preliminary MTD/MAD, the dose confirmation stage will initiate 
based on the toxicity probability interval (TPI) [66] approach to further evaluate safety, 
define the final MTD/MAD
and characterize preliminary efficacy.
In this stage 
pembrolizumab will be given at a fixed dose in combination with lenalidomide and 
dexamethasone based on the preliminary MTD/MAD defined in the previous stage
Upon completion of the dose confirmation stage, 2 expansion cohorts will be initiated:

Cohort 1: at the final MTD/MAD determined in the dose confirmation stage in 
combination with lenalidomide and dexamethasone; 
 
 
05FW09


Product:  MK-3475 
63
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential

Cohort 2: 200 mg fixed dose pembrolizumab (Q3W) in combination with carfilzomib 
and dexamethasone.  
Specific instructions for dose calculation, reconstitution, preparation of the infusion fluid, 
and administration of pembrolizumab as an IV infusion are provided in the Pharmacy
Manual.
Refer to the local product labels and institutional standards for the pertinent 
information on lenalidomide, carfilzomib and dexamethasone.
In the Dose Determination, Dose Confirmation, and Cohort 1 groups: 

For the North America Sites, lenalidomide must be prescribed through and in 
compliance with Celgene’s Revlimid REMS® program for trial participants.

For the ex-North America Sites, subjects will have lenalidomide dispensed from the 
investigational pharmacy at the site where they are enrolled in compliance with the 
country risk minimization plan.
Rules for Dose Determination and Confirmation
Dose Determination
Dose limiting toxicities (DLTs) observed in Cycle 1 will be used to determine the next dose 
level. The trial is using a modified 3+3 design based on the TPI method [66] and has 3
stages: a Dose Determination stage using a 3+3 design, a Dose Confirmation stage according 
to the TPI approach and an Expansion Cohort stage with two cohorts. The guidelines used 
for Dose Determination and Dose Confirmation are shown in Figure 7 and Table 15.
The following rules must be applied for the Dose Determination stage.
An initial cohort of 3 subjects is enrolled:

If 0/3 subjects develop a DLT, no de-escalation will occur and the current dose will 
be considered the preliminary MTD. 

If 1/3 subjects develops a DLT: 
o
Another 3 subjects will be enrolled at this dose level. 

If 0 or 1 of the 3 new subjects develops a DLT (for a total of ≤2/6 subjects 
with a DLT at this dose level), the Dose Determination stage of the trial will 
be terminated, the current dose will be considered the preliminary MTD, and 
the trial will proceed to the Dose Confirmation stage. 
If >1 of the 3 new subjects develop a DLT (for a total of >2/6 subjects with a DLT at this 
dose level), the Dose Determination stage of the trial will continue with dose de-escalation as
outlined in Table 3 until a preliminary MTD is identified. Then the trial will proceed to Dose 
Confirmation.

If ≥2/3 subjects develop a DLT, dose de-escalation will occur.
 
 
05FW09


Product:  MK-3475 
64
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
It is conceptually acceptable to de-escalate to an intermediate, not pre-defined and not 
previously-studied dose, if evaluation of toxicity at such a dose is desired in lieu of 
proceeding directly to the Dose Confirmation stage of the trial. In addition, as specified in
Table 3, it is possible to de-escalate to a lower dose of lenalidomide (Dose Level -1A) if 
lenalidomide toxicity is observed. If either approach is taken, 3 new subjects should be 
enrolled at the new intermediate dose, and the aforementioned rules should be used to 
determine further enrollment at this dose level. 
The Dose Determination stage will terminate if the candidate dose of pembrolizumab (2
mg/kg) in combination with lenalidomide and dexamethasone is studied and 0/3 subjects or 
<2/6 subjects develop a DLT.  Pembrolizumab 2 mg/kg in combination with lenalidomide 
and dexamethasone will be considered the preliminary MTD/MAD. 
Figure 7
Dose Determination Schema
Dose Confirmation
The objective of the Dose Confirmation stage is to define final MTD/MAD in the 
pembrolizumab, lenalidomide, dexamethasone combination regimen.
 
 
05FW09


Product:  MK-3475 
65
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Dose Confirmation will begin with the preliminary MTD identified in the Dose 
Determination stage described above which has been changed to a fixed dose depending on 
the results from the Dose Determination stage (i.e., if 2 mg/kg is determined as the 
MTD/MAD, then 200 mg will be the starting dose).
In this Dose Confirmation stage, an additional 7 subjects (or the number of additional 
subjects necessary to reach 13 in the MTD/MAD) will be enrolled in the pembrolizumab, 
lenalidomide, dexamethasone combination. The Dose Confirmation stage will continue until 
≤4 of 13 subjects (combined from Dose Determination and Dose Confirmation) experience a 
DLT.  As subjects become evaluable for DLT assessment, the number of subjects who are 
evaluable for DLT versus the number of subjects who developed a DLT will be continuously 
assessed as shown in Table 15. The DLTs observed during the Dose Determination stage 
will be included in the Dose Confirmation stage under the assumption of consistency 
between 2 mg/kg and 200 mg (see Section 4.2.2) as analogous.
In this stage, there will be no escalation above 200 mg; therefore, the decision to ‘escalate to 
a higher dose’ in the table below will be treated as ‘stay at the current dose’ for this situation,
i.e. 200 mg.  This table will be also used as a guide to determine the lenalidomide dose used 
for the expansion stage.
Table 15
Dose Confirmation Rules
Number of subjects treated at current dose
4
5
6
7
8
9
10
11
12
13
Number of toxicities
0
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
E
E
E
3
DU
DU
D
D
S
S
S
S
S
S
4
DU
DU
DU
DU
DU
D
D
S
S
S
5
DU
DU
DU
DU
DU
DU
D
D
D
6
DU
DU
DU
DU
DU
DU
DU
DU
E = Escalate to the next higher dose (taken as ‘stay at the current dose’ if current dose is 200 mg)
S = Stay at the current dose
D = De-escalate to the next lower dose
DU = The current dose is unacceptably toxic
Target DLT rate = 25%
a=1; b=1; k1=1.5; k2=0.5; pow=1.1
Source:  Ji et al. (2007) [66]
 
 
05FW09


Product:  MK-3475 
66
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Subjects may be enrolled continuously (i.e., without waiting for Cycle 1 completion of 
subjects who have received the first dose) unless a DLT is observed at the particular dose.  
Once a DLT is observed, the number of subjects who are enrolled at that dose, but are not yet 
fully evaluable for DLT assessment, may not exceed the number of remaining subjects who 
are at risk of developing a DLT before the dose would be considered unacceptably toxic 
(denoted as DU in Table 15).  For example, if 2/7 subjects have experienced a DLT at a 
given dose level, no more than an additional 3 subjects should be enrolled at this dose level 
until additional DLT data are available. This is because this dose level would be considered 
unacceptably toxic if all 3 of the additional subjects experience a DLT (i.e., 5/10 subjects 
with DLT in Table 15). 
If enrollment expands to 13 subjects for a dose level, and ≤4 of the 13 subjects develop a 
DLT, then the Dose Confirmation stage will stop.  If 25 mg of lenalidomide is the starting 
dose in combination with pembrolizumab and enrollment expands to 13 subjects and >4/13
subjects develop a DLT, then the 10 mg lenalidomide dose with pembrolizumab may be 
expanded to further explore the dose-response relationship. If 10 mg lenalidomide is the 
starting dose in combination with pembrolizumab, and >4/13 subjects develop a DLT, then 
the Dose Confirmation stage will stop. Note that while 25% has been the target toxicity rate 
used to generate the guidelines in Table 15, the observed rate of patients with DLT at the 
MTD may be slightly above or below 25%.  Table 16 below summarizes the operating 
characteristics of the TPI design.
Table 16
Operating Characteristics of Design Based on the Toxicity Probability Interval 
(TPI) Approach
True DLT Rate
(DL1, DL2, DL3)
Probability of selecting dose as the MTD
Average 
Sample Size
DL1
DL2
DL3
No Dose
0.05,
0.05,
0.05     
0.008
0.026
0.937
0.029
19.31
0.05,
0.10,
0.15     
0.022
0.152
0.802
0.024
19.84
0.05,
0.10,
0.25     
0.021
0.276
0.673
0.030
20.34
0.15,
0.25,
0.45     
0.191
0.504
0.112
0.193
18.10
0.25,
0.35,
0.45     
0.313
0.206
0.040
0.441
14.06
0.40,
0.45,
0.50     
0.152
0.040
0.004
0.804
8.45
DL = dose level
Expansion Cohort
After the definition of the final MTD/MAD from the dose confirmation stage around
30-45 subjects will be enrolled in each of the 2 cohorts of Expansion Cohort stage to assess 
safety and preliminary efficacy. The maximum number of subjects to be enrolled in the 
expansion arms is based on clinical rather than statistical consideration.
In the expansion cohorts, safety will be evaluated on a continuous basis but no formal rules 
for dose escalation or stopping are planned based on statistical considerations.
 
 
05FW09


Product:  MK-3475 
67
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Since the combination of pembrolizumab with carfilzomib and dexamethasone (Cohort 2) 
was not evaluated during the Dose Determination and Dose Confirmation stages, Cohort 2 
evaluation will commence with a 6 subject safety lead in and enrollment will be paused until 
completion of the first cycle of treatment for these subjects. In this safety lead in, any drug-
related AEs, which in the opinion of the investigator cannot be managed by the carfilzomib 
dose modification rules outlined in Table 13 and Table 14 will be considered a DLT with the 
following decisions:  

If >2/6 subjects develop a DLT during the first cycle of the safety lead in, Cohort 2 
will be closed and no additional subjects will be enrolled. 

If ≤2/6 subjects develop a DLT during the first cycle, the safety lead in would be 
concluded and Cohort 2 will resume enrollment continuously (i.e. without waiting for 
Cycle one completion for the remaining subjects) as planned. 
Definition of Dose Limiting Toxicities
All toxicities will be graded using National Cancer Institute (NCI) CTCAE Version 4.0 
(Appendix 12.7).
Dose Determination and Dose Confirmation
The occurrence of any of the following toxicities during Cycle 1 during the Dose 
Determination and Dose Confirmation stages will be considered a DLT, if judged by the 
investigator to be possibly, probably or definitely related to pembrolizumab in combination 
with lenalidomide/dexamethasone.
Please refer to Section 2.1 for dose level guidelines 
following DLT evaluation Cycle 1.
1. Grade 4 hematologic toxicity lasting ≥7 days.
2. Grade 4 non-hematologic toxicity (not laboratory).
3. Grade 3 non-hematologic toxicity (not laboratory) will be considered a DLT, except for 
inadequately treated nausea, hypersensitivity reactions, or fatigue lasting ≤3 days.
4. Any Grade 3 non-hematologic laboratory value if: 
1. Renal or liver function abnormality
2. Medical intervention is required to treat the subject, or
3. The abnormality leads to hospitalization, or
4. The abnormality persists for >1 week.
 
 
05FW09


Product:  MK-3475 
68
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
5. Febrile neutropenia Grade 3 or Grade 4:
●Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for 
more than one hour.

Grade 4 is defined as ANC <500/mm3 with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for 
more than one hour, with life-threatening consequences and urgent intervention 
indicated.
6. Thrombocytopenia <25,000/mm3 if associated with:
●A bleeding event which does not result in hemodynamic instability but requires an 
elective platelet transfusion, or
●A life-threatening bleeding event which results in urgent intervention and admission 
to an Intensive Care Unit.
7. Grade 5 toxicity (i.e., death).
8. A delay of > 1 week due to drug-related toxicity in initiating Cycle 2.
9. Unable to complete at least 80% of any of the three treatments during the first course of 
therapy due to treatment-related toxicity (even if not meeting above DLT criteria).
Cohort 2
For Cohort 2, during the first cycle of the safety lead in, a DLT will be defined as any drug-
related AE (possibly, probably or definitely related to carfilzomib, pembrolizumab or the 
combination) which in the opinion of the investigator cannot be managed by the carfilzomib 
dose modification rules outlined in Table 13 and Table 14.  
Replacement of Subjects in DLT Evaluation Period
In order to determine safety, all subjects selected must meet the evaluability criteria for Cycle 
1. Subjects will be considered non-evaluable and will be replaced if:

they are allocated but not treated,

they discontinue from the trial prior to completing all safety evaluations for 
reasons other than treatment-related adverse events,

they received <90% of the total pembrolizumab infusion in Cycle 1 (e.g., because 
the infusion had to be discontinued due to an infusion reaction) and did not 
experience a dose-hold or modification due to an adverse event,

they received <80% of lenalidomide, carfilzomib or dexamethasone intended for 
the trial for reasons other than treatment-related adverse events.
 
 
05FW09


Product:  MK-3475 
69
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Non-evaluable subjects will not be counted toward the cohort total for DLT evaluation.
If a subject experiences a DLT in Cycle 1, trial treatment may be discontinued following 
discussion and agreement between the Sponsor and investigator.
However, if it has been 
determined that the subject is deriving clinical benefit from the trial treatment, the subject 
may be allowed to continue at a lower dose. Please follow dose modification guidelines as 
described in Section 5.2.1.2.
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Subjects will be allocated to assignment during the Dose Determination, Dose Confirmation
and Expansion Cohort stages of the trial in accordance with Section 5.2.5.  The Sponsor 
delegate will provide the allocation number to the site from the allocation schedules.
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, IV medications, and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included in the CRF.  Subject may remain on anticoagulation 
therapy as long as the PT or PTT is within therapeutic range of the intended use of 
anticoagulants.
Periodic monitoring of digoxin levels is recommended due to increased Cmax and AUC with 
concomitant lenalidomide therapy. 
Subjects taking concomitant therapies such as 
 
 
05FW09


Product:  MK-3475 
70
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
erythropoietin stimulating agents or estrogen containing therapies may have an increased risk 
of venous thromboembolism. 
Refer to product label for lenalidomide, carfilzomib and dexamethasone for specific details
about acceptable concomitant medications.
All concomitant medications received within 28 days before screening of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications
administered up until 30 days after the last dose of trial treatment should be recorded for 
SAEs and/or ECIs as defined in Section 7.2.
Concomitant Medications for Cohort 2 Carfilzomib 
The following pre-treatments are suggested for subjects receiving carfilzomib in Cohort 2, 
and should be incorporated per investigator discretion/local clinical practice:

At least 48 hours before Cycle 1 Day 1, oral hydration should be given as follows:  
30 mL/kg/day (approximately 6 to 8 cups of liquid per day, per local clinical practice) 
continuing up to the time of treatment. Subject compliance must be assessed before 
initiating treatment, which is to be delayed if oral hydration is not adequate. Oral 
hydration may be continued in Cycle 2 and beyond at the investigator’s discretion

At least 24 hours prior to Cycle 1 Day 1, the following treatments can be started:
o
Ciprofloxacin 500 mg PO QD to continue through Cycle 1 only (a similar 
fluoroquinolone, amoxicillin, or other appropriate prophylactic antibiotic may 
be used instead at the investigator’s discretion).
o
Valacyclovir 500 mg PO QD (or equivalent antiviral), continuing for the 
duration of treatment (additional prophylaxis is at the investigator’s 
discretion). 
o
Lansoprazole 15 mg PO QD, or other oral proton-pump inhibitor to prevent 
peptic disease for the duration of treatment with dexamethasone.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

G-CSF during Cycle 1, DLT evaluation period only

GM-CSF

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol
 
 
05FW09


Product:  MK-3475 
71
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential

Investigational agents other than pembrolizumab 

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic plasmacytoma, bone lesions or to 
the brain may be allowed after consultation with Sponsor.  

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed-virus 
vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist) are 
live attenuated vaccines, and are not allowed.

Warfarin

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined. 
Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.  Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab. 
Note: if after the evaluation, the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below).  Refer to Section 5.2.1.2 for 
dose modification. 
 
 
05FW09


Product:  MK-3475 
72
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Supportive Care Guidelines Specific to Lenalidomide
Hematologic Toxicity
Lenalidomide can cause significant neutropenia, thrombocytopenia, and anemia.  Subjects 
taking lenalidomide for MM should have complete blood counts repeated every two weeks
(on Days 1 and 15 of each cycle) for all cycles.  Subjects may require dose interruption 
and/or dose reduction [See Section 5.2.1.2.3].  Subjects may require use of blood product 
support and/or growth factors.  See recommendations below for the management of 
cytopenias (Table 17).
Table 17
Recommendations for the Management of Cytopenias
Recommendations
Neutropenia
If the ANC is <1.0 x 109/l on the ﬁrst day of a new cycle, withhold 
lenalidomide treatment add G-CSF and follow CBC weekly until Grade 
1 toxicity is reached.  Reinitiate treatment at a lower dose (See Section 
5.2.1.2.3.1, Table 8).
Febrile neutropenia
Antibiotic prophylaxis should be considered. Subjects should receive 
clear instructions to seek medical care within 3 hours if febrile while 
neutropenic. 
After an occurrence of a prior episode of febrile 
neutropenia, the use of antibiotic prophylaxis is recommended.
Thrombocytopenia
If the platelet count is <75 x 109/l on the ﬁrst day of a new cycle, 
withhold treatment with lenalidomide until Grade 1 toxicity is reached.  
Reinitiate treatment at a lower dose (see Table 7).  If the platelet count 
is <25 x 109–50 x 109/l during the cycle, withhold anticoagulation.  
Reinitiate treatment at the next cycle at a lower dose (See Section 
5.2.1.2.3.1, Table 7).
Anemia
Erythropoiesis-stimulating agents1 may be used in subjects with Hb 
counts of <100 g/l, and in symptomatic patients who present with Hb 
counts of <120 g/l, per investigator’s discretion. The target level of 
treatment is an Hb count of 120 g/l, and this should not be exceeded.
Acronyms: 
ANC: absolute neutrophil count;
Hb: hemoglobin. 
1
Erythropoiesis-stimulating agents should not be used during Cycle 1 (DLT evaluation period).
[56]
Venous Thromboembolism
Venous thromboembolic events (VTE) (predominantly deep venous thrombosis and 
pulmonary embolism) have occurred in subjects with MM treated with lenalidomide 
combination therapy. 
See recommendations below for the management of venous 
thromboembolisms (Table 18).
 
 
05FW09


Product:  MK-3475 
73
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Table 18
Recommendations for the Management of Venous Thromboembolism. 
Recommendations
Screening
Neither baseline coagulation studies, nor screening for VTE in 
asymptomatic subjects are recommended.
In symptomatic subjects, 
sonography for the diagnosis of VTE is recommended.
VTE Prophylaxis
A 4 to 6 month course of prophylaxis is recommended in subjects with 
risk factors. The use of low-dose aspirin (81- 100 mg) is recommended 
for low VTE risk subjects and prophylactic doses of LMWH are 
recommended for high risk VTE subjects. 
Warfarin is prohibited (See Section 5.5.2).
VTE Treatment
The subject can be continued on treatment with lenalidomide plus 
dexamethasone or re-treated after stabilization depending on the 
severity of VTE. For therapeutic anticoagulation, subjects previously 
on aspirin should be switched to LMWH and subjects already on 
prophylactic doses of LMWH should receive therapeutic doses.  
Recommend 6 months of therapeutic-dose LMWH, after which 
prophylaxis can be restarted.
Acronyms: 
LMWH: low-molecular-weight heparin
VTE: venous thromboembolism. 
Lactose Intolerance
Lenalidomide capsules contain lactose. Risk-benefit of lenalidomide treatment should be 
evaluated in subjects with lactose intolerance.
Allergic Reactions
Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) 
and toxic epidermal necrolysis (TEN) have been reported for IMiDs.  These events can be 
fatal. Subjects with a prior history of Grade 4 rash associated with thalidomide treatment 
should not receive lenalidomide.  Lenalidomide interruption or discontinuation should be 
considered for Grade 2-3 rash. Lenalidomide must be discontinued for angioedema, Grade 4 
rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed if 
subject is discontinued for these reactions.
Tumor Lysis Syndrome
Fatal instances of tumor lysis syndrome have been reported during treatment with 
lenalidomide. The subjects at risk of tumor lysis syndrome are those with high tumor burden 
prior to treatment. These subjects should be monitored closely, and appropriate precautions 
taken.
Hepatotoxicity
Hepatic failure, including fatal cases, has occurred in subjects treated with lenalidomide in 
combination with dexamethasone. 
The mechanism of drug-induced hepatotoxicity is 
 
 
05FW09


Product:  MK-3475 
74
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
unknown.  Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant 
medications may be risk factors. Monitor liver enzymes periodically. Stop lenalidomide 
upon evaluation of liver enzymes. After return to baseline values, treatment at a lower dose 
may be considered. 
Second Primary Malignancies
Subjects with MM treated with lenalidomide in studies including melphalan and stem cell 
transplantation had a higher incidence of second primary malignancies, particularly acute 
myelogenous leukemia (AML) and Hodgkin lymphoma, compared to subjects in the control 
arms who received similar therapy but did not receive lenalidomide.  Monitor subjects for the 
development of second primary malignancies. Take into account both the potential benefit of 
the lenalidomide and the risk of second primary malignancies when considering treatment 
with lenalidomide.
Supportive Care Guidelines Specific for Carfilzomib [Cohort 2]
“First-Dose-Like Effect”
A “first-dose–like effect” has been encountered in Phase 1 trials with carfilzomib, 
characterized by fever, chills, shortness of breath, and/or rigors occurring during the evening 
following the first day of infusion and an increase in creatinine on the subsequent day, which 
may be the clinical sequelae of rapid tumor lysis and/or cytokine release. Should a “first dose 
effect” occur, glucocorticoids, IV fluids, vasopressors, oxygen, bronchodilators, and 
acetaminophen should be available for immediate use and instituted as medically indicated.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS), which may be associated with multi-organ failure, has been 
observed in treatment Cycles 1 and 2 in some subjects with multiple myeloma treated with 
carfilzomib. All subjects with multiple myeloma are considered to be at potential risk for 
TLS. In addition, multiple myeloma subjects with high tumor burden should be considered to 
be at greater risk for TLS. Hydration should be given to all subjects in Cohort 2 in Cycle 1 
and at the investigator’s discretion in Cycle 2; premedication with allopurinol or other 
approved uric acid-lowering agent is optional. Subjects with laboratory abnormalities prior to 
dosing that are consistent with lysis of tumor cells (e.g., serum creatinine ≥ 50% increase, 
LDH ≥ 2-fold increase, uric acid ≥ 50% increase, phosphate ≥ 50% increase, potassium ≥ 
30% increase, and calcium ≥ 20% decrease) should not receive the scheduled dose. Subjects 
with such abnormalities should be re-evaluated as clinically indicated. The Medical Monitor 
should be consulted if there are further delays.
Subjects should be informed of signs and symptoms that may be indicative of TLS, such as
fever, chills/rigors, nausea, vomiting, muscle tetany, weakness, or cramping, seizures, and
decreased urine output; subjects should be instructed to report such symptoms immediately
and seek medical attention.
 
 
05FW09


Product:  MK-3475 
75
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
If TLS manifests, cardiac rhythm, fluid, and serial laboratory monitoring should be instituted.
Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer
therapeutic and supportive care, including dialysis, as clinically indicated.
Renal Function
Renal function, serum creatinine, and serum uric acid should be monitored closely. 
Carfilzomib has been evaluated in a Phase 2 trial in patients with normal renal function and 
those with mild, moderate, and severe renal impairment and patients on chronic dialysis. In 
this study, the pharmacokinetics of carfilzomib was not influenced by the degree of baseline 
renal impairment, including the patients on dialysis. Since dialysis clearance of carfilzomib 
concentrations has not been studied, the drug should be administered after any dialysis
procedure. 
Cases of acute renal failure have occurred in patients receiving carfilzomib. Renal 
insufficiency adverse events (including renal failure) have occurred in approximately 10% of 
patients treated with carfilzomib. Acute renal failure was reported more frequently in patients 
with advanced relapsed and refractory multiple myeloma who received carfilzomib 
monotherapy. This risk was greater in patients with a baseline reduced estimated creatinine 
clearance (calculated using Cockcroft and Gault equation). Monitor renal function with 
regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce 
or withhold carfilzomib doses as appropriate.
See Table 13 for guidance regarding dose reduction in subjects with compromised renal 
function.
Hydration
All subjects should be well hydrated. Subjects at risk of TLS should be hydrated as medically 
indicated. Those with a history of cardiac disease (such as congestive heart failure and 
cardiomyopathy) or pulmonary edema should be monitored closely for signs of fluid
overload. Carfilzomib treatment can cause nausea, vomiting, diarrhea, or constipation
sometimes requiring the use of antiemetics or antidiarrheal agents. Fluid and electrolyte
replacement should be administered as indicated.
Other Adverse Events on Combination Therapy
Atrial ﬁbrillation:  Monitor on a regular basis.
Constipation:  Does not require additional prophylaxis or therapy.
Rash: In case of rash, treat the subject with antihistamines. If rash is persistent, continuous 
low-dose prednisone (10–20 mg/day, for 14 days) should be added. Use of corticosteroids 
should be evaluated in the context of subjects receiving dexamethasone as part of trial 
treatment.  Rash is mostly self-limiting with a duration of several days or weeks, but in some 
cases dose reduction or discontinuation of lenalidomide is necessary (See Section 5.2.1.2.3.2
 
 
05FW09


Product:  MK-3475 
76
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Table 9  for dosing levels). Pembrolizumab could cause or exacerbate rash.  Please refer to 
pembrolizumab dose modification guidelines under Section 5.2.1.2.2.
Fatigue: Other causes such as anemia, infection, depression, or hypothyroidism should be 
ruled out. Dose reduction may be considered for severe fatigue (See Section 5.2.1.2.3.2
Table 9 for dosing levels). Please refer to pembrolizumab dose modification guidelines
under Section 5.2.1.2.2.
Infection: Routine antibiotic prophylaxis, for 3 months upon initiation of treatment, should 
be considered in all subjects, but is deemed mandatory in all subjects on high-dose 
dexamethasone, elderly subjects, and in those with a history of increased infection rate.  In 
addition, vaccination against pneumococci, meningococci, and Haemophilus inﬂuenzae type 
b should be considered.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Blood Donation
Subjects enrolled in the Dose Determination, Dose Confirmation, and Expansion Cohort 1 
must not donate blood during treatment with lenalidomide (REVLIMID®) and for 120 days
following discontinuation of lenalidomide because the blood might be given to a pregnant 
female whose fetus must not be exposed to lenalidomide (REVLIMID®).
Contraception
Dose Determination, Dose Confirmation, and Expansion Cohort 1
Pembrolizumab, lenalidomide†, and dexamethasone may have adverse effects on a fetus in 
utero.  Furthermore, it is not known if pembrolizumab, lenalidomide, and dexamethasone
have transient adverse effects on the composition of sperm.  Non-pregnant, non-
breastfeeding women may be enrolled if they are considered highly unlikely to conceive.  
Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a 
woman who is ≥45 years of age and has not had menses for greater than 2 years will be 
considered postmenopausal), or 3) not heterosexually active for the duration of the study.  
The two birth control methods can be either, two barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. Subjects should start using birth control from study 
Visit 1 throughout the study period up to 120 days after the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide, as per local regulations or 
guidelines.  Appropriate hormonal contraceptives will include any registered and marketed 
 
 
05FW09


Product:  MK-3475 
77
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
contraceptive agent that contains estrogen and/or progestin (including oral, subcutaneous, 
intrauterine, or intramuscular agents).
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirements (described above) for the 
duration of the study and during the follow-up period defined in Section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study.
† Lenalidomide (REVLIMID®) is only available through a restricted distribution program 
called the REVLIMID REMS™ program in the US (formally known as the “RevAssist® 
program”). 
Required components of the REVLIMID REMS™ program include the following:

Prescribers must be certified with the REVLIMID REMS™ program by enrolling and 
complying with the REMS requirements.  Study sites in the United States register 
with Celgene’s Revlimid REMS® Program prior to prescribing the Celgene Product 
in accordance with the Revlimid REMS® guidelines. Investigators at Study sites 
outside of the United States register with the appropriate Celgene risk minimization 
program in that country prior to prescribing the Celgene product.

Study investigators must follow the Global Pregnancy Prevention Plan as presented 
by Revlimid REMS

Subjects must sign a “Patient-Prescriber agreement form” and comply with the 
REMS requirements
in the United States or the appropriate Celgene risk
minimization program for countries outside of the United States.  In particular, female 
subjects of reproductive potential who are not pregnant must comply with the 
pregnancy testing and contraception requirements and males must comply with 
contraception requirements.  Refer to local product label.

Pharmacies must be certified with the REVLIMID REMS™ program, must only 
dispense to subjects who are authorized to receive lenalidomide (REVLIMID®) and 
comply with REMS requirements. At the termination or conclusion of the study, sites
shall direct all patients to return to Celgene any unused quantities of the Celgene 
product in accordance with the Celgene REMS® Program.

Further information about the REVLIMID REMS™ program is available at 
 or by telephone at 
.
 
 
05FW09
PPD
PPD


Product:  MK-3475 
78
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Females of Reproductive Potential:

Females of reproductive potential must avoid pregnancy for at least 4 weeks before 
beginning lenalidomide (REVLIMD®) therapy, during therapy, during dose 
interruptions, and for at least 4 weeks after completing therapy.

Females must commit either to abstain continuously from heterosexual intercourse or 
to use two methods of reliable birth control, beginning 4 weeks prior to initiating 
treatment with lenalidomide (REVLIMID®), during therapy, during dose 
interruptions, and continuing for 4 weeks following discontinuation of REVLIMID®
therapy.

Two negative pregnancy tests must be obtained prior to initiating therapy.  The first 
test should be performed within 10 to 14 days and the second test within 24 hours 
prior to prescribing lenalidomide (REVLIMID) therapy; also, weekly during the first 
month and monthly thereafter in women with regular menstrual cycles or every 2 
weeks in women with irregular menstrual cycles.
Refer to local product label for 
additional details.

Pregnancy testing and counseling should be performed if a subject misses her period 
or if there is any abnormality in her menstrual bleeding.  Lenalidomide 
(REVLIMID®) treatment must be discontinued during this evaluation.
Males of Reproductive Potential:

Lenalidomide (REVLIMID®) is present in the semen of subjects receiving the drug.  
Therefore, males must always use a latex or synthetic condom during any sexual 
contact with females of reproductive potential while taking lenalidomide 
(REVLIMID) and for up to 28 days after discontinuing lenalidomide (REVLIMID®), 
even if they have undergone a successful vasectomy.  Male subjects taking 
lenalidomide (REVLIMID®) must not donate sperm. Refer to local product label for
additional details.
Expansion Cohort 2
Pembrolizumab and carfilzomib may have adverse effects on a fetus in utero.  Furthermore, it 
is not known if pembrolizumab or carfilzomib have transient adverse effects on the 
composition of sperm.  
For this part of the trial, male subjects will be considered to be of non-reproductive potential 
if they have azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition).  
 
 
05FW09


Product:  MK-3475 
79
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy. In the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:  
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s male partner 
•
contraceptive rod implanted into the skin
 
 
05FW09


Product:  MK-3475 
80
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Combination method (requires use of two of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)  
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together)
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and 
if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study.
For women of reproductive potential, one negative pregnancy test must be obtained within 72 
hours prior to initiating trial treatment.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test performed by the local trial site laboratory will be required.  
Pregnancy tests (serum and/or urine tests) should be repeated more frequently if required by 
local guidelines.  Pregnancy testing and counseling should be performed if a subject misses 
her period or if there is any abnormality in her menstrual bleeding.
 
 
05FW09


Product:  MK-3475 
81
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, 
lenalidomide* or carfilzomib, and dexamethasone, the subject will immediately be removed 
from the study.  The site will contact the subject at least monthly and document her status 
until the pregnancy has been completed or terminated.  The outcome of the pregnancy will be 
reported as a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn) to the Sponsor without 
delay and within 24 hours if the outcome.  The study investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor.  If a male subject impregnates his female partner the study 
personnel at the site must be informed immediately, the pregnancy reported to the Sponsor,
and followed as described above and in Section 7.2.2.
*Lenalidomide (REVLIMID®) can cause fetal harm when administered to a 
pregnant female.  If lenalidomide is used during pregnancy or if the subject 
becomes pregnant while taking lenalidomide, the subject should be apprised of 
the potential hazard to the fetus.  Refer to local product label for further details.
Use in Nursing Women
It is unknown whether pembrolizumab, lenalidomide, carfilzomib or dexamethasone is 
excreted in human milk.  Since many drugs are excreted in human milk, and because of the 
potential for serious adverse reactions in the nursing infant, subjects who are breastfeeding
are not eligible for enrollment.  Because of the potential for serious adverse reactions in 
nursing infants, breast feeding must be discontinued for the duration of therapy with 
pembrolizumab, lenalidomide or carfilzomib, and dexamethasone, if applicable.  A decision 
should be made whether to discontinue nursing or to discontinue the drug, taking into 
account the importance of drug to the mother.  Please refer to lenalidomide, carfilzomib, and 
dexamethasone local product labels for further information.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
 
 
05FW09


Product:  MK-3475 
82
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

Confirmed disease progression per respective response assessment criteria
Note: For unconfirmed disease progression, please see Section 5.2.3.

Unacceptable adverse experiences as described in Section 5.2.1.2.

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment

Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment

Recurrent Grade 2 pneumonitis

Intercurrent illness that prevents further administration of treatment.

Investigator’s decision to withdraw the subject.

The subject has a confirmed positive serum pregnancy test.

Noncompliance with trial treatment or procedure requirements.
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Trial Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the End of Treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the End of Treatment as described in Section 7.2.3.1).  Subjects 
who discontinue for reasons other than progressive disease will move into the Follow-Up 
Phase to monitor disease status and should be assessed every 4 weeks (± 14 days) until: (1) 
the start of new anti-cancer treatment; (2) documented disease progression; (3) death; (4) 
withdraw of consent; or (5) the end of the trial, whichever occurs first. Every effort should be 
made to collect information regarding disease response assessment in the follow-up period.  
Prior to discontinuing patients from therapy, consult with Sponsor and submit the Treatment 
Termination & Disease Assessment Termination Form.   Information regarding post-study 
anti-myeloma treatment will be collected if new treatment is initiated. After documented 
disease progression or the start of new antineoplastic therapy each subject will be followed 
by telephone every 12 weeks (± 7 days) for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
Subject Replacement Strategy
Additional subjects may be enrolled in a given cohort to ensure that the required number of 
evaluable subjects in each cohort is achieved. A subject that discontinues treatment for a 
drug-related AE will not be replaced and will be counted in the evaluable population of 
subjects for the respective cohort (see also Section 5.2.7).
 
 
05FW09


Product:  MK-3475 
83
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Beginning and End of the Trial
The trial begins when the first subject signs the informed consent. The overall trial ends 
when the last subject completes the last trial visit, a minimum of 6 months have elapsed post 
last trial assessment, or the last subject either discontinues from the trial or is lost to follow-
up (i.e., the subject is unable to be contacted by the investigator), or the Sponsor ends the 
trial, whichever occurs first. If by the end of the trial, there remains at least 1 subject still on
trial treatment for at least 6 months, the subject(s) may enter additional treatment cycles. At 
this point a database lock of the trial may occur to allow the analysis of the trial data. Any 
remaining subjects may continue to receive trial treatment and be seen by the investigator per
usual standard of care for this subject population.
In addition, the investigator will be 
expected to monitor for and report any serious adverse events, events of clinical interest, and 
pregnancies, as detailed in Section 7.2.3 (Serious Adverse Experiences). The subject is 
considered on trial until such time that he/she meets any of the discontinuation criteria and 
written notification is given to the Sponsor.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete;
2. Poor adherence to protocol or regulatory requirements;
3. Incidence or severity of adverse drug reaction in this or other trials indicates a potential 
health hazard to subjects;
4. Plans to modify or discontinue the development of the trial drug.
In the event of Sponsor decision to no longer supply trial drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
 
 
05FW09






Product:  MK-3475 
86
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
1.
For women of reproductive potential, two negative pregnancy tests must be obtained prior to initiating trial treatment. The first test should be performed within 10-14 
days and the second test within 24 hours prior to prescribing lenalidomide and administering trial treatments; then weekly during the first month, and monthly (on Day 1 
of each Cycle) thereafter in women with regular menstrual cycles or every 2 weeks (on Days 1 and 15) in women with irregular menstrual cycles. If urine pregnancy 
results cannot be confirmed as negative, a serum pregnancy test performed by the local trial site laboratory will be required.  Pregnancy tests (serum and/or urine tests) 
should be repeated more frequently if required by local guidelines.  Pregnancy testing and counseling should be performed if a subject misses her period or if there is any 
abnormality in her menstrual bleeding.  Lenalidomide (REVLIMID) treatment must be discontinued during this evaluation.  Pharmacies must be certified with the 
REVLIMID REMS™ program, and must only dispense to subjects who are authorized to receive REVLIMID® and comply with REMS requirements. Refer to 
Local risk minimization programs for ex-US sites.
2.
Bone marrow analysis will include bone marrow morphology, IHC, and cytogenetics by FISH panel (if FISH not available, then do standard karyotyping). After 
baseline assessment, bone marrow biopsy or aspirate should be performed as clinically indicated.
3.
Blood for correlative biomarker studies to be collected from all subjects at screening or C1D1 and at C2D1.  In addition, subjects in the US and Canada only must 
provide a new bone marrow aspirate sample at screening or C1D1 and at C2D1. Cycle 2 Day 1 bone marrow aspirate is not required for subjects in Cohort 1. Refer to 
the Procedures Manual for collection and shipping details.
4.
If the subject signs the Future Biomedical Research (FBR) consent, any leftover material that would ordinarily be discarded at the end of the trial will be retained for 
FBR.  A copy of the local pathology report, with subject information removed, should also be sent to the lab to accompany the biopsy specimen.
5.
Required for all subjects who discontinue trial treatment for a reason other than disease progression, until the start of new therapy, disease progression, death or end of 
study.
6.
On 03-JUL-2017, the US FDA placed KN183, KN185, and cohort 1 of KN023 on clinical hold based on safety data from KN183 and KN185 presented to the DMC.  
The FDA determined that the risks of pembrolizumab plus pomalidomide or lenalidomide outweighed any potential benefit for patients with multiple myeloma.  Based 
on this decision, the treatment phase of KN183, KN185, and Cohort 1 of KN023 is closed effective immediately.  All subjects must stop study treatment, complete the 
Discontinuation Visit and move into the long term safety and survival follow-up (every 12 weeks) per protocol.
7.
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated 
survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a 
scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants that have a death event 
previously recorded).
 
 
05FW09


Product:  MK-3475 
87
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Trial Treatment Administration Schedule Dose Determination, Dose Confirmation, and Cohort 1
Cycle Day (Cycle = 28 Days)5
Trial 
Treatment/ 
Cycle Day
(± 3 days window after 
C1D1)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Pembrolizumab Q 2 
Weeks1
X
X
Lenalidomide 2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dexamethasone 3
X
X
X
X
Pill 
count 
for 
lenalidomide 
and 
dexamethasone 4
X
1 Pembrolizumab will be administered as 2 mg/kg (Dose Determination) or as 200 mg (Dose Confirmation & Expansion Cohort 1) every two weeks (on Days 1 and 15) of each 
28-day cycle as an IV infusion over 30 minutes.
2 Lenalidomide will be administered as 25 mg once daily orally on Days 1-21 of repeated 28-day cycles.  Lenalidomide must be prescribed through and in compliance with 
the REVLIMID REMS™ program. Refer to local product label. 
3 Dexamethasone will be administered as 40 mg once daily orally on Days 1, 8, 15, and 22 of each 28-day Cycle. A dexamethasone dose of 20 mg on Days 1, 8, 15, and 22 in 
subjects aged >75 years is recommended [56]. Refer to local product label.
4 Site should document drug accountability as per their institutional guidelines.
5 On 03-JUL-2017, the US FDA placed KN183, KN185, and cohort 1 of KN023 on clinical hold based on safety data from KN183 and KN185 presented to the DMC.  The 
FDA determined that the risks of pembrolizumab plus pomalidomide or lenalidomide outweighed any potential benefit for patients with multiple myeloma.  Based on this 
decision, the treatment phase of KN183, KN185, and Cohort 1 of KN023 is closed effective immediately.  All subjects must stop study treatment, complete the 
Discontinuation Visit and move into the long term safety and survival follow-up (every 12 weeks) per protocol.
 
 
05FW09




Product:  MK-3475 
89
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
1. Procedures for sample collection are described in the Procedures Manual.
2. For the Dose Determination portion of the trial: All pre-infusion pembrolizumab PK samples should be drawn within 24 hours before infusion. Pre-infusion pembrolizumab
PK samples will be collected at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 15, Cycle 4 Day 1, and on Day 1 of each cycle every 3 Cycles thereafter. PK samples will also be 
collected 30 days after discontinuation of trial treatment (or until the subject starts new anti-cancer therapy). Post-infusion pembrolizumab PK samples will be collected at 
Cycle 1 Day 1 (within 30 minutes after the end of infusion), Cycle 1 Day 2 (24 hours post-infusion), Cycle 1 Day 5 (96 hours post-infusion) and Cycle 1 Day 15 within 30 
minutes after the end of the second infusion.
3. For the Dose Confirmation and Cohort 1 portion of the trial: All pre-infusion pembrolizumab PK samples should be drawn within 24 hours before infusion. Pre-infusion 
pembrolizumab PK samples will be collected at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 15, Cycle 4 Day 1, and on Day 1 of each cycle every 3 Cycles thereafter. PK 
samples will also be collected 30 days after discontinuation of trial treatment. Post-infusion pembrolizumab PK samples will be collected at Cycle 1 Day 1 (within 30 minutes 
after the end of infusion), 1 sample between 24 and 96 hours post-infusion, and at Cycle 1 Day 15 (within 30 minutes after the end of the second infusion) and at Cycle 4 Day 1 
(within 30 minutes after the end of infusion).
4. Anti-pembrolizumab antibodies should be drawn with all pre-infusion pembrolizumab PK samples (of both the Dose Determination as well as the Dose Confirmation portion of 
the trial), at 30 days after discontinuation of pembrolizumab.
5.
On 03-JUL-2017, the US FDA placed KN183, KN185, and cohort 1 of KN023 on clinical hold based on safety data from KN183 and KN185 presented to the DMC.  The 
FDA determined that the risks of pembrolizumab plus pomalidomide or lenalidomide outweighed any potential benefit for patients with multiple myeloma.  Based on this 
decision, the treatment phase of KN183, KN185, and Cohort 1 of KN023 is closed effective immediately.  All subjects must stop study treatment, complete the 
Discontinuation Visit and move into the long term safety and survival follow-up (every 12 weeks) per protocol.
 
 
05FW09








Product:  MK-3475 
93
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Trial Treatment Administration Schedule Cohort 2 
Each Cycle = 28 Days (Cycles 1-3 to be repeated beyond 3 cycles) 5
Cycle 1
Cycle 2
Cycle 3
Trial Treatment/ Day of Cycle
(± 3 days window after C1D1)
Days 
1-7 
Days 
8-14
Days 
15-21
Days 
22-28
Days 
1-7 
Days 
8-14
Days 
15-21
Days 
22-28
Days 
1-7 
Days 
8-14
Days 
15-21
Days 
22-28
Pembrolizumab Q 3 Weeks1
1
22
15
8
Carfilzomib2
1, 2
8, 9
15, 16
1, 2
8, 9
15, 16
1, 2
8, 9
15, 16
Dexamethasone3
1,2
8,9
15,16
22,23
1,2
8,9
15,16
22,23
1,2
8,9
15,16
22,23
Pill count for dexamethasone4
1
1
1
1 Pembrolizumab (MK-3475) will be administered as 200 mg every 3 weeks as an IV infusion over 30 minutes
2 Carfilzomib will be administered as a 30 minute IV infusion two consecutive days each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest 
period (Days 17 to 28).  The starting dose is 20 mg/m2/day in Cycle 1 on Days 1 and 2. If tolerated, the dose should be escalated to a target dose of 56 mg/m2/day starting 
on Day 8 of Cycle 1 and continuing on Day 9, 15, and 16 of Cycle 1, then on Days 1, 2, 8, 9, 15 and 16 of subsequent cycles.
3 Dexamethasone will be administered as 20 mg orally or IV on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day Cycle.
4 If applicable, site should document drug accountability as per their institutional guidelines. 
5 On 15-SEP-2017, the US FDA placed Cohort 2 of KN023, on partial clinical hold. Enrollment was stopped and all subjects who derived clinical benefit from therapy are 
allowed to continue if reconsented, at least verbally. Enrollment will not be reopened by the sponsor after a full safety and efficacy evaluation did not demonstrate any 
significant difference from historical controls. Those subjects who are already enrolled and deriving clinical benefit from therapy were allowed to continue if reconsented, 
at least verbally, and will continue on study until protocol-specific end of treatment, and then progress into long term safety and follow-up. Those subjects who are not 
deriving clinical benefit, must stop study treatment, complete the Discontinuation Visit and move into the long term safety and follow-up per protocol.
 
 
05FW09




Product:  MK-3475 
95
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
05FW09


Product:  MK-3475 
96
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to Future Biomedical Research.  A copy of the informed 
consent will be given to the subject.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card after the subject provides written 
informed consent.
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. Details regarding the disease 
for which the subject has enrolled in this trial will be recorded separately and not listed as 
medical history.
Prior history of acute and chronic GVHD, maximum grade, and dates will be collected.
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in the trial will be recorded separately and not listed as a prior medication.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2.
 
 
05FW09


Product:  MK-3475 
97
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Disease Details and Treatments
7.1.1.6.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status.
7.1.1.6.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation, and surgeries. 
7.1.1.6.3 Subsequent Antineoplastic Therapy Status
The investigator or qualified designee will review all new antineoplastic therapy initiated 
after the last dose of trial treatment.  Collect any SCT details, including the conditioning 
regimen, date, and type of transplant.  If a subject initiates a new antineoplastic therapy 
within 30 days after the last dose of treatment, the 30 day Safety Follow-up visit must occur 
before the first dose of new therapy. Once new antineoplastic therapy has been initiated the 
subject will move into survival follow-up.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.  
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Assignment of Randomization Number
All eligible subjects will be allocated, by non-random assignment, in Dose Determination,
Dose confirmation and Expansion Cohort, and will receive a randomization number.  The 
randomization number identifies the subject for all procedures occurring after treatment 
allocation.  This unique number is termed a randomization number throughout the protocol 
for operational purposes. Once a randomization number is assigned to a subject, it can never 
be re-assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for 4 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
 
 
05FW09


Product:  MK-3475 
98
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Administration of trial treatment will be witnessed by the investigator and/or trial staff. The 
total volume of pembrolizumab or carfilzomib infused will be compared to the total volume 
prepared to determine compliance with each dose of pembrolizumab or carfilzomib 
administered. The total daily dose of lenalidomide and dexamethasone will be compared to 
the number of doses a subject reports taking on the pill diary card.
Medication Compliance
Subject compliance for lenalidomide and dexamethasone will be monitored by pill count.  
Sites should document drug accountability as per their institutional guidelines. Noncompliant 
subjects will be instructed about the importance of taking trial treatment as instructed. 
The instructions for preparing and administering pembrolizumab will be provided/referenced
in the Pharmacy Manual.
Prior to discontinuing patients from therapy, consult with Sponsor and submit the Treatment 
Termination & Disease Assessment Termination Form.  
Clinical Procedures/Assessments
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the trial and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.6).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment. 
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated 
to determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Section 5.6.1 regarding the identification, evaluation, and management 
of AEs of a potential immunological etiology.  
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
This trial is a dose determination trial to establish the MTD/MAD of the combination 
therapy; therefore, each dose escalation will be based on the safety and tolerability of the 
combination therapy as experienced by subjects at each dose level. 
The safety and 
tolerability of each cohort will be reviewed prior to the start of the next cohort. The Sponsor
and principal investigators will review the safety and tolerability of the trial treatment and 
communicate the appropriateness of dose escalation, when each cohort is completed and 
before the next cohort is opened for enrollment.  Frequency of these communications will 
depend on the enrollment of each of the cohorts as well as any potential new information 
regarding a safety concern seen in this trial or other trials.
 
 
05FW09


Product:  MK-3475 
99
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
As a Phase I trial, there is no plan for an external safety reviewer. Data from individual 
subjects will be closely followed on an ongoing basis by the Principal Investigator and the 
Sponsor.
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history. A full physical exam should be performed during screening and repeated as per the 
frequency defined in the Trial Flow Charts. After the first dose of trial treatment new 
clinically significant abnormal findings should be recorded as AEs.
7.1.2.2.2 Directed Physical Exam
For cycle days that do not require a full physical exam, the investigator or qualified designee 
will perform a directed physical exam per the Trial Flow Charts and as clinically indicated 
prior to trial treatment administration. New clinically significant abnormal findings should be 
recorded as AEs.
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Charts (Section 6.0).  Vital signs should include temperature, pulse, 
respiratory rate, weight, and blood pressure.  Height will be measured at Screening only.
Electrocardiogram (ECG)
In Dose Determination, Dose Confirmation and Cohort 1, a standard 12-lead ECG will be 
performed using local standard procedures at Screening.  Clinically significant abnormal 
findings should be recorded as medical history.
In Cohort 2, a standard 12-lead ECG with QTc interval will be performed at Screening, 
Cycle 3, 6, 9, 12 and every 3 cycles thereafter. The QTc interval should be calculated and 
recorded. 
Assessment of LVEF using ECHO
Subjects enrolling to Cohort 2 and receiving Carfilzomib must have a Left Ventricular 
Ejection Fraction (LVEF) of at least 40% at study entry. Therefore, a screening 
Echocardiogram (ECHO) must be performed to assess cardiac ejection fraction.  Additional 
echocardiograms may be performed at investigator's discretion as clinically indicated.
 
 
05FW09


Product:  MK-3475 
100
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (See Section 12.5) at 
Screening, prior to the administration of each dose of the trial treatment, and discontinuation 
of trial treatment as specified in the Trial Flow Charts (Section 6.0).
Assessment of Disease and Tumor Imaging
7.1.2.7.1 Criteria for Assessment of Disease
The International Myeloma Working Group criteria (IMWG 2006) will be applied by the site 
as the primary measure for assessment of disease response and as a basis for all protocol 
guidelines related to disease status (e.g., discontinuation of trial treatment) [1].
Myeloma Disease Measurements
Primary Myeloma Panel
The Primary Myeloma Panel that the investigator followed for subject’s disease status should 
be specified on the trial eCRF. Along with other Myeloma Markers, the clinical site should 
consistently record and follow the Primary Myeloma Panel throughout the trial.
Monoclonal Protein Considerations
Laboratory tests for measurement of Serum M-protein level are quantitated using 
densitometry on SPEP, except in cases where the SPEP is felt to be unreliable such as in 
patients with IgA monoclonal proteins migrating in the beta region.  If SPEP is not available 
or is thought to be unreliable (e.g., in some cases of IgA myeloma) for routine M-protein 
quantitation during therapy, then quantitative immunoglobulin levels on nephelometry or 
turbidimetry can be accepted.  However, this must be explicitly reported, and only 
nephelometry can be used for that patient to assess response; SPEP and nephelometric values 
cannot be used interchangeably.
Urine M-protein measurement is estimated using 24-h UPEP only.  Random or 24-hr urine 
tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended.
See Appendix 12.7 for Myeloma Response Criteria.
7.1.2.7.2 Imaging for Subjects with Myeloma Bone Disease
Skeletal survey must be performed at baseline to determine the extent of the subject’s 
myeloma bone disease. Skeletal survey should include a chest (PA or AP; lateral), skull 
(lateral), upper extremities (shoulder to elbow), lower extremities (hip to knee; AP), pelvis 
(AP), cervical/thoracic/lumbar spine (AP and lateral).  A skeletal survey and/or an MRI or 
CT or PET/CT (according to subject’s bone disease or plasmacytoma as clinically indicated) 
 
 
05FW09


Product:  MK-3475 
101
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
performed as standard of care prior to signing consent can be used for screening if performed 
within 28 days of Day 1. 
During the course of the trial, imaging should be performed as clinically indicated and, at the 
time of a complete response assessment, for all subjects without bone disease. For subjects 
with unmeasurable bone lesions, a skeletal survey should be performed as clinically indicated 
during the course of the study and at the time of a complete response assessment. Subjects 
with measurable plasmacytomas at baseline should have imaging performed as clinically 
indicated and at the time of a complete response assessment. 
At any time a subject develops bone pain or there is a suspicion of new bone disease 
indicative of disease progression, appropriate imaging according to clinical practice should 
take place to confirm disease progression.
7.1.2.7.3 Disease Assessment of Immunotherapeutic Agents
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses, which may be functionally 
anergic.  The response patterns seen with such an approach may extend beyond the typical 
time course of responses seen with cytotoxic agents, and can manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions.  Standard 
response assessment criteria may not provide a complete response assessment of 
immunotherapeutic agents such as pembrolizumab.  Therefore in the setting where a 
subject’s assessment shows PD, study drug should not be discontinued unless progression is 
confirmed at least 4 weeks later, provided that the subject’s clinical condition is stable.
7.1.2.7.4 Timing of Disease Assessments
Disease response will be assessed by the investigator per the International Myeloma Working 
Group criteria for multiple myeloma (IMWG 2006 Criteria) [1]. Disease response assessment 
will be performed on day 1 of every 28-day treatment cycle for all cohorts starting C2D1. For 
subjects with biochemical progression, two consecutive assessments are needed to confirm 
PD, according to IMWG 2006. In the setting where a subject’s disease response assessment 
shows confirmed PD according to the IMWG 2006 criteria, the subject may continue on 
study treatment if the investigator considers the subject is deriving clinical benefit from study 
treatment upon consultation with the Sponsor.
7.1.2.7.5 Initial Disease Assessment
Initial, baseline disease assessments must be performed within 28 days prior to the first dose 
of trial treatment (See 6.0 – Trial Flow Charts).
Bone marrow aspirates or biopsies performed as part of standard of care prior to signing 
informed consent may be used for screening if performed within 60 days of Day 1.  
Myeloma laboratory disease assessments should be performed within 28 days prior to the 
first dose of trial treatment (See 6.0 – Trial Flow Charts).
 
 
05FW09


Product:  MK-3475 
102
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
7.1.2.7.6 Disease Assessment During Trial
Disease assessments should be performed per the frequency defined in Section 6.0 – Trial 
Flow Charts. There is a ±3 day window for assessments performed after Day 1. Disease 
assessments should not be delayed for delays in cycle starts.
Disease assessments should continue to be performed until documented disease progression, 
the start of new anti-cancer treatment, withdrawal of consent, death, or the end of the study, 
whichever occurs first.  Additionally, disease assessments should be performed to confirm 
complete response or stringent CR or as clinically indicated. Prior to discontinuing patients 
from therapy, consult with Sponsor and submit the Treatment Termination & Disease 
Assessment Termination Form.  
7.1.2.7.7 Confirmation Assessments
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses, which may be functionally 
anergic.  The response patterns seen with such an approach may extend beyond the typical 
time course of responses seen with cytotoxic agents, and can manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions.  Standard 
response assessment criteria may not provide a comprehensive response assessment of 
immunotherapeutic agents such as pembrolizumab. 
In the setting where a subject’s disease response assessment shows confirmed PD according 
to the IMWG criteria, the subject may continue on study treatment if the investigator 
considers the subject is deriving clinical benefit from study treatment upon consultation with 
the Sponsor. Subjects may only receive treatment after a PD assessment if the following 
criteria are met:

Absence of signs and symptoms indicating disease progression;

No decline in ECOG performance status;

Absence of rapid progression of disease;

Absence of progressive tumor at critical anatomical sites (e.g. cord compression) 
requiring urgent alternative medical intervention.
For any other subjects who have stable disease, minor response, partial response, very good 
partial response or complete response disease assessments should continue per the regular 
frequency.  
In subjects who discontinue study therapy for reasons other than confirmed disease 
progression, a response assessment should be performed at the time of treatment 
discontinuation (i.e. date of discontinuation ± 4 week window), and them monthly in the 
follow up phase until disease progression is confirmed, withdraw of consent, initiation of a 
new anti-myeloma therapy or death, whichever occurs first.  
 
 
05FW09


Product:  MK-3475 
103
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
7.1.2.7.8 Biopsy Collection and Correlative Studies Blood Collection
Dose Determination, Dose Confirmation, Cohort 1
All subjects enrolled into this study must be able to provide an archived or newly obtained 
bone marrow biopsy or aspirate sample for disease characterization. Archival (≤ 60 days) 
bone marrow biopsy or aspirate results, previously done for disease assessment as part of 
routine clinical management, will be acceptable for screening purposes. Bone marrow 
analysis will include bone marrow morphology, IHC, and cytogenetics by FISH panel.  FISH 
panel should include del 1p, del 13, del 17p13, t(4;14), t(11;14), t(14;16), and 1q21 
amplification. If FISH not available, then do standard karyotyping. Bone marrow biopsies or 
aspirate samples will be collected as per Table 19.
Additionally, subjects in the US and Canada only must be willing to provide a newly 
obtained bone marrow aspirate sample at screening or C1D1 and C2D1 for biomarker 
characterization. However, subjects in Cohort 1 are not required to provide a C2D1 bone 
marrow aspirate for biomarker characterization. 
Whole blood for correlative biomarker studies will be collected at screening or C1D1 and
C2D1 for all subjects. These samples must be collected even if a bone marrow aspirate at the 
same time point is unable to be collected. All samples will be collected as indicated in
Table 19.
Table 19
Bone Marrow and Whole Blood Sample Collection (Dose Determination, Dose 
Confirmation, Cohort 1)
Indication
Timing of Biopsy or Aspirate
Bone marrow biopsy or aspirate 
for disease characterization at 
local institution.

Bone marrow biopsy archived material, or newly obtained biopsy or 
aspirate at Screening 

As clinically indicated, or to confirm CR per IMWG. 
(See Section 6.0 for Trial Flow Chart and Procedures Manual for further 
details).
Bone marrow aspirate  (US and 
Canada sites only)

Screening or Cycle 1 Day 1
o
For  biomarker assessment

Cycle 2 Day 1 (not required for Cohort 1)
o
For biomarker assessment
(See Section 6.0 for Trial Flow Chart and Procedures Manual for further 
details).
Whole blood

Screening or Cycle 1 Day 1
o
For biomarker assessment

Cycle 2 Day 1
o
For biomarker assessment
(See Section 6.0 for Trial Flow Chart and Procedures Manual for further 
details).
 
 
05FW09


Product:  MK-3475 
104
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Cohort 2
All subjects enrolled into this study must be able to provide an archived or newly obtained 
bone marrow biopsy or aspirate sample for disease characterization. Archival (≤ 60 days) 
bone marrow biopsy or aspirate results previously done for disease assessment as part of 
routine clinical management will be acceptable for screening purposes. Bone marrow 
analysis will include bone marrow morphology, IHC, and cytogenetics by FISH panel.  FISH 
panel should include del 1p, del 13, del 17p13, t(4;14), t(11;14), t(14;16), and 1q21 
amplification. If FISH is not available, then do standard karyotyping.
Additionally, subjects in US and Canada only, must be willing to provide a newly obtained 
bone marrow aspirate sample at screening or C1D1, C2D1 and at the time of discontinuation 
for biomarker characterization. 
Whole blood for correlative biomarker studies will be collected at screening or C1D1, C2D1 
and at the time of discontinuation for all subjects. These samples must be collected even if a 
bone marrow aspirate at the same time point is unable to be collected. All samples will be 
collected as per Table 20.
Table 20
Bone Marrow and Whole Blood Sample Collection (Cohort 2)
Indication
Timing of Biopsy or Aspirate
Bone marrow biopsy or aspirate 
for disease characterization at 
local institution.

Bone marrow biopsy archived material, or newly obtained biopsy or 
aspirate at Screening 

As clinically indicated, or to confirm CR per IMWG. 
(See Section 6.0 for Trial Flow Chart and Procedures Manual for further 
details).
Bone marrow aspirate (US and 
Canada sites only)

Screening or Cycle 1 Day 1
o
For  biomarker assessment

Cycle 2 Day 1
o
For biomarker assessment

Treatment Discontinuation
o
For biomarker assessment
(See Section 6.0 for Trial Flow Chart and Procedures Manual for further 
details).
Whole blood

Screening or Cycle 1 Day 1
o
For biomarker assessment

Cycle 2 Day 1
o
For biomarker assessment

Treatment Discontinuation
o
For biomarker assessment
(See Section 6.0 for Trial Flow Chart and Procedures Manual for further 
details).
 
 
05FW09


Product:  MK-3475 
105
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 21.  
 
 
05FW09


Product:  MK-3475 
106
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Table 21
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG) a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR) b
Platelet count
Alanine aminotransferase (ALT)
Protein
aPTT b
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
Total Triiodothyronine (T3)c
Red Blood Cell 
Count
Bicarbonate/Carbon Dioxided
Microscopic exam, if 
abnormal results are 
noted
Free thyroxine (T4)
Absolute 
Neutrophil Count
Calcium
Urine pregnancy testa
Thyroid stimulating 
hormone (TSH)
Chloride
Anti-pembrolizumab
Antibodies
Creatinine
PK
GFR
Serum or plasma viscosity
Uric Acid
Calcium
Glucose
LDH
Phosphorus
Potassium
Sodium
Magnesium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogen/Ureae
a. Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required.
b. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  
Any subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout 
the trial. 
c. Free T3 may be performed in place of Total T3 per local standards.
d. Test only if part of standard of care locally.
e. Blood urea nitrogen is preferred; if not available, urea may be tested.
Laboratory tests for Screening should be performed within 7 days prior to the first dose of 
treatment. If laboratory tests for screening are performed within 3 days of Cycle 1 Day 1, the 
laboratory tests do not need to be repeated at the Cycle 1 Day 1 visit. After Cycle 1, predose
laboratory procedures can be conducted up to 72 hours prior to dosing.  Results must be 
reviewed by the investigator or qualified designee and found to be acceptable prior to each 
dose of trial treatment.
 
 
05FW09


Product:  MK-3475 
107
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
In Cohort 2, an abbreviated panel of serum chemistries is performed per the Flow Chart on 
Day 2, 8, and 9 of each cycle before Carfilzomib administration.  The analytes include: 
albumin, blood urea nitrogen, creatinine, creatinine clearance, glucose, uric acid, bicarbonate, 
calcium, chloride, phosphorus, potassium, sodium, and lactate dehydrogenase.  
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2.1 Blood Collection for Pembrolizumab
Sample collection, storage, and shipment instructions for samples will be provided in the
Procedure Manual.
The time points for pembrolizumab PK blood sampling are described in Section 6.0 – Trial 
Flow Chart.
Note: If ongoing ADA and PK results continue to be consistent with existing ADA and PK 
data from other pembrolizumab clinical trials, it may be decided to discontinue further 
sample collection in this study.
7.1.3.2.2 Blood Collection for Anti-Pembrolizumab Antibodies
Sample collection, storage and shipment instructions for blood samples will be provided in 
the Procedures Manual. 
The time points for Anti-pembrolizumab antibodies are described in Section 6.0 – Trial Flow 
Chart.
Note: If ongoing ADA and PK results continue to be consistent with existing ADA and PK 
data from other pembrolizumab clinical trials, it may be decided to discontinue further 
sample collection in this study.
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use

Leftover bone marrow aspirate samples

Leftover correlative blood samples
 
 
05FW09


Product:  MK-3475 
108
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Other Procedures
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical trial that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
trial site.
 
 
05FW09


Product:  MK-3475 
109
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening Period
Approximately 28 days prior to enrollment, potential subjects will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5.1.  Visit requirements are 
outlined in Section 6.0 – Trial Flow Chart.
Written consent for the main study must be obtained prior to performing any protocol-
specific procedure.  Results of a test performed prior to the subject signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame. Screening procedures are to be completed within 28 days prior to the 
first dose of trial treatment except for the following:

Laboratory tests are to be performed within 7 days prior to the first dose of trial 
treatment.

Archival (≤ 60 days) bone marrow biopsy or aspirate results, previously done for 
disease assessment as part of routine clinical management, will be acceptable for 
screening purposes.

For women of reproductive potential assigned to dose determination, dose 
confirmation or  Cohort 1 treated with combination of pembrolizumab, lenalidomide, 
and dexamethasone, two negative pregnancy tests must be obtained prior to initiating 
therapy. The first test should be performed within 10-14 days and the second test 
within 24 hours prior to the first dose of trial treatment. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed 
by the local study site laboratory).

For women of reproductive potential assigned to Cohort 2 treated with the 
combination of pembrolizumab, carfilzomib, and dexamethasone, one negative 
pregnancy test must be obtained within 72 hours of initiating therapy.  If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study site laboratory).
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria are met.
Treatment Period
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.
 
 
05FW09


Product:  MK-3475 
110
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
On 03-JUL-2017, the US FDA placed KN183, KN185, and cohort 1 of KN023 on clinical 
hold based on safety data from KN183 and KN185 presented to the DMC.  The FDA 
determined that the risks of pembrolizumab plus pomalidomide or lenalidomide outweighed 
any potential benefit for patients with multiple myeloma.  Based on this decision, the 
treatment phase of KN183, KN185, and Cohort 1 of KN023 is closed effective immediately.  
All subjects must stop study treatment, complete the Discontinuation Visit and move into the 
long term safety and survival follow-up (every 12 weeks) per protocol.
On 15-SEP-2017, the US FDA placed Cohort 2 of KN023, on partial clinical hold. 
Enrollment was stopped and all subjects who derived clinical benefit from therapy are 
allowed to continue if reconsented, at least verbally. Enrollment will not be reopened by the 
sponsor after a full safety and efficacy evaluation did not demonstrate any significant 
difference from historical controls. Those subjects who are already enrolled and deriving 
clinical benefit from therapy were allowed to continue if reconsented, at least verbally, and 
will continue on study until protocol-specific end of treatment, and then progress into long 
term safety and follow-up. Those subjects who are not deriving clinical benefit, must stop 
study treatment, complete the Discontinuation Visit and move into the long term safety and 
follow-up per protocol.
Post-Treatment Visits
7.1.5.3.1 Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new antineoplastic treatment, 
whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution of the AE 
to Grade 0-1 or until the beginning of a new antineoplastic therapy, whichever occurs first.
SAEs that occur within 90 days of the end of treatment or before initiation of a new 
antineoplastic treatment should also be followed and recorded.  
In the event a subject receives an allo-SCT within 24 months of the last dose of 
pembrolizumab or before the trial ends, the following events will be collected as ECIs 
through 18 months from the date of allo-SCT: GVHD, febrile syndrome treated with steroids, 
pulmonary complications, hepatic veno-occlusive disease and/or sinusoidal syndrome, 
immune-mediated AEs, critical illness, and transplant-related mortality. 
If available and relevant to an event post-allogeneic SCT, concomitant medications and/or 
laboratory results may also be reported.  Additional medically important AEs may be 
submitted at the investigator’s discretion.
Efficacy Follow-Up Visits
Subjects who discontinue for reasons other than progressive disease will move into the 
Follow-Up Phase to monitor disease status and should be assessed every 4 weeks (± 14 days) 
until: (1) the start of new anti-cancer treatment; (2) documented disease progression; (3) 
 
 
05FW09


Product:  MK-3475 
111
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
death; (4) withdraw of consent; or (5) the end of the trial, whichever occurs first. Every effort 
should be made to collect information regarding disease response assessment in the follow-
up period.  Prior to discontinuing patients from therapy, consult with Sponsor and submit the 
Treatment Termination & Disease Assessment Termination Form.   Information regarding 
post-study anti-myeloma treatment will be collected if new treatment is initiated.
7.1.5.4.1 Survival Follow-Up
Once a subject experiences confirmed disease progression or starts a new antineoplastic 
therapy, the subject moves into the Survival Follow-up phase and should be contacted by 
telephone approximately every 12 weeks
for at least 12 months following their 
discontinuation visit to assess for survival status until death, withdrawal of consent, or the 
end of the study, whichever occurs first.  The first survival follow-up assessment should be 
scheduled as described below: 
For participants who discontinue treatment intervention and who will not enter the efficacy 
follow-up phase, the first survival follow-up assessment will be scheduled 12 weeks after the 
discontinuation visit and/or safety follow-up visit (whichever is last).  
For participants who completed assessments in the efficacy follow-up phase, the first 
survival follow-up assessment will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
7.1.5.4.2 Follow-up After Allogeneic Stem Cell Transplantation
In the event a subject receives an allo-SCT within 24 months of the last dose of 
pembrolizumab or before the end of the study, the following events will be collected as ECIs 
(see Section 7.2.3.2) through 18 months from the date of allo-SCT: GVHD, febrile syndrome
treated with steroids, pulmonary complications, hepatic veno-occlusive disease and/or 
sinusoidal syndrome, immune-mediated AEs, critical illness, and transplant-related mortality.
Post-allogenic-stem cell transplant events of clinical interest (ECIs) that occur after the 
normal safety follow up period must be assessed for seriousness and causality and reported to 
the sponsor as follows: within 24 hours if serious, regardless of causality or if non-serious 
and considered to be drug-related; and 5 calendar days if non-serious and not considered to 
be drug-related.
If available and relevant to an event post-allogeneic SCT, concomitant medications and/or 
laboratory results may also be reported.  Additional medically important AEs may be 
submitted at the investigator’s discretion.
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis.
Upon Sponsor 
 
 
05FW09


Product:  MK-3475 
112
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the sponsor defined time period will be contacted for their survival status (excluding 
participants that have previously recorded a death event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
05FW09


Product:  MK-3475 
113
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose of pembrolizumab (MK-3475) will be defined as any 
dose of 1,000 mg or greater. No specific information is available on the treatment of 
overdose of pembrolizumab (MK-3475). In the event of overdose, the subject should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided 
if clinically indicated. An overdose for all other trial treatments will be defined as any dose 
exceeding the prescribed dose by 20%.  In the event of overdose, the subject should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided 
if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject’s female partner 
that occurs during the trial.  
Pregnancies and lactations of subjects and female partners of male subjects that occur after 
the consent form is signed but before treatment allocation/randomization must be reported by 
the investigator if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.  
Pregnancies and lactations of subjects and female partners of male subjects that occur from 
the time of treatment allocation/randomization through 120 days following cessation of 
Sponsor’s product, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, must be reported by the investigator.  All reported 
pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious 
 
 
05FW09


Product:  MK-3475 
114
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
events (Important Medical Events). If the pregnancy continues to term, the outcome (health 
of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper.  Sponsor Contact information can be found in the Investigator Trial File Binder (or 
equivalent).
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events     
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 22 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
 
 
05FW09


Product:  MK-3475 
115
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent)
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines.  Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
 
 
05FW09


Product:  MK-3475 
116
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
7.2.3.2.1 Adverse Events Follow-up post-Allogeneic Stem Cell Transplantation
In the event a subject receives an allo-SCT within 24 months of the last dose of 
pembrolizumab or before the trial ends, the following events will be collected as ECIs 
through 18 months from the date of allo-SCT: GVHD, febrile syndrome treated with steroids, 
pulmonary complications, hepatic veno-occlusive disease and/or sinusoidal syndrome, 
immune-mediated AEs, critical illness, and transplant-related mortality.
Post-allogenic-stem cell transplant events of clinical interest (ECIs) that occur after the 
normal safety follow up period must be assessed for seriousness and causality and reported to 
the sponsor as follows: within 24 hours if serious, regardless of causality or if non-serious 
and considered to be drug-related; and 5 calendar days if non-serious and not considered to 
be drug-related.
If available and relevant to an event post-allogeneic SCT, concomitant medications and/or 
laboratory results may also be reported.  Additional medically important AEs may be 
submitted at the investigator’s discretion.
Guidance on details to be collected and suggested events to be reported can be found in the 
Procedure Manual.
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3- Immediate Reporting of Adverse Events to the Sponsor.  Any such event 
will be submitted to the Sponsor within 24 hours either by electronic or paper media.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.  
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial.  Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
 
 
05FW09


Product:  MK-3475 
117
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
 
 
05FW09


Product:  MK-3475 
118
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Table 22
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 
CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
test drug 
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
05FW09


Product:  MK-3475 
119
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to 
Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with 
Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, 
there 
is 
a 
reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
 
 
05FW09


Product:  MK-3475 
120
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9).  Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, along with an 
explanation as to when and why they occurred, will be listed in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.  No 
separate Statistical Analysis Plan (SAP) will be issued for this study.
On 03-JUL-2017, the US FDA placed KN183, KN185, and cohort 1 of KN023 on clinical 
hold based on safety data from KN183 and KN185 presented to the DMC.  The FDA 
determined that the risks of pembrolizumab plus pomalidomide or lenalidomide outweighed 
any potential benefit for patients with multiple myeloma.  Based on this decision, the 
treatment phase of KN183, KN185, and Cohort 1 of KN023 is closed effective immediately.  
All subjects must stop study treatment, complete the Discontinuation Visit and move into the 
long term safety and survival follow-up (every 12 weeks) per protocol.
On 15-SEP-2017, the US FDA placed Cohort 2 of KN023, on partial clinical hold. 
Enrollment was stopped and all subjects who derived clinical benefit from therapy are 
allowed to continue if reconsented, at least verbally. Enrollment will not be reopened by the 
sponsor after a full safety and efficacy evaluation did not demonstrate any significant 
difference from historical controls. Those subjects who are already enrolled and deriving
clinical benefit from therapy were allowed to continue if reconsented, at least verbally, and 
will continue on study until protocol-specific end of treatment, and then progress into long 
term safety and follow-up. Those subjects who are not deriving clinical benefit, must stop 
study treatment, complete the Discontinuation Visit and move into the long term safety and 
follow-up per protocol.
Due to the current status of the study the statistical analysis of this section may be modified 
and will be reported in the CSR.
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
 
 
05FW09


Product:  MK-3475 
121
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Efficacy Analyses
The primary and key secondary endpoints, primary analysis population, and statistical 
methods that will be employed for the efficacy analyses are presented in Table 23 below.
The objective response rate (ORR) per 2006 International Myeloma Working Group criteria 
(IMWG 2006) based on investigator assessment will be conducted in the All-Subjects-as-
Treated (ASaT) population.  No multiplicity adjustment is planned.
Table 23
Summary of Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time point)
Statistical Method
Analysis 
Population
Missing Data Approach
ORR and DCR per IMWG 2006 
criteria based on investigator 
assessment
Point estimate, 
Clopper-Pearson 95% 
CI
ASaT
Subjects with missing 
data are considered as 
non-responders
Safety Analyses
The All-Subjects-as-Treated (ASaT) population will be employed for safety analyses.  DLT 
will be summarized by dose level for the Dose Determination stage and Dose Confirmation 
stage.  Descriptive tables that summarize the number and percentage of subjects that 
experience adverse events as categorized in the NCI CTCAE Version 4 will be generated by 
dose level. 
Power and Sample Size
The sample size of the Dose Determination stage of the study depends primarily on clinical 
considerations rather than on statistical considerations. Specifically, the final number of 
subjects enrolled in the trial will depend on empirical safety (DLT) observations. However, 
it is estimated that a maximum of 12 subjects evaluable for safety and tolerability will be 
enrolled in the Dose Determination portion of this trial to adequately assess the toxicity of 
pembrolizumab in combination with lenalidomide and low-dose dexamethasone.  If 
lenalidomide toxicity is observed, then 6 to 12 additional subjects may be enrolled to further 
evaluate pembrolizumab and lenalidomide/low-dose dexamethasone with a lower dose of 
lenalidomide.
The Dose Confirmation stage will enroll a small cohort of subjects (approximately 7-13) to 
establish the MTD/MAD fixed dose evaluated for efficacy; and the Expansion Cohort stage
of the study will enroll approximately up to 45 subjects in each cohort.
 
 
05FW09


Product:  MK-3475 
122
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Statistical Analysis Plan
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The preliminary Dose Determination stage, the Dose Confirmation stage and the Expansion
Cohort stage of the study will be conducted as an open-label study. 
The Clinical Biostatistics department will generate an allocation schedule for all enrolled 
subjects.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated by dosing schedules, dose levels and 
disease-specific cohorts are listed below.
Efficacy Endpoints
Key efficacy endpoints for the trial are listed below.

ORR: defined as the proportion of subjects who have achieved a response (Partial 
Response or better) by investigator assessment.  Subjects with missing outcome on 
objective response will be considered non-responders. 

DCR: defined as the proportion of subjects who have achieved a response (Partial 
Response or better) or have demonstrated stable disease for at least 12 weeks prior to 
any evidence of progression.
Exploratory endpoints include:

DOR: for subjects who demonstrate a response (Partial response or better), duration 
of response is defined as the time from first documented evidence of a response until 
disease progression or death due to any cause, whichever occurs earlier.  The 
censoring rules for DOR are summarized in Table 24.

PFS: defined as the time from first day of study treatment to first documented 
progressive disease (PD) or death due to any course, whichever occurs earlier.  
Subjects without documented PD/death will be censored at the last disease 
assessment date. 

TTP: defined as the time from first dose to first documented progressive disease (PD). 
Subjects without documented PD will be censored at the last disease assessment date.
 
 
05FW09


Product:  MK-3475 
123
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
In addition, overall survival (OS) and change from baseline in bone marrow/aspirate PD-L1 
expression will also be evaluated.
Safety Endpoints
The primary safety endpoints of the study include the DLT rate and AEs graded using 
CTCAE (Version 4.0) criteria.  Safety will be assessed by quantifying the toxicities and 
grades experienced by subjects who have received pembrolizumab, including serious AEs 
and events of clinical interest (ECIs).  Other safety endpoints include laboratory safety 
assessments, vital signs and physical examinations.  Safety measurements are described in 
Section 7.
Analysis Populations
Efficacy Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of efficacy data 
in this trial.  The ASaT population consists of all subjects who received at least one dose of 
trial treatment. Subjects will be analyzed according to the assigned dose level.  The analysis 
of response duration is based on all responders. Details on the approach to handling missing 
data are provided in Section 8.2.5 Statistical Methods.  In addition, a response evaluable 
population will be used for supportive analyses for the primary efficacy endpoints (ORR and 
DCR) and will consist of all treated subjects who have at least two post-baseline efficacy 
assessments and did not have a significant major protocol violation at study entry as defined 
by the Sponsor.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this trial.  The ASaT population consists of all subjects who received at least one dose of trial 
treatment. Subjects will be analyzed according to the assigned dose level.  At least one 
laboratory or vital sign measurement obtained subsequent to at least one dose of trial 
treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.2.5 Statistical Methods.
For safety analysis related to DLT rate, the DLT evaluable population will be used. The 
DLT evaluable population consists of all DLT evaluable subjects.  In order to be considered 
evaluable, the subject must complete the first cycle of combination therapy or discontinue 
from the trial due to a drug-related adverse event.  Subjects who discontinue prematurely due 
to a non drug-related cause are not included in the DLT evaluable population.
 
 
05FW09


Product:  MK-3475 
124
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Statistical Methods
Statistical Methods for Efficacy Analyses
Efficacy analyses will be performed separately by treatment and by Cohort.  The 
pembrolizumab 2 mg/kg dose and 200 mg fixed dose will be combined for the same 
lenalidomide dose level. Subjects from the Dose Determination and Dose Confirmation 
stages who were treated with the same study treatment as Expansion Cohort 1 will be 
combined with subjects from Expansion Cohort 1.  For other subjects who were enrolled 
during the Dose Determination and Dose Confirmation stages, given the small number of 
subjects in each treatment group, efficacy results, such as objective response, PFS and OS, 
will be listed only.
For the efficacy endpoints ORR and DCR, the point estimate and 95% confidence intervals
will be provided using the Clopper-Pearson methods.  There is no plan for any formal 
comparison between any two treatment regimens of the Expansion Cohort stage.
Since subjects who have progressed by investigator assessment may continue study 
treatment, supportive analyses (point estimate and 95% confidence intervals) will be 
conducted for ORR to consider these subjects who later achieve partial response or better 
post-progression as responders. 
Kaplan-Meier estimates of time to event endpoints, including DOR, PFS, TTP and OS, will 
be provided for each treatment.  
For DOR, the censoring rules are summarized in Table 24.  Subjects who are alive, have not 
progressed, have not initiated new anti-cancer treatment, and have not been determined to be 
lost to follow-up are considered responders at the time of analysis.
Table 24
Censoring Rules for the Analysis of DOR
Situation
Date of progression or censoring
Outcome
No progression nor death, no new anti-
cancer therapy initiated
Last adequate assessment
Censor 
(non-event)
No progression nor death, new anti-
cancer therapy initiated
Last adequate assessment before new 
anti-cancer therapy initiated
Censor 
(non-event)
≥ 2 consecutive missed adequate disease 
assessments at any time prior to 
progression or death
Last adequate assessment prior to ≥ 2 
missed adequate disease assessments
Censor 
(non-event)
Death or  progression after ≤1 missed 
adequate disease assessments
Death or progression
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
Subjects are considered to have an ongoing response if censored, alive, have not progressed, have not started 
a new anti-cancer therapy, have not had ≥ 2 consecutive missed disease assessments, and have not been 
determined to be lost to follow-up.
 
 
05FW09


Product:  MK-3475 
125
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
For PFS, subjects without documented PD/death will be censored at the last disease 
assessment date.  For OS, subjects without documented death at the time of analysis will be 
censored at the last known alive date.  For TTP, subjects without documented PD will be 
censored at the last disease assessment date.  Table 25 summarizes the primary efficacy 
analyses; supportive analyses for the primary efficacy endpoints (ORR and DCR) will also 
be conducted in the response evaluable population defined in Section 8.2.4.1.
Table 25
Analysis Strategy for Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Analysis 
Population
Statistical Method
Missing Data 
Approach
ORR and DCR per IMWG 
2006 criteria based on 
investigator assessment
P
ASaT
Point 
estimate, 
Clopper-Pearson 
95% CI
Subjects 
with 
missing data are 
considered as non-
responders
DOR
per 
IMWG 
2006 
criteria 
based 
on 
investigator assessment
P
All 
responders
Summary 
statistics 
using 
Kaplan-Meier 
method
Non-responders are 
excluded 
in 
analysis
PFS per IMWG 2006 criteria 
based 
on 
investigator 
assessment
P
ASaT
Summary 
statistics 
using 
Kaplan-Meier 
method
Censored 
at 
last 
disease assessment 
date
OS
P
ASaT
Summary 
statistics 
using 
Kaplan-Meier 
method
Censored at the last 
date known to be 
alive
TTP per IMWG 2006 criteria 
based 
on 
investigator 
assessment
P
ASaT
Summary 
statistics 
using 
Kaplan-Meier 
method
Censored at the last 
non-PD assessment 
date
  P=Primary approach; ASaT = All Subjects as Treated; CI = Confidence interval
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), ECOG, laboratory tests, vital signs, and ECG measurements, and 
will be performed separately by treatment.  The pembrolizumab 2 mg/kg dose and 200 mg 
fixed dose will be combined for the same lenalidomide dose level.  
Dose limiting toxicities will be summarized and listed for the Dose Determination stage and 
Dose Confirmation stage.  
Summary statistics (median and range) for time to first Grade 3-5 AE, which is defined as the 
time from the first day of study treatment to the first event of Grade 3-5 AE, will be 
provided.  Adverse experiences will be summarized as counts, frequencies and grade by NCI 
CTCAE version 4.0 for each dose level of each combination regimen. Laboratory values will 
 
 
05FW09


Product:  MK-3475 
126
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
be graded by NCI CTCAE version 4.0.  The percentage of subjects with laboratory 
abnormalities by grades will be tabulated.  The change of grades during the study will be
summarized by a lab shift table.  In this analysis, the percentage of subjects who improve or 
worsen from baseline for each laboratory test will be summarized.  A clinically meaningful 
worsening in CTCAE grade was defined as a shift from less than Grade 3 at baseline to 
Grade 3 or above, or a shift from Grade 0 to Grade 2. Summary statistics for baseline, on
treatment, and change from baseline values of continuous measures such as changes from 
baseline in laboratory and vital signs will be provided by dose level in table format.  
Immune-related AEs (irAEs) that are designated as events of special interest will be 
summarized separately from other AEs.  
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics 
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened, the primary reasons for 
screening failure, and the primary reason for discontinuation will be displayed.  Demographic 
variables (such as age) and baseline characteristics will be summarized by treatment either by 
descriptive statistics or categorical tables.
Other Analyses
Change from baseline in bone marrow aspirate/biopsy PD-L1 expression will be summarized 
by dosing schedules using descriptive statistics.
Multiplicity
There is no multiplicity adjustment planned for this study. 
Sample Size and Power Calculations
The sample size of the study depends primarily on clinical considerations rather than on 
statistical considerations; see Section 5.2.5 for details
Stage 1: Dose Determination (Cohort 1)
The final number of subjects enrolled in the Dose Determination stage of the trial will 
depend on empirical safety (DLT) observations.  A standard 3+3 dose scheme will be applied 
in the preliminary dose finding portion of the study for each regimen. A maximum of 12 
subjects (6 subjects per dose level) will be enrolled in each dosing schedule of 
pembrolizumab in combination with lenalidomide and dexamethasone.  If lenalidomide 
toxicity is observed during Dose Determination, then 6-12 additional subjects may be 
enrolled to further evaluate the triplet with a lower dose of lenalidomide. 
 
 
05FW09


Product:  MK-3475 
127
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Stage 2: Dose Confirmation (Cohort 1)
The Dose Confirmation stage will enroll 7-13 subjects for a total of 13 in all when combined 
with subjects in the Dose Determination stage.  Table 16 summarizes the operating 
characteristics the TPI design.
Stage 3: Expansion Cohort (Cohorts 1 and 2)
The Expansion Cohort stage of the study will enroll approximately up to 45 treated subjects, 
allowing for subjects who are not response evaluable in each cohort, to further assess safety 
and preliminary efficacy. Table 26 displays the two-sided 95% CIs of ORR with the sample 
size of 30 response evaluable subjects for different observed response rates based on the 
method of Clopper and Pearson (1934) [67] with a maximum half-width of 19%.  For a 
sample size of 45 subjects, the precision of the CI is greater, with a maximum half-width of 
15%.
Table 26
Two-sided 95% Confidence Intervals of ORR with 30 Subjects
Number of Observed 
Responders
ORR Estimates
(%)
95% CI of ORR
(%)
10
33.3
(17.3, 52.8)
15
50.0
(31.3, 68.7)
20
66.7
(47.2, 82.7)
25
83.3
(65.3, 94.4)
Subgroup Analyses and Effect of Baseline Factors
There is no formal subgroup analysis for this study.
Interim Analysis
There is no planned interim analysis for this study.
Compliance (Medication Adherence)
For IV drugs, drug accountability data for trial treatment will be collected during the study. 
Any deviation from protocol-directed administration will be reported.
Compliance with oral drugs will be assessed using the prime therapy records provided in the 
electronic Case Report Forms (eCRFs). Compliance will be defined as the percentage of the 
“Number of Days on Therapy” over the “Number of Days Should be on Therapy”. A day 
within the study will be considered an “On-Therapy” day if the subject takes study drug on a 
scheduled day for treatment administration without dose variation or with dose variation, 
including dose reduction and dose interruption, for reasons other than noncompliance.  For 
each subject, the “Number of Days Should be on Therapy” is the total number of scheduled 
days for treatment administration from entry to the study to the date of discontinuation.
 
 
05FW09


Product:  MK-3475 
128
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
For each subject, percent compliance will then be calculated using the following formula:
Therapy
on 
be
Should
Days
of
Number 
Therapy
on 
Days
of
Number 
Compliance
Percent 

x 100.
Summary statistics will be provided on percent compliance by treatment group for the ASaT 
population.  
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.  Dose intensity 
will also be summarized as appropriate.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 27. 
Table 27
Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab (MK-3475) 100 mg/4 mL
Solution for Infusion
All other supplies not indicated in Table 27 above will be provided centrally by the Sponsor 
or locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site is responsible for recording the lot number, manufacturer, and expiry date for
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
 
 
05FW09


Product:  MK-3475 
129
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Pembrolizumab vials will be provided in an open label fashion for subject dosing.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. 
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
 
 
05FW09


Product:  MK-3475 
130
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
 
 
05FW09


Product:  MK-3475 
131
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
 
 
05FW09


Product:  MK-3475 
132
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The sponsor also recognizes that documents may need 
to be retained for a longer period if required by local regulatory requirements. All trial 
documents shall be made available if required by relevant regulatory authorities. The 
investigator must consult with and obtain written approval by the Sponsor prior to discarding 
trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
 
 
05FW09


Product:  MK-3475 
133
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialregister.eu
or other local registries. Merck, as Sponsor of this trial, will review this protocol and submit 
the information necessary to fulfill these requirements. Merck entries are not limited to 
FDAAA or the EMA clinical trials directive mandated trials. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.   
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
 
 
05FW09


Product:  MK-3475 
134
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided by the Sponsor.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
 
 
05FW09


Product:  MK-3475 
135
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
05FW09


Product:  MK-3475 
136
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
11.0 LIST OF REFERENCES
[1]
Durie BGM, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. 
International uniform response criteria for multiple myeloma. Leukemia 
2006;20:1467-73.
[2]
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
[3]
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune 
evasion. Nat Med 2002;8(8):793-800.
[4]
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 
2002;2(2):116-26.
[5]
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al.
Blockade of programmed death-1 ligands on dendritic cells enhances T cell 
activation and cytokine production. J Immunol 2003;170(3):1257-66.
[6]
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42.
[7]
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. 
PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor 
outcome for 
patients with renal cell carcinoma. Clin 
Cancer Res 
2007;13(6):1757-61.
[8]
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer Metastasis Rev 2007;26(3-4):373-400.
[9]
Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic 
factors in renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
[10]
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. 
Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small 
cell lung cancer. Clin Cancer Res 2008;14(16):5220-7.
[11]
Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, et 
al. Tumor infiltrating lymphocytes: an intriguing player in the survival of 
colorectal cancer patients. BMC Immunol 2010;11:19.
[12]
Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18(1B):689-94.
 
 
05FW09


Product:  MK-3475 
137
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
[13]
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, 
et al. Type, density, and location of immune cells within human colorectal tumors 
predict clinical outcome. Science 2006;313(5795):1960-4.
[14]
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
molecular biology. Int J Clin Oncol 2010;15(6):544-51.
[15]
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. 
Prolonged survival of a patient affected by pancreatic adenocarcinoma with 
massive lymphocyte and dendritic cell infiltration after interleukin-2 
immunotherapy. Report of a case. Tumori 2008;94(3):426-30.
[16]
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. 
J Cutan Pathol 2010;37(Suppl 1):48-53.
[17]
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
Oncol. 2009 Sep;10(9):840-1.
[18]
Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol 
Immunother 2008;57(1):97-106.
[19]
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic 
implications of type and density of tumour-infiltrating lymphocytes in gastric 
cancer. Br J Cancer 2008;99(10):1704-11.
[20]
Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema 
H, et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary 
and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol 
Immunother 2009;58(3):449-59.
[21]
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification 
of positive selection in the thymus of PD-1-deficient mice. J Exp Med. 2000 Mar 
6;191(5):891-8.
[22]
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes 
correlates 
with 
poor 
prognosis 
in 
renal 
cell 
carcinoma. 
BJU 
Int 
2011;107(9):1500-6.
[23]
Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic 
value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 
1997;182(3):318-24.
 
 
05FW09


Product:  MK-3475 
138
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
[24]
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et 
al. 
Adoptive 
cell 
transfer 
therapy 
following 
non-myeloablative 
but 
lymphodepleting chemotherapy for the treatment of patients with refractory 
metastatic melanoma. J Clin Oncol 2005;23(10):2346-57.
[25]
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with autologous CD4+ T cells against NY-
ESO-1. N Engl J Med 2008;358(25):2698-703.
[26]
Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. 
Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated 
with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer 
Immunol Immunother 2010;59(6):909-19.
[27]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
[28]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[29]
LeBlanc R, Hideshima T, Catley LP, Shringarpure R, Burger R, Mitsiades N, et 
al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. 
Blood. 2004 Mar 1;103(5):1787-90.
[30]
Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ, et al. 
Differential cytokine modulation and T cell activation by two distinct classes of 
thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol. 1999 
Jul 1;163(1):380-6.
[31]
Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, 
et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well 
tolerated in patients with relapsed multiple myeloma. Blood 2002;100(9):3063-7.
[32]
Richardson P, Jagannath S, Hussein M, Berenson J, Singhal S, Irwin D, et al. A 
multicenter, single-arm, open-label study to evaluate the efficacy and safety of 
single-agent lenalidomide in patients with relapsed and refractory multiple 
myeloma; prelininary results [abstract]. Blood. 2005;106(11):1565.
[33]
Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, et 
al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed 
or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-
64.
 
 
05FW09


Product:  MK-3475 
139
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
[34]
Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al. 
Lenalidomide plus dexamethasone for relapsed multiple myeloma in North 
America. N Engl J Med. 2007 Nov 22;357(21):2133-42.
[35]
Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, 
et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple 
myeloma. N Engl J Med. 2007 Nov 22;357(21):2123-32. Erratum in: N Engl J 
Med. 2009 Jul 30;361(5):544.
[36]
Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, et 
al. Long-term follow-up on overall survival from the MM-009 and MM-010 
phase III trials of lenalidomide plus dexamethasone in patients with relapsed or 
refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52.
[37]
U.S. Prescribing Information: REVLIMID [lenalidomide] capsules, for oral use: 
2015.
[38]
Chen C, Reece DE, Siegel D, Niesvizky R, Boccia RV, Stadtmauer EA, et al. 
Expanded 
Access 
Program 
(EAP) 
for 
lenalidomide 
(Revlimid) 
plus 
dexamethasone in over 1400 subjects with relapsed or refractory multiple 
myeloma [abstract]. Blood. 2006;108(11):3556.
[39]
Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, et 
al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-
dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an 
open-label randomised controlled trial. Lancet Oncol. 2010 Jan;11(1):29-37. 
Erratum in: Lancet Oncol. 2010 Jan;11(1):14.
[40]
Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, 
et al. Lenalidomide and dexamethasone in transplant-ineligible patients with 
myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17.
[41]
Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. 
Lenalidomide, bortezomib, and dexamethasone combination therapy in patients 
with newly diagnosed multiple myeloma. Blood. 2010 Aug 5;116(5):679-86.
[42]
Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, et al. A 
phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with 
relapsed and relapsed/refractory myeloma. Blood. 2014 Mar 6;123(10):1461-9.
[43]
Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, et al. 
Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide 
plus dexamethasone as induction treatment before autologous stem cell 
transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 
24;118(22):5752-8.
 
 
05FW09


Product:  MK-3475 
140
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
[44]
Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, et al. 
Bortezomib with thalidomide plus dexamethasone compared with thalidomide 
plus dexamethasone as induction therapy before, and consolidation therapy after, 
double autologous stem-cell transplantation in newly diagnosed multiple 
myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85.
[45]
Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, et al. 
Superiority of the triple combination of bortezomib-thalidomide-dexamethasone 
over the dual combination of thalidomide-dexamethasone in patients with 
multiple myeloma progressing or relapsing after autologous transplantation: the 
MMVAR/IFM 2005-04 Randomized Phase III Trial from the Chronic Leukemia 
Working Party of the European Group for Blood and Marrow Transplantation. J 
Clin Oncol. 2012 Jul 10;30(20):2475-82. Erratum in: J Clin Oncol. 2012 Sep 
20;30(27):3429. J Clin Oncol. 2014 Apr 20;32(12):1285.
[46]
Thounaojam MC, Dudimah DF, Pellom ST Jr, Uzhachenko RV, Carbone DP, 
Dikov MM, et al. Bortezomib enhances expression of effector molecules in anti-
tumor CD8+ T lymphocytes by promoting Notch-nuclear factor-κB crosstalk. 
Oncotarget. 2015 Oct 20;6(32):32439-55.
[47]
Shanker A, Pellom ST Jr, Dudimah DF, Thounaojam MC, de Kluyver RL, 
Brooks AD, et al. Bortezomib Improves Adoptive T-cell Therapy by Sensitizing 
Cancer Cells to FasL Cytotoxicity. Cancer Res. 2015 Dec 15;75(24):5260-72.
[48]
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, et al. 
Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N 
Engl J Med. 2015 Jan 8;372(2):142-52.
[49]
Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hajek R, et al. 
Carfilzomib and dexamethasone versus bortezomib and dexamethasone for 
patients with relapsed or refractory multiple myeloma (ENDEAVOR): a 
randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 
Jan;17(1):27-38.
[50]
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 
2013 Jan;63(1):11-30.
[51]
Phekoo KJ, Schey SA, Richards MA, Bevan DH, Bell S, Gillett D, et al. A 
population study to define the incidence and survival of multiple myeloma in a 
National Health Service Region in UK. Br J Haematol 2004;127:299-304.
[52]
Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O. et al. 
Incidence of hematologic malignancies in Europe by morphologic subtype: 
results of the HAEMACARE project. Blood. 2010 Nov 11;116(19):3724-34.
 
 
05FW09


Product:  MK-3475 
141
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
[53]
Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of haematological 
malignancy by sub-type: a report from the Haematological Malignancy Research 
Network. Br J Cancer. 2011 Nov 22;105(11):1684-92.
[54]
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 
2012 Jan-Feb;62(1):10-29.
[55]
Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008 Mar 15;111(6):2962-
72.
[56]
Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple 
myeloma. Lancet 2009;374:324-39.
[57]
Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et 
al. Improved survival in multiple myeloma and the impact of novel therapies. 
Blood 2008;111(5):2516-20.
[58]
Combination chemotherapy versus melphalan plus prednisone as treatment for 
multiple myeloma: an overview of 6,633 patients from 27 randomized trials. 
Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998 Dec;16(12):3832-42.
[59]
Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al. 
Risk of progression and survival in multiple myeloma relapsing after therapy 
with IMiDs and bortezomib: a multicenter international myeloma working group 
study. Leukemia. 2012 Jan;26(1):149-57.
[60]
Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, et al. 
Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and 
increase expression after stimulation with IFN-gamma and TLR ligands via a 
MyD88-, TRAF6-, and MEK-dependent pathway. Blood 2007;110(1):296-304
[61]
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-
L1 on tumor cells in the escape from host immune system and tumor 
immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 
2002;99(19):12293-7.
[62]
Hallett WHD, Jing W, Drobyski WR, Johnson BD. Immunosuppressive effects of 
multiple myeloma are overcome by pd-li blockade. Biol Blood Marrow 
Transplant 2011;17:1133-45.
[63]
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. 
Phase I safety and pharmacokinetic study of CT-011, a humanized antibody 
interacting with PD-1, in patients with advanced hematologic malignancies. Clin 
Cancer Res 2008;14(10):3044-51.
 
 
05FW09


Product:  MK-3475 
142
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
[64]
Durie BG. Staging and kinetics of multiple myeloma. Semin Oncol. 1986 
Sep;13(3):300-9.
[65]
Palumbo A, Dimopoulos M, San Miguel J, Harousseau JL, Attal M, Hussein M, 
et al. Lenalidomide in combination with dexamethasone for the treatment of 
relapsed or refractory multiple myeloma. Blood Rev. 2009 Mar;23(2):87-93.
[66]
Ji Y, Li Y, Bekele BN. Dose-finding in phase I clinical trials based on toxicity 
probability intervals. Clin Trials 2007;4:235-44.
[67]
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of binomial. Biometrika 1934;26(4):404-13.
 
 
05FW09


Product:  MK-3475 
143
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing. In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
05FW09


Product:  MK-3475 
144
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
05FW09


Product:  MK-3475 
145
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The DNA, blood, and bone marrow specimen(s) collected in the current trial will be used 
to study various causes for how subjects may respond to a drug/vaccine.  The DNA, 
blood, and bone marrow specimen(s) will be stored to provide a resource for future trials 
conducted by Merck focused on the study of biomarkers responsible for how a 
drug/vaccine enters and is removed by the body, how a drug/vaccine works, other 
pathways a drug/vaccine may interact with, or other aspects of disease.  The specimen(s) 
may be used for future assay development and/or drug/vaccine development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
 
 
05FW09


Product:  MK-3475 
146
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in Future Biomedical Research in order to 
participate in the main trial. Subjects who decline to sign the Future Biomedical 
Research informed consent will not have the specimen collected nor will they be 
discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for Future Biological Research purposes. Any 
specimens for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an objective 
to the main trial, this analysis is detailed in the main body of this protocol (Section 8.0 –
Statistical Analysis Plan).  These specimens will be processed, analyzed, and the 
remainder of the specimen will be destroyed.  The results of these analyses will be 
reported along with the other trial results.  A separate specimen will be obtained from 
properly-consented subjects in this protocol for storage in the biorepository for Future 
Biomedical Research.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
 
 
05FW09


Product:  MK-3475 
147
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
 
 
05FW09


Product:  MK-3475 
148
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in the FBR contract.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
writing to the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from Future Biomedical 
Research will be maintained by Merck.  This is done to separate the future exploratory 
test results (which include genetic data) from the clinical trial database thereby 
maintaining a separation of subject number and these results.  The separate databases are 
accessible only to the authorized Sponsor and the designated trial administrator research 
 
 
05FW09


Product:  MK-3475 
149
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
personnel and/or collaborators.  Database user authentication is highly secure, and is 
accomplished using network security policies and practices based in international 
standards (e.g., ISO17799) to protect against unauthorized access.  The Merck Entrusted 
Keyholder maintains control over access to all specimen data.  These data are collected 
for future biomedical research purposes only and will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time routine blood specimens are drawn in the main trial. 
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
 
 
05FW09


Product:  MK-3475 
150
Protocol/Amendment No.:  023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
 
 
05FW09


Product:  MK-3475 
151
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
 
 
05FW09


Product:  MK-3475 
152
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
 
 
05FW09


Product:  MK-3475 
153
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
 
 
05FW09


Product:  MK-3475 
154
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
 
 
05FW09


Product:  MK-3475 
155
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
 
 
05FW09


Product:  MK-3475 
156
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
 
 
05FW09


Product:  MK-3475 
157
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
 
 
05FW09


Product:  MK-3475 
158
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
 
 
05FW09


Product:  MK-3475 
159
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
 
 
05FW09


Product:  MK-3475 
160
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
 
 
05FW09


Product:  MK-3475 
161
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
 
 
05FW09


Product:  MK-3475 
162
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Multiple Myeloma Diagnostic Criteria
Durie, Seminars in Oncology, Vol 13, No 3 (September), 1986: pp300-309:
 
 
05FW09


Product:  MK-3475 
163
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
 
 
05FW09


Product:  MK-3475 
164
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov)
 
 
05FW09


Product:  MK-3475 
165
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
MM Disease Response Criteria
Durie et al.  International uniform response criteria for multiple myeloma.  Leukemia.  2006; 
20:1467-1473.
Criteria for multiple myeloma disease assessment:
 
 
05FW09


Product:  MK-3475 
166
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Durie et al.  Corrigendum: International uniform response criteria for multiple myeloma.  
Leukemia.  2007; 21:1134.
Correction to the above tables of criteria for multiple myeloma disease assessment:
 
 
05FW09


Product:  MK-3475 
167
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
List of Abbreviations
Abbreviation/Term
Definition
AE
Adverse event
ADA
Anti-Drug/pembrolizumab Antibodies
ADCC
Antibody-Dependent Cell-Mediated Cytotoxicity
ALT
Alanine aminotransferase
AML
Acute Myelogenous Leukemia
ANC
Absolute neutrophil count
APC
Antigen Presenting Cells
aPTT
Activated partial thromboplastin time
ASaT
All Subjects as Treated
AUC
Area Under Curve
AST
Aspartate aminotransferase
ᵝ-HCG
Beta human chorionic gonadotropin
CBC
Complete blood count
CDC
Complement-Dependent Cytotoxicity
CNS
Central nervous system
CR
Complete response
CrCl
Calculated creatinine clearance
CRF
Case report form
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTL
Cytotoxic T Lymphocytes
CTLA-4
Cytotoxic T-lymphocyte-associated antigen-4
Dex
Dexamethasone
DL
Dose Level
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of Response
ECI
Events of clinical interest
ECI-ie
Events of clinical interest with a potential 
immunologic etiology
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EMA
European Medicines Agency
ERC
Ethics review committee
FAS
Full analysis set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FLC
Free Light Chain
 
 
05FW09


Product:  MK-3475 
168
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Abbreviation/Term
Definition
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
Hb
Hemoglobin
HBV
Hepatitis B
HCV
Hepatitis C
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
IMiD
Immunomodulatory
IMWG
International Myeloma Working Group
INR
International normalized ratio
irAEs
Immune-related adverse events
IRB
Institutional Review Board
ISS
International Staging System
ITIM
Immunoreceptor tyrosine-based switch motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
IV
Intravenous
K
Carfilzomib (Kyprolis®)
Kg
kilogram
LDH
lactate dehydrogenase
Len
Lenalidomide
LMWH
Low-molecular weight heparin
mAb
Monoclonal antibody
MAD
Maximum administered dose
mcL
Millimeters
MEL
Melanoma 
MG
Milligram
Mg/kg
Milligram per kilogram
ML
milliliter
MM
Multiple Myeloma
MRI
Magnetic resonance imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck 
& Co., Inc.
MTD
Maximum tolerated dose
NA or N/A
Not Applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NK
Natural Killer
NSAID
Non-steroidal anti-inflammatory drug
ORR
Overall response rate
OS
Overall survival
OTC
Over-the-counter
 
 
05FW09


Product:  MK-3475 
169
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
Abbreviation/Term
Definition
PD
Progressive disease
PD-1
Programmed death-1
PD-L1
Programmed death-ligand 1
PD-L2
Programmed death-ligand 2
PET
Positron emission tomography
PFS
Progression-free survival
PGt
Pharmacogenetic
PK
Pharmacokinetic
PK-PD
Pharmacokinetic-Pharmacodynamic
PO
Oral administration
PR
Partial response
PT
Prothrombin time
rMM
Refractory or relapsed multiple myeloma
rrMM
Refractory or relapsed and refractory multiple 
myeloma
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 Dose
RR
Response rate
Q2W
Every 2 weeks
SAE
Serious adverse events
SAP
Statistical Analysis Plan
sCR
Stringent Complete Response
SFU
Survival follow-up
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SoC
Standard of Care
SJS
Stevens-Johnson Syndrome
SOP
Standard Operating Procedures
SPEP
serum protein electrophoresis
TEN
Toxic Epidermal Necrolysis
TIL
Tumor-infiltrating lymphocytes
TLS
Tumor lysis syndrome
TPI
Toxicity Probability Interval
TSH
Thyroid stimulating hormone
TTP
Time To Progression
ULN
Upper limit of normal
UPEP
urinary protein electrophoresis
VTE
Venous Thromboembolism
WHO
World Health Organization
 
 
05FW09


Product:  MK-3475 
170
Protocol/Amendment No.: 023-07 
MK-3475-023-07 Final Protocol
10-Mar-2020
Confidential
13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
05FW09